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This review covers the results of the application of mass spectrometric (MS) techniques to study the diversity of beta‐amyloid (Aβ) peptides in human samples. Since Aβ is an important hallmark of Alzheimer's disease (AD), which is a socially significant neurodegenerative disorder of the elderly worldwide, analysis of its endogenous variations is of particular importance for elucidating the pathogenesis of AD, predicting increased risks of the disease onset, and developing effective therapy. MS approaches have no alternative for the study of complex samples, including a wide variety of Aβ proteoforms, differing in length and modifications. Approaches based on matrix‐assisted laser desorption/ionization time‐of‐flight and liquid chromatography with electrospray ionization tandem MS are most common in Aβ studies. However, Aβ forms with isomerized and/or racemized Asp and Ser residues require the use of special methods for separation and extra sensitive and selective methods for detection. Overall, this review summarizes current knowledge of Aβ species found in human brain, cerebrospinal fluid, and blood plasma; focuses on application of different MS approaches for Aβ studies; and considers the potential of MS techniques for further studies of Aβ‐peptides. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most frequent neurodegenerative disorder in the elderly aged over 65. The extracellular accumulation of beta‐amyloid (Aβ) aggregates in the brain is considered as the major event worsening the AD symptoms, but its underlying reason has remained unclear. Here the piezoelectric characteristics of Aβ aggregates are revealed. The vector piezoresponse force microscopy (PFM) analysis results exhibit that Aβ fibrils have spiraling piezoelectric domains along the length and a lateral piezoelectric constant of 44.1 pC N‐1. Also, the continuous sideband Kelvin probe force microscopy (KPFM) images display that the increment of charge‐induced surface potential on a single Aβ fibril is allowed to reach above +1700 mV in response to applied forces. These findings shed light on the peculiar mechano‐electrical surface properties of pathological Aβ fibrils that exceed those of normal body components. [ABSTRACT FROM AUTHOR]

The Alzheimer's disease (AD) research community continues to make great strides in expanding approaches for early detection and treatment of the disease, including recent advances in our understanding of fundamental AD pathophysiology beyond the classical targets: beta‐amyloid and tau. Recent clinical trial readouts implicate a variety of non‐amyloid/non‐tau (NANT) approaches that show promise in slowing cognitive decline for people with AD. The Alzheimer's Association Research Roundtable (AARR) meeting held on December 13–14, 2022, reviewed the current state of NANT targets on underlying AD pathophysiology and their contribution to cognitive decline, the current data on a diverse range of NANT biomarkers and therapeutic targets, and the integration of NANT concepts in clinical trial designs. Participants also discussed the current definition of therapies that target underlying AD pathophysiology, what endpoints best define what is considered a meaningful change beyond the current approved definition for clinical efficacy, and how the recent NANT findings should inform the development of future guidelines for AD classification and personalized treatment strategies. Highlights: The Alzheimer's Association Research Roundtable (AARR) convened leaders from industry, academia, and government to review the current state of non‐beta amyloid and non‐tau (NANT) targets on underlying Alzheimer's disease (AD) pathophysiology.The totality of scientific and clinical evidence supports the hypothesis that emerging NANT targets play a role in cognitive decline and neurodegeneration in AD. New biomarkers based on NANT targets must be globally developed and implemented with specific consideration of fluid biomarkers as a cost‐effective clinical option, to ensure better, more equitable treatment options for AD. [ABSTRACT FROM AUTHOR]

Microglia play a crucial role in synaptic elimination by engulfing dystrophic neurons via triggering receptors expressed on myeloid cells 2 (TREM2). They are also involved in the clearance of beta‐amyloid (Aβ) plaques in Alzheimer's disease (AD); nonetheless, the driving force behind TREM2‐mediated phagocytosis of beta‐amyloid (Aβ) plaques remains unknown. Here, using advanced 2D/3D/4D co‐culture systems with loss‐of‐function mutations in TREM2 (a frameshift mutation engineered in exon 2) brain organoids/microglia/assembloids, it is identified that the clearance of Aβ via TREM2 is accelerated by externalized phosphatidylserine (ePtdSer) generated from dystrophic neurons surrounding the Aβ plaques. Moreover, it is investigated whether microglia from both sporadic (CRISPR‐Cas9‐based APOE4 lines) and familial (APPNL‐G‐F/MAPT double knock‐in mice) AD models show reduced levels of TREM2 and lack of phagocytic activity toward ePtdSer‐positive Aβ plaques. Herein new insight is provided into TREM2‐dependent microglial phagocytosis of Aβ plaques in the context of the presence of ePtdSer during AD progression. [ABSTRACT FROM AUTHOR]

Synaptic plasticity is believed to underlie the cellular and molecular basis of memory formation. Mitochondria are one of the main organelles involved in metabolism and energy maintenance as plastic organelles that change morphologically and functionally in response to cellular needs and regulate synaptic function and plasticity through multiple mechanisms, including ATP generation, calcium homeostasis, and biogenesis. An increased neuronal activity enhances synaptic efficiency, during which mitochondria's spatial distribution and morphology change significantly. These organelles build up in the pre‐and postsynaptic zones to produce ATP, which is necessary for several synaptic processes like neurotransmitter release and recycling. Mitochondria also regulate calcium homeostasis by buffering intracellular calcium, which ensures proper synaptic activity. Furthermore, mitochondria in the presynaptic terminal have distinct morphological properties compared to dendritic or postsynaptic mitochondria. This specialization enables precise control of synaptic activity and plasticity. Mitochondrial dysfunction has been linked to synaptic failure in many neurodegenerative disorders, like Alzheimer's disease (AD). In AD, malfunctioning mitochondria cause delays in synaptic vesicle release and recycling, ionic gradient imbalances, and mostly synaptic failure. This review emphasizes mitochondrial plasticity's contribution to synaptic function. It also explores the profound effect of mitochondrial malfunction on neurodegenerative disorders, focusing on AD, and provides an overview of how they sustain cellular health under normal conditions and how their malfunction contributes to neurodegenerative diseases, highlighting their potential as a therapeutic target for such conditions. [ABSTRACT FROM AUTHOR]

Inhibition of the cyclic‐AMP degrading enzyme phosphodiesterase type 4 (PDE4) in the brains of animal models is protective in Alzheimer's disease (AD). We show for the first time that enzymes from the subfamily PDE4D not only colocalize with beta‐amyloid (Aβ) plaques in a mouse model of AD but that Aβ directly associates with the catalytic machinery of the enzyme. Peptide mapping suggests that PDE4D is the preferential PDE4 subfamily for Aβ as it possesses a unique binding site. Intriguingly, exogenous addition of Aβ to cells overexpressing the PDE4D5 longform caused PDE4 activation and a decrease in cAMP. We suggest a novel mechanism where PDE4 longforms can be activated by Aβ, resulting in the attenuation of cAMP signalling to promote loss of cognitive function in AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Animal research has shown that tau pathology in the locus coeruleus (LC) is associated with reduced norepinephrine signaling, lower projection density to the medial temporal lobe (MTL), atrophy, and cognitive impairment. We investigated the contribution of LC‐MTL functional connectivity (FCLC‐MTL) on cortical atrophy across Braak stage regions and its impact on cognition. METHODS: We analyzed functional magnetic resonance imaging and amyloid beta (Aβ) positron emission tomography data from 128 cognitively normal participants, associating novelty‐related FCLC‐MTL with longitudinal atrophy and cognition with and without Aβ moderation. RESULTS: Cross‐sectionally, lower FCLC‐MTL was associated with atrophy in Braak stage II regions. Longitudinally, atrophy in Braak stage 2 to 4 regions related to lower baseline FCLC‐MTL at elevated levels of Aβ, but not to other regions. Atrophy in Braak stage 2 regions mediated the relation between FCLC‐MTL and subsequent cognitive decline. DISCUSSION: FCLC‐MTL is implicated in Aβ‐related cortical atrophy, suggesting that LC‐MTL connectivity could confer neuroprotective effects in preclinical AD. Highlights: Novelty‐related functional magnetic resonance imaging (fMRI) LC‐medial temporal lobe (MTL) connectivity links to longitudinal Aβ‐dependent atrophy.This relationship extended to higher Braak stage regions with increasing Aβ burden.Longitudinal MTL atrophy mediated the LC‐MTL connectivity–cognition relationship.Our findings mirror the animal data on MTL atrophy following NE signal dysfunction. [ABSTRACT FROM AUTHOR]

