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Objective(s):To assess the effect of catalpol, the major bioactive constituents of Rehmannia glutinosa, on our Alzheimer's disease (AD) in vitro model. Materials and Methods: We employed the immortalized lymphocytes (lymphoblastoid cell line, LCL) from late-onset AD patients and co-cultured "them" to mimic the pathological process of late-onset AD and investigated the effect of catalpol on our AD in vitro model. Results: In the co-culture model, AD-derived LCL triggered excessive Aβ1-42 in SKNMC cells due to its high levels of oxidative stress and resulted in neuronal oxidative stress injury through inhibiting Keap1-Nrf2/ARE signaling pathway. Treatment with catalpol and N-acetylcysteine (NAC), an antioxidant, prevented the AD LCL-induced Aβ1-42 overproduction and reduced the level of β-site amyloid precursor protein cleaving enzyme-1 (BACE1) and amyloid precursor protein (APP)-C99. Catalpol and NAC also enhanced the antioxidant capacity and reduced apoptosis in SKNMC cells co-cultured with AD LCL. The anti-oxidative effect of catalpol was antagonized by ML385, the Nrf2 inhibitor. Therefore, we speculate that the antioxidant and anti-apoptotic effects of catalpol are mediated by activating the Keap1-Nrf2/ARE signaling pathway. Conclusion: Catalpol affects the anti-Aβ generation and the antioxidative and antiapoptotic properties in the AD co-cultured model. So, it might be a novel natural drug and offer a potential therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a common neurodegenerative disease, which is mainly caused by brain lesions. The activation of complement system plays an important role in the process of AD lesions. The activated complement can bind to cell membrane receptors and regulate downstream signals. Therefore, inhibiting complement activation provides a new idea for AD treatment. This article reviews the progress in the mechanism and drug development of complement activation in AD, which may provide a new perspective for the diagnosis, treatment and drug development of AD. [ABSTRACT FROM AUTHOR]

Recent studies suggest that increased cerebrospinal fluid (CSF) phospho-tau is associated with brain amyloid pathology rather than the tau pathology. However, confirmation using gold standard neuropathological assessments remains limited. This study aimed to determine background pathologies associated with aberrant CSF p-tau181 and amyloid-beta 1–42 (Aβ42) in Alzheimer's disease (AD) and other neurodegenerative diseases. We retrospectively studied all patients with antemortem CSF and postmortem neuropathologic data at our institution. Comprehensive neuropathologic assessments were conducted for all patients, including Thal phase, Braak NFT stage, and CERAD score for AD. CSF concentrations of p-tau181 and Aβ42 were compared between AD neuropathological scores at autopsy by one-way ANOVA stratified by other pathologies. A total of 127 patients with AD (n = 22), Lewy body disease (n = 26), primary tauopathies (n = 30), TDP-43 proteinopathy (n = 16), and other diseases (n = 33) were included. The age at lumbar puncture was 76.3 ± 9.1 years, 40.8% were female, and median time from lumbar puncture to autopsy was 637 (175–1625) days. While Braak NFT 0–II was prevalent without amyloid pathology, Braak NFT ≥IV was observed exclusively in patients with amyloid pathology. Stratified analyses showed that CSF p-tau181 was slightly but significantly higher in patients with high Thal phase or CERAD score even in those with Braak NFT 0–II at autopsy. In patients with amyloid pathology, CSF p-tau181 was significantly and more profoundly elevated in those with Braak NFT ≥III at autopsy. CSF Aβ42 was lower in patients with high amyloid pathological scores. However, 34% with Thal ≤ 2 and 38% with CERAD ≤ sparse also showed decreased Aβ42. Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) were overrepresented in this group. These results neuropathologically confirmed previous studies that CSF p-tau181 levels were slightly elevated with amyloid pathology alone and were even higher with tau pathology, and that CSFAβ42 can be decreased in PSP/CBD. [ABSTRACT FROM AUTHOR]

Extracellular amyloid‐β (Aβ) plaques, primarily formed by Aβ(1‐40) and Aβ(1‐42) fibrils, are a hallmark of Alzheimer's disease. The Aβ peptide can undergo a high variety of different post‐translational modifications including formation of a pyroglutamate (pGlu, pE) at N‐terminal Glu3 or Glu11 of truncated Aβ(3‐x) or Aβ(11‐x), respectively. Here we studied structural similarities and differences between pEAβ(3‐42) and LS‐shaped Aβ(1‐42) fibrils grown under identical conditions (pH 2) using solid‐state NMR spectroscopy. We show that the central region of pEAβ(3‐42) fibrils including the turn region around V24 is almost identical to Aβ(1‐42) showing similar β‐strands also at the N‐terminus. The missing N‐terminal residues D1‐A2 along with pE3 formation in pEAβ(3‐42) preclude a salt bridge between K28‐D1' as in Aβ(1‐42) fibrils. G37 and G38 act as highly sensitive internal sensors for the modified N‐terminus, which remains rigid over ~five pH units. [ABSTRACT FROM AUTHOR]