Gamma‐hydroxy‐butyric acid (GABA) and glutamate are neurotransmitters with essential importance for cognitive processing. Here, we investigate relationships between GABA, glutamate, and brain ß‐amyloid (Aß) burden before clinical manifestation of Alzheimer's disease (AD). Thirty cognitively healthy adults (age 69.9 ± 6 years) received high‐resolution atlas‐based 1H‐magnetic resonance spectroscopic imaging (MRSI) at ultra‐high magnetic field strength of 7 Tesla for gray matter‐specific assessment of GABA and glutamate. We assessed Aß burden with positron emission tomography and risk factors for AD. Higher gray matter GABA and glutamate related to higher Aß‐burden (ß = 0.60, p < 0.05; ß = 0.64, p < 0.02), with positive effect modification by apolipoprotein‐E‐epsilon‐4‐allele (APOE4) (p = 0.01‐0.03). GABA and glutamate negatively related to longitudinal change in verbal episodic memory performance (ß = ‐0.48; p = 0.02; ß = ‐0.50; p = 0.01). In vivo measures of GABA and glutamate reflect early AD pathology at old age, in an APOE4‐dependent manner. GABA and glutamate may represent promising biomarkers and potential targets for early therapeutic intervention and prevention. Highlights: Gray matter‐specific metabolic imaging with high‐resolution atlas‐based MRSI at 7 Tesla.Higher GABA and glutamate relate to ß‐amyloid burden, in an APOE4‐dependent manner.Gray matter GABA and glutamate identify older adults with high risk of future AD.GABA and glutamate might reflect altered synaptic and neuronal activity at early AD. [ABSTRACT FROM AUTHOR]

INTRODUCTION: The "prion‐like" features of Alzheimer's disease (AD) tauopathy and its relationship with amyloid‐β (Aβ) have never been experimentally studied in primates phylogenetically close to humans. METHODS: We injected 17 macaques in the entorhinal cortex with nanograms of seeding‐competent tau aggregates purified from AD brains or control extracts from aged‐matched healthy brains, with or without intracerebroventricular co‐injections of oligomeric‐Aβ. RESULTS: Pathological tau injection increased cerebrospinal fluid (CSF) p‐tau181 concentration after 18 months. Tau pathology spreads from the entorhinal cortex to the hippocampal trisynaptic loop and the cingulate cortex, resuming the experimental progression of Braak stage I to IV. Many AD‐related molecular networks were impacted by tau seeds injections regardless of Aβ injections in proteomic analyses. However, we found mature neurofibrillary tangles, increased CSF total‐tau concentration, and pre‐ and postsynaptic degeneration only in Aβ co‐injected macaques. DISCUSSION: Oligomeric‐Aβ mediates the maturation of tau pathology and its neuronal toxicity in macaques but not its initial spreading. Highlights: This study supports the "prion‐like" properties of misfolded tau extracted from AD brains.This study empirically validates the Braak staging in an anthropomorphic brain.This study highlights the role of oligomeric Aβ in driving the maturation and toxicity of tau pathology.This work establishes a novel animal model of early sporadic AD that is closer to the human pathology. [ABSTRACT FROM AUTHOR]

Leading neurodegenerative diseases Alzheimer's disease (AD) and Parkinson's disease (PD) are characterized by the impairment of memory and motor functions, respectively. Despite several breakthroughs, there exists a lack of disease‐modifying treatment strategies for these diseases, as the available drugs provide symptomatic relief and bring along side effects. Bioactive compounds are reported to bear neuroprotective properties with minimal toxicity, however, a detailed elucidation of their modes of neuroprotection is lacking. The review elucidates the neuroprotective mechanism(s) of some of the major phyto‐compounds in pre‐clinical and clinical studies of AD and PD to understand their potential in combating these diseases. Curcumin, eugenol, resveratrol, baicalein, sesamol and so on have proved efficient in countering the pathological hallmarks of AD and PD. Curcumin, resveratrol, caffeine and so on have reached the clinical phases of these diseases, while aromadendrin, delphinidin, cyanidin and xanthohumol are yet to be extensively explored in pre‐clinical phases. The review highlights the need for extensive investigation of these compounds in the clinical stages of these diseases so as to utilize their disease‐modifying abilities in the real field of treatment. Moreover, poor pharmacokinetic properties of natural compounds are constraints to their therapeutic yields and this review suggests a plausible contribution of nanotechnology in overcoming these limitations. [ABSTRACT FROM AUTHOR]

Docosahexaenoic acid (DHA) is an essential omega‐3 polyunsaturated fatty acid implicated in cognitive functions by promoting synaptic protein expression. While alterations of specific DHA‐containing phospholipids have been described in the neocortex of patients with Alzheimer's disease (AD), the status of these lipids in dementia with Lewy bodies (DLB), known to manifest aggregated α‐synuclein‐containing Lewy bodies together with variable amyloid pathology, is unclear. In this study, post‐mortem samples from the parietal cortex of 25 DLB patients and 17 age‐matched controls were processed for phospholipidomics analyses using a liquid chromatography–tandem mass spectrometry (LC–MS/MS) platform. After controlling for false discovery rate, six out of the 46 identified putative DHA‐phospholipid species were significantly decreased in DLB, with only one showing increase. Altered putative DHA‐phospholipid species were subsequently validated with further LC–MS/MS measurements. Of the DHA‐containing phospholipid (DCP) species showing decreases, five negatively correlated with soluble beta‐amyloid (Aβ42) levels, whilst three also correlated with phosphorylated α‐synuclein (all p < 0.05). Furthermore, five of these phospholipid species correlated with deficits of presynaptic Rab3A, postsynaptic neurogranin, or both (all p < 0.05). Finally, we found altered immunoreactivities of brain lysolipid DHA transporter, MFSD2A, and the fatty acid binding protein FABP5 in DLB parietal cortex. In summary, we report alterations of specific DCP species in DLB, as well as their associations with markers of neuropathological burden and synaptopathology. These results support the potential role of DHA perturbations in DLB as well as therapeutic targets. [ABSTRACT FROM AUTHOR]

Non‐invasive sensory stimulation in the range of the brain's gamma rhythm (30–100 Hz) is emerging as a new potential therapeutic strategy for the treatment of Alzheimer's disease (AD). Here, we investigated the effect of repeated combined exposure to 40 Hz synchronized sound and light stimuli on hippocampal long‐term potentiation (LTP) in vivo in three rat models of early AD. We employed a very complete model of AD amyloidosis, amyloid precursor protein (APP)‐overexpressing transgenic McGill‐R‐Thy1‐APP rats at an early pre‐plaque stage, systemic treatment of transgenic APP rats with corticosterone modelling certain environmental AD risk factors and, importantly, intracerebral injection of highly disease‐relevant AD patient‐derived synaptotoxic beta‐amyloid and tau in wild‐type animals. We found that daily treatment with 40 Hz sensory stimulation for 2 weeks fully abrogated the inhibition of LTP in all three models. Moreover, there was a negative correlation between the magnitude of LTP and the level of active caspase‐1 in the hippocampus of transgenic APP animals, which suggests that the beneficial effect of 40 Hz stimulation was dependent on modulation of pro‐inflammatory mechanisms. Our findings support ongoing clinical trials of gamma‐patterned sensory stimulation in early AD. [ABSTRACT FROM AUTHOR]

Background and Purpose: Therapies based on apolipoprotein A‐I (ApoA‐I), classically tested for cardiovascular diseases, were recently proposed for Alzheimer's disease (AD). Based on a drug reprofiling approach, our objective was to explore the use of a natural variant of ApoA‐I form, ApoA‐I‐Milano (M), as a treatment for AD. ApoA‐I‐M contains the R173C mutation, and confers protection against atherosclerosis development, although ApoA‐I‐M carriers exhibit low HDL levels. Experimental Approach: Middle‐aged (12‐month‐old) and aged (21‐month‐old) APP23 mice were intraperitoneally treated for 10 weeks with human recombinant ApoA‐I‐M (hrApoA‐I‐M) protein or saline. Pathology progression through behavioural parameters and biochemical determinations was evaluated. Key Results: In middle‐aged group, hrApoA‐I‐M treatment reduced the anxiety behaviour associated with this AD model. In aged mice, hrApoA‐I‐M reversed T‐Maze performance alterations, a cognitive improvement accompanied by neuronal loss recovery in the dentate gyrus. Aged mice treated with hrApoA‐I‐M showed lower brain Aβ40 soluble levels and elevated Aβ40 levels in cerebrospinal fluid, without modifying insoluble brain Aβ burden. Interestingly, hrApoA‐I‐M sub‐chronic treatment induced a molecular effect on the cerebrovasculature, increasing occludin expression and ICAM‐1 presence, as well as promoting an elevation of plasma soluble RAGE in all hrApoA‐I‐M‐treated mice, drastically decreasing the AGEs/sRAGE ratio, a marker of endothelial damage. Conclusion and Implications: Peripheral hrApoA‐I‐M treatment shows a beneficial impact on working memory, involving mechanisms related with brain Aβ mobilization and modulation of the levels of cerebrovascular markers. Our study shows the potential therapeutic applicability of a safe and non‐invasive treatment based on peripheral administration of hrApoA‐I‐M in AD. [ABSTRACT FROM AUTHOR]

Aims: This study aims to study the association between pancreatic islet amyloid polypeptide (IAPP) and Alzheimer's disease neuropathological change (ADNC) in brain biopsies obtained from subjects with idiopathic normal pressure hydrocephalus (iNPH) and in post‐mortem (PM) brain samples obtained from aged individuals. Methods: For the immunohistochemical (IHC) analyses, two IAPP antibodies (Abs), monoclonal and polyclonal, and Abs directed towards ADNC were applied. Results: The iNPH cohort included 113 subjects. Amyloid‐β (Aβ) was detected in 50% and hyperphosphorylated τ (HPτ) in 47% of the cases. Concomitant pathology was seen in 32%. The PM cohort included 77 subjects. Aβ was detected in 69% and HPτ in 91% of the cases. Combined Aβ/HPτ pathology was seen in 62%. Reactivity for the monoclonal IAPP was not detected in the brain tissue in either of the cohorts. Reactivity for the polyclonal IAPP was observed in all 77 PM brain samples. Conclusions: There was no specific expression of IAPP in human brain tissue; hence, an association between IAPP and ADNC is not assessable. Of note, the observed reactivity of the polyclonal IAPP Ab was not reproduced with a specific monoclonal Ab; thus, we considered the observed staining with the polyclonal Ab to be unreliable. When using IHC, several pitfalls, especially the choice of an Ab, always need to be considered. Polyclonal Abs cross‐react with other epitopes and proteins, thus leading to false‐positive results. This seems to be the case for the polyclonal IAPP Abs in the human brain. [ABSTRACT FROM AUTHOR]

While iron over‐accumulation has been reported in late stage Alzheimer's disease (AD), whether this occurs early in the asymptomatic stage of AD remains unknown. We aimed to assess brain iron levels in asymptomatic AD using quantitative MR relaxometry of effective transverse relaxation rate (R2*) and longitudinal relaxation rate (R1), and recruited 118 participants comprised of three groups including healthy young participants, and cognitively normal older individuals without or with positive AD biomarkers based on cerebrospinal fluid (CSF) proteomics analysis. Compared with the healthy young group, increased R2* was found in widespread cortical and subcortical regions in the older groups. Further, significantly higher levels of R2* were found in the cognitively normal older subjects with positive CSF AD biomarker (i.e., asymptomatic AD) compared with those with negative AD biomarker in subcortical regions including the left and right caudate, left and right putamen, and left and right globus pallidus (p <.05 for all regions), suggesting increased iron content in these regions. Subcortical R2* of some regions was found to significantly correlate with CSF AD biomarkers and neuropsychological assessments of visuospatial functions. In conclusion, R2* could be a valuable biomarker for studying early pathophysiological changes in AD. [ABSTRACT FROM AUTHOR]

Cerebral amyloid angiopathy (CAA) is a disease with several clinical manifestations. It is characterised by amyloid‐beta deposition in cerebral blood vessels, making them prone to bleeding. The incidence of CAA increases with age and may be associated or co‐exist with intraparenchymal neurodegenerative proteinopathies, which makes it an increasingly relevant condition for adult physicians in all areas of medical practice. The vast majority of cases of CAA are sporadic with a small minority of familial cases. CAA is asymptomatic in many older adults but increases the risk of fatal intracerebral or subarachnoid haemorrhage. We review the existing literature on CAA and summarise the key findings. We specifically explore clinical challenges relevant to CAA, particularly in diagnosis, management of intracranial haemorrhage and management of concurrent medical conditions. [ABSTRACT FROM AUTHOR]

Among the various neurodegenerative disorders, Alzheimer's disease (AD) is identified as one of primary causes of dementia in the elderly, which progresses slowly leading to cognitive decline and ability to function independently. Although various pathological mechanisms have been proposed, the exact mechanism is not yet elucidated. Numerous processes such as old age, mitochondrial dysfunction, and genetics lead to the aggregation of beta‐amyloid (Aβ) as amyloid plaques and tau proteins as neurofibrillary tangles in the neurons leading to their death and destruction, finally leading to AD. The current treatment measures can only temporarily improve the symptoms, slowing cognitive decline without any effect on AD pathology for better therapeutic effect. Furthermore, the high failure rates of a number of drugs during clinical trials due to their side effects has led the researchers to focus on alternative sources for drug development. As natural ingredients were considered the primary line of treatment in the olden days, and as several medicinal plant products are also proven as effective AD targets, it will be wise to investigate those with significant ethnobotanical value as potential neuroprotectives, nootropics or memory boosters. Throughout the study, propanoids, glycosides, iridoids, carotenoids and flavonoids that show potential anti‐inflammatory, antioxidant, and anti‐cholinesterase were also found to be inhibitors of Aβ and tau aggregation, where Saikosaponin C, Fisetin, and Morin can act as dual inhibitors. The review provides an insight in the need for proper and complete scientific evaluation of these ethnobotanically useful medicinal plants to be identified as potential leads in AD therapy. [ABSTRACT FROM AUTHOR]

Introduction: Beta‐amyloid (Aβ) plaque deposition is a biomarker of preclinical Alzheimer's disease (AD). Impairments in sensory function are associated with cognitive decline. We sought to investigate the relationship between PET‐indicated Aβ deposition and sensory impairment. Methods: Using data from 174 participants ≥55 years in the Baltimore Longitudinal Study of Aging, we analyzed associations between sensory impairments and Aβ deposition measured by PET and Pittsburgh Compound B (PiB) mean cortical distribution volume ratio (cDVR). Results: The combinations of hearing and proprioceptive impairment and hearing, vision, and proprioceptive impairment, were positively correlated with cDVR (β = 0.087 and p = 0.036, β = 0.110 and p = 0.018, respectively). In stratified analyses of PiB+ participants, combinations of two, three, and four sensory impairments (all involving proprioception) were associated with higher cDVR. Discussion: Our findings suggest a relationship between multi‐sensory impairment (notably proprioceptive impairment) and Aβ deposition, which could reflect sensory impairment as an indicator or potentially a risk factor for Aβ deposition. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is an extensive age‐associated neurodegenerative disorder. In spite of wide‐ranging progress in understanding the AD pathology for the past 50 years, clinical trials based on the hypothesis of amyloid‐beta (Aβ) have reserved worsening particularly at late‐stage human trials. Consequently, very few old drugs are presently used for AD with inadequate clinical consequences and various side effects. We focus on widespread pharmacological and beneficial principles for existing as well as future drugs. Multitargeting approaches by means of general antioxidant and anti‐inflammatory mechanisms allied with particular receptor and/or enzyme‐mediated actions in neuroprotection and neurodegeneration. The plant kingdom comprises a vast range of species with an incredible diversity of bioactive metabolites with diverse chemical scaffolds. In recent times, an increasing body of facts recommended the use of phytochemicals to decelerate AD's onset and progression. The definitive goal of AD investigation is to avert the onset of neurodegeneration, thereby allowing successful aging devoid of cognitive decline. At this point, we discussed the neurological protective role of natural products and naturally derived therapeutic agents for AD from various natural polyphenolic compounds and medicinal plants. In conclusion, medicinal plants act as a chief source of different bioactive constituents. [ABSTRACT FROM AUTHOR]

Aim: Ninjinyoeito (NYT), a Japanese herbal medicine, is widely used to treat patients with insomnia, anemia, amnesia, and neurosis. Recently, NYT was reported to be clinically effective in Alzheimer's disease (AD). We investigated the effects of NYT in a neurodegeneration model comprising cultured autaptic neurons exposed to β‐amyloid (Aβ)25–35. Methods: We used an autaptic culture system consisting of a single neuron on astrocyte feeder micro‐islands. The effects of NYT (0.1 mg/ml) on neurotoxicity induced by Aβ25–35 (1 μmol/L) were assessed by immunocytochemical assays and Sholl analysis of microtubule‐associated protein 2 (MAP2)‐positive and tau‐positive neurites. Nerve growth factor (Ngf) and brain‐derived neurotrophic factor (Bdnf) gene expression were examined in primary cocultured astrocytes and neurons using reverse transcription polychromatic chain reaction (RT‐PCR). Results: Aβ25–35 treatment attenuated the arborization of axons and dendrites of single autaptic hippocampal neurons in a concentration‐dependent manner. NYT treatment for three days ameliorated the Aβ25–35‐induced impairment of tau‐positive axon outgrowth. However, NYT did not ameliorate the Aβ25–35‐induced suppression of MAP2‐positive dendrite arborization. NYT increased the expression of Ngf but not Bdnf in Aβ25–35‐exposed primary cocultured astrocytes and neurons. Conclusion: We propose a new model of neurodegeneration in which dendrite and axon outgrowth in autaptic neuronal cultures is inhibited by Aβ25–35. Our results indicate that NYT protects against Aβ25–35‐induced neuronal injury through induction of nerve growth factor expression. These findings provide a mechanistic basis for treating AD with NYT. [ABSTRACT FROM AUTHOR]

Background: Multiple pathologies may underlie corticobasal syndrome (CBS), including Alzheimer's disease (AD). Dopamine transporter density imaging with Ioflupane 123 I SPECT (DaTscan) may be normal in CBS. No studies to date have examined the relationship between DaTscan status and underlying pathology in CBS. Objectives: The main objective of the study was to test whether a normal DaTscan in CBS patients is indicative of an underlying AD pathology, as determined by cerebrospinal fluid (CSF) biomarkers. Methods: Eighteen CBS patients were included. They were divided into patients with an AD and a non‐AD disease pathology, based on their cerebrospinal fluid biochemical profile. A typical AD CSF profile was defined as an increase in total and phosphorylated at threonine 181 tau protein in addition to a decrease in amyloid‐beta with 42 amino acids. DaTscan data were compared in these two groups. Results: Eight of the 18 CBS patients (44%) had a normal DaTscan. Seven of the 18 CBS patients (39%) had an AD cerebrospinal fluid biochemical profile. Two of seven CBS patients with AD biomarker profile had abnormal DaTscans. Three of 11 CBS patients with a non‐AD biomarker profile had normal DaTscans. A normal DaTscan was indicative of AD pathology with suboptimal (~70%) sensitivity and specificity. Semi‐quantitative DaTscan analysis did not differentiate between AD from non‐AD CSF biomarker profile in CBS. Conclusion: A normal DaTscan is indicative of AD in CBS, but the sensitivity and specificity of DaTscan as an in vivo marker of AD pathology is suboptimal. [ABSTRACT FROM AUTHOR]

Objectives: To explore the feasibility, efficacy, and safety of ultrasound‐targeted microbubbles destruction (UTMD) assisted dual delivery of beta‐amyloid (Aβ) antibody loaded by microbubbles (MBAβ) and neural stem cells (NSCs) on Alzheimer's disease (AD). Methods: Twenty‐seven APP/PS1 double transgenic mice (Tg mice) and 33 wild‐type mice were used. Wild‐type mice were insonated by diagnostic ultrasound with microbubbles (MB) for 5 min to observe the blood brain barrier (BBB) opening. The survival situation of engrafted NSCs crossing the opened BBB mediated by UTMD in Tg mice was evaluated by in vivo imaging system. We further explored the combination therapy effects of UTMD mediated Aβ antibody and NSCs dual delivery. Tg mice in each group were exposed to diagnostic ultrasound for 5 min once a week for four times, with MB, MBAβ, and/or NSCs administration according to groups. Cognition and memory functions were explored by Morris water maze test, Aβ plaques deposition was evaluated by immunohistochemical, and brain‐derived neurotrophic factor (BDNF) and synaptophysin (SYN) expression were detected by western blot and immunofluorescence. Results: BBB was opened mediated by diagnostic ultrasound with MB, and the duration of opening was about 10 h. The transplanted NSCs survived in Tg mice for no more than 72 h. Compared with control group, the Tg mice in combined delivery of NSCs and Aβ antibody by UTMD group improved memory function and spatial learning with shorter latency to find the platform, longer distance traveled, and longer time spent in targeted quadrant, and more crossing times (p < 0.05). Besides, the combination delivery group promoted the clearance of Aβ plaques compared with control group both in hippocampus (p < 0.01) and cortex (p < 0.05). Moreover, the expression of BDNF in combination delivery group was significantly higher than that in control group and ultrasound‐mediated MB group (p < 0.05). No significant change of SYN was observed in each group. Conclusion: UTMD assisted dual delivery of Aβ antibody and NSCs crossing the BBB into AD mice brain could help to clear Aβ plaques, increase the expression of BDNF, and restore the impaired neural function. This finding may offer potential insight into treatment of AD. [ABSTRACT FROM AUTHOR]

Understanding of Alzheimer's disease (AD) pathophysiology requires molecular assessment of how key pathological factors, specifically amyloid β (Aβ) plaques, influence the surrounding microenvironment. Here, neuronal lipids have been implicated in Aβ plaque pathology, though the lipid microenvironment in direct proximity to Aβ plaques is still not fully resolved. A further challenge is the microenvironmental molecular heterogeneity, across structurally polymorphic Aβ features, such as diffuse, immature, and mature, fibrillary aggregates, whose resolution requires the integration of advanced, multimodal chemical imaging tools. Herein, we used matrix‐assisted laser desorption/ionization trapped ion mobility spectrometry time‐of‐flight based mass spectrometry imaging (MALDI TIMS TOF MSI) in combination with hyperspectral confocal microscopy to probe the lipidomic microenvironment associated with structural polymorphism of Aβ plaques in transgenic Alzheimer's disease mice (tgAPPSWE). Using on tissue and ex situ validation, TIMS MS/MS facilitated unambiguous identification of isobaric lipid species that showed plaque pathology‐associated localizations. Integrated multivariate imaging data analysis revealed multiple, Aβ plaque‐enriched lipid patterns for gangliosides (GM), phosphoinositols (PI), phosphoethanolamines (PE), and phosphatidic acids (PA). Conversely, sulfatides (ST), cardiolipins (CL), and polyunsaturated fatty acid (PUFA)‐conjugated phosphoserines (PS), and PE were depleted at plaques. Hyperspectral amyloid imaging further delineated the unique distribution of PA and PE species to mature plaque core regions, while PI, LPI, GM2 and GM3 lipids localized to immature Aβ aggregates present within the periphery of Aβ plaques. Finally, we followed AD pathology‐associated lipid changes over time, identifying plaque‐ growth and maturation to be characterized by peripheral accumulation of PI (18:0/22:6). Together, these data demonstrate the potential of multimodal imaging approaches to overcome limitations associated with conventional advanced MS imaging applications. This allowed for the differentiation of both distinct lipid components in a complex micro‐environment as well as their correlation to disease‐relevant amyloid plaque polymorphs. Cover Image for this issue:https://doi.org/10.1111/jnc.15390 [ABSTRACT FROM AUTHOR]

Background and purpose: Subcortical vascular cognitive impairment (SVCI) is characterized by the presence of cerebral small vessel disease (CSVD) markers. Some SVCI patients also show Alzheimer's disease and cerebral amyloid angiopathy markers. However, the effects of these imaging markers on long‐term clinical outcomes have not yet been established. The present study, therefore, aimed to determine how these imaging markers influence functional disability and/or mortality. Methods: We recruited 194 participants with SVCI from the memory clinic and followed them up. All participants underwent brain magnetic resonance imaging at baseline, and 177 (91.2%) participants underwent beta‐amyloid (Aβ) positron emission tomography. We examined the occurrence of ischemic or hemorrhagic strokes. We also evaluated functional disability and mortality using the modified Rankin scale. To determine the effects of imaging markers on functional disability or mortality, we used Fine and Gray competing regression or Cox regression analysis. Results: During a 8.6‐year follow‐up period, 46 of 194 patients (23.7%) experienced a stroke, 110 patients (56.7%) developed functional disabilities and 75 (38.6%) died. Aβ positivity (subdistribution hazard ratio [SHR] = 2.73), greater white matter hyperintensity (WMH) volume (SHR = 3.11) and ≥3 microbleeds (SHR = 2.29) at baseline were independent predictors of functional disability regardless of the occurrence of stroke. Greater WMH volume (hazard ratio = 2.07) was an independent predictor of mortality. Conclusions: Our findings suggest that diverse imaging markers may predict long‐term functional disability and mortality in patients with SVCI, which in turn may provide clinicians with a more insightful understanding of the long‐term outcomes of SVCI. [ABSTRACT FROM AUTHOR]

The aggregation of β‐amyloid peptide 42 results in the formation of toxic oligomers and plaques, which plays a pivotal role in Alzheimer's disease pathogenesis. Aβ42 is one of several Aβ peptides, all of Aβ30 to Aβ43 that are produced as a result of γ‐secretase–mediated regulated intramembrane proteolysis of the amyloid precursor protein. γ‐Secretase modulators (GSMs) represent a promising class of Aβ42‐lowering anti‐amyloidogenic compounds for the treatment of AD. Gamma‐secretase modulators change the relative proportion of secreted Aβ peptides, while sparing the γ‐secretase–mediated processing event resulting in the release of the cytoplasmic APP intracellular domain. In this study, we have characterized how GSMs affect the γ‐secretase cleavage of three γ‐secretase substrates, E‐cadherin, ephrin type A receptor 4 (EphA4) and ephrin type B receptor 2 (EphB2), which all are implicated in important contexts of cell signalling. By using a reporter gene assay, we demonstrate that the γ‐secretase–dependent generation of EphA4 and EphB2 intracellular domains is unaffected by GSMs. We also show that γ‐secretase processing of EphA4 and EphB2 results in the release of several Aβ‐like peptides, but that only the production of Aβ‐like proteins from EphA4 is modulated by GSMs, but with an order of magnitude lower potency as compared to Aβ modulation. Collectively, these results suggest that GSMs are selective for γ‐secretase–mediated Aβ production. [ABSTRACT FROM AUTHOR]

This preface introduces the content of the special issue on 'Mass Spectrometry in Alzheimer Disease'. Here, an overview is provided on how mass spectrometry is contributing to a broader understanding of AD pathobiology. Mass spectrometry has become a major technology in biomedical analysis and research. This includes biochemical and clinical studies that aim to detail our understanding of Alzheimer disease pathogenesis and pathobiology (AD). In this special issue, key experts in the field present exciting developments and applications of MS in the context of studying AD pathology. These studies span from basic biochemical and neuropathological studies, over advanced metabolomics‐ and proteomics, towards comprehensive biomarker studies, as well as more recently, in situ mass spectrometry‐based imaging (MSI). Together, these studies highlight the key relevance of current and emerging MS technologies to detect, delineate and understand principle pathogenic mechanisms underlying AD. [ABSTRACT FROM AUTHOR]

To study the potential relationship between melatonin and beta‐amyloid (Abeta), we established a liquid chromatography–mass spectrometry (LC‐MS) method to quantitatively analyze melatonin, deuterated isotopes (melatonin‐D4), and internal standard 6‐iodo‐2‐(4'‐dimethylamino‐) phenyl‐imidazo(1,2) pyridine (IMPY) under positive (+) mode. The gradient elution was set to 6 min, and the corresponding peak time of melatonin and its isotope melatonin‐D4 was 3.14 min, while the peak time for the internal standard IMPY was 3.24 min. Next, we established and optimized the molecule receptor saturation binding assay based on LC‐MS to determine the melatonin affinity for beta‐amyloid (Abeta). Melatonin showed a high and specific binding for Abeta. The corresponding equilibrium dissociation constant (Kd) of melatonin with Abeta 1‐40 and Abeta 1‐42 was 814.37 ± 36.62 and 628.33 ± 13.57 nmol·L−1; besides, the Kd of melatonin with mixed plaques (1‐40 and 1‐42) was 461.13 ± 45.37 nmol·L−1. The results may suggest the potential mechanism of action of MT on Abeta and provide a theoretical basis for the improvement of MT treatment of Alzheimer's disease. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES: Cognitive decline associated with impaired kidney function might involve neurodegeneration. Our objectives were to evaluate the longitudinal association between kidney function and cognitive decline in older adults and to assess the involvement of cortical beta‐amyloid and hippocampal atrophy (features of Alzheimer's disease (AD)) in this association. DESIGN: Secondary analysis of the randomized controlled Multidomain Alzheimer Preventive Trial (MAPT). SETTINGS: Thirteen memory centers (France and Monaco, 2008–2016). PARTICIPANTS: A total of 1,334 community‐dwellers >70 years old without dementia at baseline. MEASUREMENTS: We estimated glomerular filtration rate (eGFR) from serum creatinine using CKD‐Epi equation. Cognition was assessed at baseline, 6, 12, 24, 36, 48, and 60 months using a composite Z‐score designed for MAPT. The Clinical Dementia Rating (CDR) score was used to assess cognition and functional independence. We examined the association between eGFR and (1) evolution of the composite cognitive Z‐score using mixed‐effect models and (2) progression on CDR using Cox models and mixed‐effect models. Adjustments were made for age, sex, education, ApoE genotype, cardiovascular risk factors and disease, hippocampal volume (measured with magnetic resonance), and cortical beta‐amyloid (measured with positron emission tomography). RESULTS: Median (IQR) eGFR was 73(60–84) mL/min/1.73 m2. Two hundred sixty‐nine participants experienced progression on CDR score during follow‐up. eGFR<60 was significantly associated with progression on CDR score (adjusted hazard ratio (aHR) = 1.35, 95% CI 1.01–1.80) and with both the cognitive and functional independence components of CDR, but not with the evolution of the composite cognitive Z‐score (adjusted β‐coefficient −0.004, 95% CI −0.014; 0.006). Associations were not modified after further adjustment for beta‐amyloid (subsample: n = 252) and hippocampal volume (subsample: n = 270). CONCLUSIONS: We did not find a mild to moderate renal insufficiency to be associated with brain imaging features of AD, and our results do not support the involvement of AD mechanisms in the incidence of cognitive impairment and functional decline associated with chronic kidney disease. [ABSTRACT FROM AUTHOR]

Combination of ischemia and β‐amyloid (Aβ) toxicity has been shown to simultaneously increase neuro‐inflammation, endogenous Aβ deposition, and neurodegeneration. However, studies on the evolution of infarct and panorama of cellular degeneration as a synergistic or overlapping mechanism between ischemia and Aβ toxicity are lacking. Here, we compared fluorojade B (FJB) and hematoxylin and eosin (H&E) stains primarily to examine the chronology of infarct, and the viability and morphological changes in neuroglia and neurons located in different brain regions on d1, d7, and d28 post Aβ toxicity and endothelin‐1 induced ischemia (ET1) in rats. We demonstrated a regional difference in cellular degeneration between cortex, corpus callosum, striatum, globus pallidus, and thalamus after cerebral injury. Glial cells in the cortex and corpus callosum underwent delayed FJB staining from d7 to d28, but neurons in cortex disappeared within the first week of cerebral injury. Striatal lesion core and globus pallidus of Aβ + ET1 rats showed extensive degeneration of neuronal cells compared with ET1 rats alone starting from d1. Differential and exacerbated expressions of cyclooxygenase‐2 might be the cause of excessive neuronal demise in the striatum of Aβ + ET1 rats. Such an investigation may improve our understanding to identify and manipulate a critical therapeutic window post comorbid injury. [ABSTRACT FROM AUTHOR]

Introduction: Relationships between brain atrophy patterns of typical aging and Alzheimer's disease (AD), white matter disease, cognition, and AD neuropathology were investigated via machine learning in a large harmonized magnetic resonance imaging database (11 studies; 10,216 subjects). Methods: Three brain signatures were calculated: Brain‐age, AD‐like neurodegeneration, and white matter hyperintensities (WMHs). Brain Charts measured and displayed the relationships of these signatures to cognition and molecular biomarkers of AD. Results: WMHs were associated with advanced brain aging, AD‐like atrophy, poorer cognition, and AD neuropathology in mild cognitive impairment (MCI)/AD and cognitively normal (CN) subjects. High WMH volume was associated with brain aging and cognitive decline occurring in an ≈10‐year period in CN subjects. WMHs were associated with doubling the likelihood of amyloid beta (Aβ) positivity after age 65. Brain aging, AD‐like atrophy, and WMHs were better predictors of cognition than chronological age in MCI/AD. Discussion: A Brain Chart quantifying brain‐aging trajectories was established, enabling the systematic evaluation of individuals' brain‐aging patterns relative to this large consortium. [ABSTRACT FROM AUTHOR]

The present study explored the role and mechanisms of mineralocorticoid receptor antagonists in β‐amyloid (Aβ)‐induced cognitive impairment. A single intracerebroventricular injection of Aβ1‐42 was given to mice, and after 14 days of injection, memory was evaluated using the Morris water maze test. Spironolactone (25 and 50 mg/kg) and eplerenone (50 and 100 mg/kg) were administered for two days before and for 14 days after Aβ injection. Mineralocorticoid receptor blockers attenuated Aβ‐induced cognitive impairment assessed in terms of decrease in day 4 escape latency time (ELT) in comparison to day 1 ELT (suggesting an increase in learning) along with an increase in time spent in target quadrant on day 5 (suggesting the retrieval of learned things). These drugs also increased the expression of BDNF, H2S, Nrf2, reduced glutathione, and decreased β‐amyloid and TNF‐α in the frontal cortex and hippocampus. Co‐administration of ANA‐12, BDNF receptor antagonist (0.25 and 0.5 mg/kg) abolished cognitive improving functions of mineralocorticoid receptor blockers, attenuated H2S, Nrf2, reduced glutathione, and decreased β‐amyloid and TNF‐α. It is concluded that spironolactone and eplerenone attenuate cognitive decline of Alzheimer's type, possibly through upregulation of BDNF levels in the frontal cortex and hippocampus, which may increase H2S, decrease Aβ, activate Nrf2‐dependent antioxidant system, and decrease neuroinflammation. [ABSTRACT FROM AUTHOR]

Key points: Alzheimer's disease (AD) patients and transgenic mice have beta‐amyloid (Aβ) aggregation in the gastrointestinal (GI) tract.It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion‐like properties.The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β‐amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits.These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. Alzheimer's disease (AD) is the most common age‐related cause of dementia, characterised by extracellular beta‐amyloid (Aβ) plaques and intracellular phosphorylated tau tangles in the brain. Aβ deposits have also been observed in the gastrointestinal (GI) tract of AD patients and transgenic mice, with overexpression of amyloid precursor protein. In the present studies, we investigate whether intra‐GI administration of Aβ can potentially induce amyloidosis in the central nervous system (CNS) and AD‐related pathology such as dementia. We micro‐injected Aβ1–42 oligomers (4 μg per site, five sites) or vehicle (saline, 5 μl) into the gastric wall of ICR mice under general anaesthesia. Immunofluorescence staining and in vivo imaging showed that HiLyte Fluor 555‐labelled Aβ1–42 had migrated within 3 h via the submucosa to nearby areas and was internalised into cholinergic neurons. At 1 month, HiLyte Fluor 555‐labelled Aβ1–42 in the body of the stomach and proximal colon had partly re‐distributed to the fundus and jejunum. At 1 year, the jejunum showed functional alterations in neuromuscular coupling (P < 0.001), and Aβ deposits were present in the vagus and brain, with animals exhibiting cognitive impairments in the Y‐maze spontaneous alteration test (P < 0.001) and the novel object recognition test (P < 0.001). We found that enteric Aβ oligomers induce an alteration in gastric function, amyloidosis in the CNS, and AD‐like dementia via vagal mechanisms. Our results suggest that Aβ load is likely to occur initially in the GI tract and may translocate to the brain, opening the possibility of new strategies for the early diagnosis and prevention of AD. Key points: Alzheimer's disease (AD) patients and transgenic mice have beta‐amyloid (Aβ) aggregation in the gastrointestinal (GI) tract.It is possible that Aβ from the periphery contributes to the load of Aβ in the brain, as Aβ has prion‐like properties.The present investigations demonstrate that Aβ injected into the GI tract of ICR mice is internalised into enteric cholinergic neurons; at 1 month, administration of Aβ into the body of the stomach and the proximal colon was observed to partly redistribute to the fundus and jejunum; at 1 year, vagal and cerebral β‐amyloidosis was present, and mice exhibited GI dysfunction and cognitive deficits.These data reveal a previously undiscovered mechanism that potentially contributes to the development of AD. [ABSTRACT FROM AUTHOR]

Background: The APOE‐ε4 allele is an established risk factor for Alzheimer's disease (AD). TOMM40 located adjacent to APOE has also been implicated in AD but reports of TOMM40 associations with AD that are independent of APOE‐ε4 are at variance. Methods: We investigated associations of AD with haplotypes defined by three TOMM40 and two APOE single nucleotide polymorphisms in 73 and 71 autopsy cases with intermediate and high likelihood of AD (defined by BRAAK stages 0.02. The two haplotypes encoding APOE‐E4 showed strong associations with AD that did not differ between intermediate and high likelihood AD. In contrast, a TOMM40 haplotype encoding APOE‐E3 was identified as risk haplotype of high‐ (p =.0186), but not intermediate likelihood AD (p =.7530). Furthermore, the variant allele of rs2075650 located in intron 2 of TOMM40, increased the risk of high‐, but not intermediate likelihood AD on the APOE‐ε3/ε3 background (p =.0230). Conclusion: The striking association of TOMM40 only with high likelihood AD may explain some contrasting results for TOMM40 in clinical studies and may reflect an association with more advanced disease and/or suggest a role of TOMM40 in the pathogenesis of neurofibrillary tangles. [ABSTRACT FROM AUTHOR]

Aim: It has been suggested that personality traits, particularly neuroticism and conscientiousness, are risk factors for Alzheimer's disease (AD) and related cognitive decline. However, the underlying pathological links between personality traits and AD‐related cognitive impairments remain unclear. Thus, the present study investigated associations of neuroticism and conscientiousness with in vivo cerebral amyloid‐beta (Aβ) burden, AD‐signature regional neurodegeneration, and white matter hyperintensities (WMH) in non‐demented middle‐ and old‐aged adults. Methods: A total of 397 non‐demented participants underwent comprehensive clinical and neuropsychological assessments, 11C‐labeled Pittsburgh Compound B positron emission tomography, and magnetic resonance imaging. Additionally, the NEO Five‐Factor Inventory was administered to both the participants and their informants to measure neuroticism and conscientiousness. Results: Neither neuroticism nor conscientiousness was associated with cerebral Aβ deposition or WMH. In contrast, higher neuroticism and lower conscientiousness, reported by informants in particular, were significantly associated with reduced AD‐signature region cortical thickness. In regards to the direct and indirect effect of each personality on AD‐signature region cortical thickness, only the direct effects were found, whereas indirect effects via Aβ deposition or WMH were not. Conclusion: The present findings suggest that amyloid‐independent regional neurodegeneration might underlie relations of neuroticism and conscientiousness with AD. [ABSTRACT FROM AUTHOR]

Introduction: Frontal variant of Alzheimer's disease (fvAD) is a rare nonamnestic syndrome of Alzheimer's disease (AD). Differentiating it from behavior variant of frontotemporal dementia (bvFTD), which has implications for treatment responses and prognosis, remains a clinical challenge. Methods: Molecular neuroimaging and biofluid markers were performed for the index patient for accurate premortem diagnosis of fvAD. The clinical, neuroimaging, and biofluid characteristics of the patient were compared to those reported in previous studies of fvAD from 1999 to 2019. Results: A 66‐year‐old man presented with progressive executive dysfunction, personality and behavioral changes, and memory decline since age 59. He had no family history of neurodegenerative disorders. A stimulus‐sensitive myoclonus was noted over his left upper extremity. Neuropsychological assessment revealed moderate dementia with a Mini‐Mental State Exam score of 10/30 and compromised executive and memory performance. Brain imaging showed asymmetrical atrophy and hypometabolism over the right frontal and temporal areas, mimicking bvFTD. However, we observed increased tau depositions based on 18F‐labeled T807 Tau PET in these areas and diffusely increased amyloid deposition based on 11C‐labeled Pittsburgh compound B positron emission tomography (PET). Plasma biomarker measures indicated an AD profile with increased Aβ1‐42 (18.66 pg/ml; cutoff: 16.42 pg/ml), Aβ1‐42/Aβ1‐40 ratio (0.45; cutoff: 0.30), total tau (29.78 pg/ml; cutoff: 23.89 pg/ml), and phosphorylated tau (4.11 pg/ml; cutoff: 3.08 pg/ml). These results supported a diagnosis of fvAD. Conclusions: Our results with asymmetrical presentations extend current knowledge about this rare AD variant. Application of biofluid and molecular imaging markers could assist in early, accurate diagnosis. [ABSTRACT FROM AUTHOR]

One of the major hallmarks of Alzheimer's disease (AD) pathology is the formation of extracellular amyloid β (Aβ) plaques. While Aβ has been suggested to be critical in inducing and, potentially, driving the disease, the molecular basis of AD pathogenesis is still under debate. Extracellular Aβ plaque pathology manifests itself upon aggregation of distinct Aβ peptides, resulting in morphologically different plaque morphotypes, including mainly diffuse and cored senile plaques. As plaque pathology precipitates long before any clinical symptoms occur, targeting the Aβ aggregation processes provides a promising target for early interventions. However, the chain of events of when, where and what Aβ species aggregate and form plaques remains unclear. The aim of this study was to investigate the potential of matrix‐assisted laser desorption/ionization imaging mass spectrometry as a tool to study the evolving pathology in transgenic mouse models for AD. To that end, we used an emerging, chemical imaging modality – matrix‐assisted laser desorption/ionization imaging mass spectrometry – that allows for delineating Aβ aggregation with specificity at the single plaque level. We identified that plaque formation occurs first in cortical regions and that these younger plaques contain higher levels of 42 amino acid‐long Aβ (Aβ1–42). Plaque maturation was found to be characterized by a relative increase in deposition of Aβ1–40, which was associated with the appearance of a cored morphology for those plaques. Finally, other C‐terminally truncated Aβ species (Aβ1–38 and Aβ1–39) exhibited a similar aggregation pattern as Aβ1–40, suggesting that these species have similar aggregation characteristics. These results suggest that initial plaque formation is seeded by Aβ1–42; a process that is followed by plaque maturation upon deposition of Aβ1–40 as well as deposition of other C‐terminally modified Aβ species. [ABSTRACT FROM AUTHOR]

Recent advances in the understanding of basic pathological mechanisms in various neurological diseases depend directly on the development of novel bioanalytical technologies that allow sensitive and specific chemical imaging at high resolution in cells and tissues. Mass spectrometry‐based molecular imaging (IMS) has gained increasing popularity in biomedical research for mapping the spatial distribution of molecular species in situ. The technology allows for comprehensive, untargeted delineation of in situ distribution profiles of metabolites, lipids, peptides and proteins. A major advantage of IMS over conventional histochemical techniques is its superior molecular specificity. Imaging mass spectrometry has therefore great potential for probing molecular regulations in CNS‐derived tissues and cells for understanding neurodegenerative disease mechanism. The goal of this review is to familiarize the reader with the experimental workflow, instrumental developments and methodological challenges as well as to give a concise overview of the major advances and recent developments and applications of IMS‐based protein and peptide profiling with particular focus on neurodegenerative diseases. This article is part of the Special Issue "Proteomics". [ABSTRACT FROM AUTHOR]

Since the discovery of a natural catalytic antibody in 1989, many catalytic antibodies targeting peptides, nucleotides, virus and bacterial proteins, and many molecules have been prepared. Although catalytic antibodies should have features superior to non‐catalytic monoclonal antibodies, the reports on catalytic antibodies are far fewer than those on normal (non‐catalytic) antibodies. Nowadays, we can obtain any monoclonal antibody we want, which is not the case for catalytic antibodies. To overcome this drawback of catalytic antibodies, much basic research must be done. As one way to attain this purpose, we have been making a protein bank of human antibody light chains, in which the light chains were expressed, purified, and stored for use in screening against many kinds of antigen, to then get clues to introducing a catalytic function in normal antibodies. As the number of stored light chains in the above protein bank has reached the hundreds, in this study, we screened them against amyloid‐beta (Aβ), which is well‐known as one of the molecules causing Alzheimer's disease. We found two interesting light chains, #7TR and #7GY. The former could degrade both a fluorescence resonance energy transfer‐Aβ substrate and Aβ1‐40 full peptide. In contrast, #7GY, whose sequence is identical to that of #7TR except for the amino acids at the 29th and 30th positions, did not degrade the FRET‐Aβ substrate at all. By using a synthetic substrate, Arg‐pNA, the difference between the chemical features of the two light chains was investigated in detail. In addition, we found that the presence of Zn(II) ion hugely influenced the catalytic activity of the #7TR light chain but not #7GY. Through these facts and the discussion, we propose one of the clues to how to put a catalytic function in a normal (non‐catalytic) antibody. [ABSTRACT FROM AUTHOR]

Summary: Alzheimer's disease (AD) is characterized by extensive neurodegeneration and inflammation in selective brain areas, linked to severely disabling cognitive deficits. Before full manifestation, different stages appear with progressively increased brain pathology and cognitive impairment. This significantly extends the time lag between initial molecular triggers and appearance of detectable symptoms. Notably, a number of studies in the last decade have revealed that in the early stage of mild cognitive impairment, events that appear in contrast with neuronal distress may occur. These have been reproduced in vitro and in animal models and include increase in synaptic elements, increase in synaptic and metabolic activity, enhancement of neurotrophic milieu and changes in glial cell reactivity and inflammation. They have been interpreted as compensatory responses that could either delay disease progression or, in the long run, result detrimental. For this reason, these mechanisms define a new and previously undervalued window of opportunity for intervention. Their importance resides especially in their early appearance. Directing efforts to better characterize this stage, in order to identify new pharmacological targets, is an exciting new avenue to future advances in AD research. [ABSTRACT FROM AUTHOR]

Beta-amyloid (Aβ) aggregates are a major cause of Alzheimer's disease (AD), and the inhibition of Aβ aggregation is a good therapeutic target against AD. Thus, the effects of Perilla extract (4-100 µg/mL) on the aggregation of Aβ (20 µM) monomers and disaggregation of pre-aggregated Aβ aggregates were determined. The Perilla methanol extract and its hexane fraction significantly reduced Aβ aggregation determined by a Theoflavin T fluorescence assay (IC50 = 24.5 and 19.8 µg/mL, respectively) and confirmed by Western blot analysis with native gels. The inhibition of Aβ aggregation by hexane fraction of Perilla extract (20 and 100 µg/mL) rescued the PC12 cells from Aβ aggregate-induced toxicity to the levels of DMSO-treated control groups. Furthermore, hexane fraction efficiently disaggregated the preformed Aβ aggregates (IC50 = 10.2 µg/mL). Perilla frutescens var. acuta leaves exhibited anti-amyloidogenic effects against Aβ aggregation and disaggregation. Practical application These results suggest that P. frutescens var. acuta has the potential to be developed as a preventive and therapeutic agent. [ABSTRACT FROM AUTHOR]

The accumulation and deposition of beta-amyloid (Aβ) is a key neuropathological hallmark of Alzheimer's disease ( AD). Histone deacetylases ( HDACs) are promising therapeutic targets for the treatment of AD, while the specific HDAC isoforms associated with cognitive improvement are poorly understood. In this study, we investigate the role of HDAC3 in the pathogenesis of AD. Nuclear HDAC3 is significantly increased in the hippocampus of 6- and 9-month-old APPswe/ PS1dE9 ( APP/ PS1) mice compared with that in age-matched wild-type C57 BL/6 (B6) mice. Lentivirus -mediated inhibition or overexpression of HDAC3 was used in the hippocampus of APP/PS1 mice to investigate the role of HDAC3 in spatial memory, amyloid burden, dendritic spine density, glial activation and tau phosphorylation. Inhibition of HDAC3 in the hippocampus attenuates spatial memory deficits, as indicated in the Morris water maze test, and decreases amyloid plaque load and Aβ levels in the brains of APP/ PS1 mice. Dendritic spine density is increased, while microglial activation is alleviated after HDAC3 inhibition in the hippocampus of 9-month-old APP/ PS1 mice. Furthermore, HDAC3 overexpression in the hippocampus increases Aβ levels, activates microglia, and decreases dendritic spine density in 6-month-old APP/ PS1 mice. In conclusion, our results indicate that HDAC3 negatively regulates spatial memory in APP/ PS1 mice and HDAC3 inhibition might represent a potential therapy for the treatment of AD. [ABSTRACT FROM AUTHOR]

Aims To investigate the roles of N-myc downstream-regulated gene 2 ( NDRG2) in the pathology of aging and neurodegenerative disease such as Alzheimer's disease ( AD). Results In this study, we confirmed the upregulation of NDRG2 in the brains of aging and AD animal models. To explore the role of NDRG2 in the pathology of AD at molecular level, we conducted a cell-based assay of highly expressed wild-type human APP695 SK-N- SH cells ( SK-N- SH APPwt). By silencing and overexpressing gene of NDRG2, we demonstrated that NDRG2-mediated increase in Aβ1-42 was through the pathways of BACE1 and GGA3. NGRG2 improved tau phosphorylation via enhanced activity of CDK5 and decreased Pin1, but it was not affected by GSK3β pathway. NDRG2 might also induce cell apoptosis through the extrinsic (caspase 8) apoptotic pathway by interaction with STAT3. Conclusion Our study confirmed the upregulation of NDRG2 in AD animal models and demonstrated its important roles in AD pathology. NDRG2 might be a potential target for studying and treatment of AD. [ABSTRACT FROM AUTHOR]

Aβ deposition is a driving force of Alzheimer's disease pathology and can be detected early by amyloid positron emission tomography. Identifying presymptomatic structural brain changes associated with Aβ deposition might lead to a better understanding of its consequences and provide early diagnostic information. In this respect we analyzed measures of cortical thickness and subcortical volumes along with hippocampal, thalamic and striatal shape and surface area by applying novel analysis strategies for structural magnetic resonance imaging. We included 69 cognitively normal elderly subjects after careful clinical and neuropsychological workup. Standardized uptake value ratios (cerebellar reference) for uptake of 11-C-Pittsburgh Compound B (PiB) were calculated from positron emission tomographic data for a cortical measurement and for bilateral hippocampus, thalamus and striatum. Associations to shape, surface area, volume and cortical thickness were tested using regression models that included significant predictors as covariates. Left anterior hippocampal shape was associated with regional PiB uptake ( P < 0.05, FDR corrected), whereas volumes of the hippocampi and their subregions were not associated with cortical or regional PiB uptake (all P > 0.05, FDR corrected). Within the entorhinal cortical region of both hemispheres, thickness was negatively associated with cortical PiB uptake ( P < 0.05, FDR corrected). Hence, localized shape measures and cortical thickness may be potential biomarkers of presymptomatic Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The beta-amyloid (Aβ) peptide was used as an important biomarker for Alzheimer's disease (AD) diagnosis. The development of an accurate, selective, rapid, and highly sensitive technique for detecting of Aβ level is an important issue in biology, and medicine to assess human health risks. Here, gold nanoparticles (Au NPs) with different size were electrochemically deposited onto the indium tin oxide (ITO) substrate in the presence of different molecular weights of surfactants. The modified substrates were used as a high sensitive electrochemical sensor of in-vitro as well as ex-vivo monitoring of Aβ based on cyclic voltammetry and square wave voltammetry techniques. Our findings revealed that the modification of ITO electrode with Au NPs could enhance its sensor performance with high sensitivity for low concentration levels of Aβ over a wide linear range with a detection limit of about 20.7 ng/g, which is less than the concentration of insoluble Aβ40 (105.4±40.2 μg/g) in brain of AD induced. In addition, Au NPs/ITO modified electrodes have demonstrated ability to monitor Aβ in the brain extracted samples without any potential interference with other components. Raman spectroscopy has been used to confirm the presence of Aβ in the AD-induced samples. Thus, it is applicable for analyzing ex-vivo samples. [ABSTRACT FROM AUTHOR]

Aims To clarify the correlation between chronic sleep restriction ( CSR) and sporadic Alzheimer disease ( AD), we determined in wild-type mice the impact of CSR, on cognitive performance, beta-amyloid (A β) peptides, and its feed-forward regulators regarding AD pathogenesis. Methods Sixteen nine-month-old C57 BL/6 male mice were equally divided into the CSR and control groups. CSR was achieved by application of a slowly rotating drum for 2 months. The Morris water maze test was used to assess cognitive impairment. The concentrations of A β peptides, amyloid precursor protein ( APP) and β-secretase 1 ( BACE1), and the mRNA levels of BACE1 and BACE1-antisense ( BACE1- AS) were measured. Results Following CSR, impairments of spatial learning and memory consolidation were observed in the mice, accompanied by A β plaque deposition and an increased A β concentration in the prefrontal and temporal lobe cortex. CSR also upregulated the β-secretase-induced cleavage of APP by increasing the protein and mRNA levels of BACE1, particularly the BACE1- AS. Conclusions This study shows that a CSR accelerates AD pathogenesis in wild-type mice. An upregulation of the BACE1 pathway appears to participate in both cortical A β plaque deposition and memory impairment caused by CSR. BACE1- AS is likely activated to initiate a cascade of events that lead to AD pathogenesis. Our study provides, therefore, a molecular mechanism that links CSR to sporadic AD. [ABSTRACT FROM AUTHOR]

As populations across the world both age and become more obese, the numbers of individuals with Alzheimer's disease and diabetes are increasing; posing enormous challenges for society and consequently becoming priorities for governments and global organizations. These issues, an ageing population at risk of neurodegenerative diseases such as Alzheimer's disease and an increasingly obese population at risk of metabolic alterations such as type 2 diabetes, are usually considered as independent conditions, but increasing evidence from both epidemiological and molecular studies link these disorders. The aim of this review was to highlight these multifactorial links. We will discuss the impact of direct links between insulin and IGF-1 signalling and the Alzheimer's disease-associated pathological events as well as the impact of other processes such as inflammation, oxidative stress and mitochondrial dysfunction either common to both conditions or perhaps responsible for a mechanistic link between metabolic and neurodegenerative disease. An understanding of such associations might be of importance not only in the understanding of disease mechanisms but also in the search for novel therapeutic options. [ABSTRACT FROM AUTHOR]

A library of substituted tetrahydroacridin-9-amine derivatives were designed, synthesized, and evaluated as dual cholinesterase and amyloid aggregation inhibitors. Compound 8e ( N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine) was identified as a potent inhibitor of butyrylcholinesterase (BuChE IC50 = 20 n m; AChE IC50 = 2.2 μ m) and was able to inhibit amyloid aggregation (40% inhibition at 25 μ m). Compounds 9e (6-chloro- N-(3,4-dimethoxybenzyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50 = 0.8 μ m; BuChE IC50 = 1.4 μ m; Aβ-aggregation inhibition = 75.7% inhibition at 25 μ m) and 11b (6-chloro- N-(3,4-dimethoxyphenethyl)-1,2,3,4-tetrahydroacridin-9-amine, AChE IC50 = 0.6 μ m; BuChE IC50 = 1.9 μ m; Aβ-aggregation inhibition = 85.9% inhibition at 25 μ m) were identified as the best compounds with dual cholinesterase and amyloid aggregation inhibition. The picolylamine-substituted compound 12c (6-chloro- N-(pyridin-2-ylmethyl)-1,2,3,4-tetrahydroacridin-9-amine) was the most potent AChE inhibitor ( IC50 = 90 n m). These investigations demonstrate the utility of 3,4-dimethoxyphenyl substituent as a novel pharmacophore possessing dual cholinesterase inhibition and anti-Aβ-aggregation properties that can be used in the design and development of small molecules with multitargeting ability to treat Alzheimer's disease. [ABSTRACT FROM AUTHOR]

ABSTRACT Alzheimer's disease (AD) is characterized phenotypically by memory impairment, histologically by accumulation of pTau and β-amyloid peptide and morphologically by a loss of nerve terminals in cortical and hippocampal regions. As glutamate is the principle excitatory neurotransmitter of the central nervous system (CNS), the glutamatergic system may play an important role in AD. To date, not many studies have addressed the deleterious effects of Aβ on glutamatergic terminals; therefore the aim of this study was to investigate how Aβ affects glutamatergic terminals and to assess the extent to which alterations in the glutamatergic neurotransmission could impact susceptibility to the illness. The present study shows that Aβ caused a loss of glutamatergic terminals, measured by VGLUT1 protein levels, in Tg2576 primary cell cultures, Tg2576 mice and AD patient brains, and also when Aβ was added exogenously to hippocampal cell cultures. Interestingly, no correlation was found between cognition and decreased VGLUT1 levels. Moreover, when Aβ1-42 was intracerebroventricularlly administered into VGLUT1+/- mice, altered synaptic plasticity and increased neuroinflammation was observed in the hippocampus of those animals. In conclusion, the present study not only revealed susceptibility of glutamatergic nerve terminals to Aβ induced toxicity but also underlined the importance of VGLUT1 in the progression of AD, as the decrease of this protein levels could increase the susceptibility to subsequent deleterious inputs by exacerbating Aβ induced neuroinflammation and synaptic plasticity disruption. © 2016 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

The mechanistic relationship between amyloid β1-42 (Aβ1-42) and the alteration of Tau protein are debated. We investigated the effect of Aβ1-42 monomers and oligomers on Tau, using mice expressing wild-type human Tau that do not spontaneously develop Tau pathology. After intraventricular injection of Aβ1-42, mice were sacrificed after 3 h or 4 days. The short-lasting treatment with Aβ monomers, but not oligomers, showed a conformational PHF-like change of Tau, together with hyperphosphorylation. The same treatment induced increase in concentration of GSK3 and MAP kinases. The inhibition of the kinases rescued the Tau changes. Aβ monomers increased the levels of total Tau, through the inhibition of proteasomal degradation. Aβ oligomers reproduced all the aforementioned alterations only after 4 days of treatment. It is known that Aβ1-42 monomers foster synaptic activity. Our results suggest that Aβ monomers physiologically favor Tau activity and dendritic sprouting, whereas their excess causes Tau pathology. Moreover, our study indicates that anti-Aβ therapies should be targeted to Aβ1-42 monomers too. [ABSTRACT FROM AUTHOR]

Objective Donepezil (DNPZ) is a drug commonly used for Alzheimer's disease (AD) that may favour a T helper 2 phenotype leading to increased naturally occurring auto-antibodies (NAb) against beta-amyloid (Aβ). We hypothesized the involvement of the cholinergic receptors [α7-nicotnic acetylcholine receptor (α7nAChR)] expressed on peripheral blood mononuclear cells (PBMC). Methods Fifty patients with mild-to-moderate AD, DNPZ treated (DNPZ+, n = 25) or not (DNPZ−, n = 25), and 25 matched controls were enrolled and PBMC extracted for both in vitro cultures, and real-time polymerase chain reaction and chromatin immunoprecipitation assay. Plasma samples were also obtained for Aβ and NAb determination. Results Donepezil increased in vitro the expression of the transcription factor GATA binding protein 3 (GATA3) through α7nAChR, because prevented by the specific antagonist methyllycaconitine. Ex vivo PBMC α7nAChR mRNA expression was increased in both AD groups, while GATA3 expression was not. A significant increase in the GATA3/interleukin 5 promoter association was found in DNPZ+ patients. Finally, DNPZ+ patients showed both significantly higher plasma levels of anti-Aβ NAb with respect to DNPZ− patients and Aβ 1-42 with respect to normal controls. Conclusions Donepezil might modulate a T helper 2 bias via α7nAChR leading to increased expression of NAb. Further studies on the role of the modulation of the immune response against Aβ may pave the way to innovative therapeutic strategies for AD. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]