The most common aging-related neurodegenerative disorder is Alzheimer's disease (AD), of which the main symptom is memory disturbance. Though the mechanism of AD pathogenesis is not fully defined, abnormal aggregation of amyloid beta (Aβ) plaques and tau have been considered as key factors and main histological hallmarks of the disease. Astrocyte is responsible for the control of cells and the environment around brain and spinal cord cells. Astrocytes have been implicated with AD. However, the exact function of astrocytes in AD has not been established. In this study, we investigated the regulation of astrocytes in the AD model using primary cultures. We have demonstrated that oligomerized Aβ is toxic to neurons and can induce cell death in primary cultures. In the primary cultures containing neurons and astrocytes, amyloid beta uptake was observed in both neurons and astrocytes. To verify if the uptake of amyloid beta in astrocytes is dependent on neurons, we separated and cultured primary astrocytes with no neurons. Amyloid uptake was still observed in this pure astrocyte culture, suggesting that the uptake of amyloid beta is a neuron-independent function of astrocytes. Astrocyte activation was observed in both pure and mixed cultures. Taken together, our data suggest that astrocyte is activated by oligomerized Aβ and uptakes it, which is independent of neurons. [ABSTRACT FROM AUTHOR]

Background: Alzheimer's Disease (AD) is one of the most prevalent chronic neurodegenerative disorders. The present study aims to better understand the mechanism by which Citrus aurantium (C. aurantium) and Lavandula angustifolia (L. angustifolia) hydro-alcoholic extracts were used to treat AD and anti-oxidant issues in a laboratory model. Methods: 15 male Wistar rats, weighing 250±20 gr, aged 6-8 weeks, were used. Amyloids in the brain were found and identified using the shuttle box and Congo red test. ELISA testing for norepinephrine and serotonin, Superoxide Dismutase (SOD), Malondialdehyde (MDA), and Real-time PCR for expression of the APP and GLT1 genes were done. Results: The shuttle box test demonstrated that AD produces behavioral harm, since it significantly reduces passive avoidance learning. The Congo red test revealed that the AD models had much more amyloid beta in their brain tissue than the control. Norepinephrine levels were also decreased by using both extracts in test group. Treatment with both extracts led to a substantial rise in SOD activity and fall in MDA concentration. Conclusion: The gene expression data indicated that the relative expression of the APP and GLT1 genes was shown to be lower in the groups treated with both extracts. C. aurantium and L. angustifolia may therefore offer a multi-target treatment strategy for AD, which calls for more research in this area. [ABSTRACT FROM AUTHOR]

Amyloid‐β oligomers (Aβo) are the most pathologically relevant Aβ species in Alzheimer's disease (AD), because they induce early synaptic dysfunction that leads to learning and memory impairments. In contrast, increasing VEGF (Vascular Endothelial Growth Factor) brain levels have been shown to improve learning and memory processes, and to alleviate Aβ‐mediated synapse dysfunction. Here, we designed a new peptide, the blocking peptide (BP), which is derived from an Aβo‐targeted domain of the VEGF protein, and investigated its effect on Aβ‐associated toxicity. Using a combination of biochemical, 3D and ultrastructural imaging, and electrophysiological approaches, we demonstrated that BP strongly interacts with Aβo and blocks Aβ fibrillar aggregation process, leading to the formation of Aβ amorphous aggregates. BP further impedes the formation of structured Aβo and prevents their pathogenic binding to synapses. Importantly, acute BP treatment successfully rescues long‐term potentiation (LTP) in the APP/PS1 mouse model of AD, at an age when LTP is highly impaired in hippocampal slices. Moreover, BP is also able to block the interaction between Aβo and VEGF, which suggests a dual mechanism aimed at both trapping Aβo and releasing VEGF to alleviate Aβo‐induced synaptic damage. Our findings provide evidence for a neutralizing effect of the BP on Aβ aggregation process and pathogenic action, highlighting a potential new therapeutic strategy. [ABSTRACT FROM AUTHOR]

Objective: Brain reserve, cognitive reserve, and education are thought to protect against late-life cognitive decline, but these variables have not been directly compared to one another in the same model, using future cognitive and functional decline as outcomes. We sought to determine whether the influence of these protective factors on executive function (EF) and daily function decline was dependent upon Alzheimer's disease (AD) pathology severity, as measured by the total tau to beta-amyloid (T-τ/Aβ1-42) ratio in cerebrospinal fluid (CSF). Method: Participants were 1201 older adult volunteers in the Alzheimer's Disease Neuroimaging Initiative (ADNI) study. Brain reserve was defined using a composite index of structural brain volumes (total brain matter, hippocampus, and white matter hyperintensity). Cognitive reserve was defined as the variance in episodic memory performance not explained by brain integrity and demographics. Results: At higher levels of T-τ/Aβ1-42, brain and cognitive reserve predicted slower decline in EF. Only brain reserve attenuated decline at lower levels of T-τ/Aβ1-42. Education had no independent association with cognitive decline. Conclusions: These results point to a hierarchy of protection against aging- and disease-associated cognitive decline. When pathology is low, only structural brain integrity predicts rate of future EF decline. The ability of cognitive reserve to predict future EF decline becomes stronger as CSF biomarker evidence of AD increases. Although education is typically thought of as a proxy for cognitive reserve, it did not show any protective effects on cognition after accounting for brain integrity and the residual cognitive reserve index. [ABSTRACT FROM AUTHOR]

Purpose To investigate the MRI markers for the prediction of amyloid β (Aβ)-positivity in mild cognitive impairment (MCI) and Alzheimer's disease (AD), and to evaluate the differences in MRI markers between Aβ-positive (Aβ [+]) and -negative groups using the machine learning (ML) method. Materials and Methods This study included 139 patients with MCI and AD who underwent amyloid PET-CT and brain MRI. Patients were divided into Aβ (+) (n = 84) and Aβ-negative (n = 55) groups. Visual analysis was performed with the Fazekas scale of white matter hyperintensity (WMH) and cerebral microbleeds (CMB) scores. The WMH volume and regional brain volume were quantitatively measured. The multivariable logistic regression and ML using support vector machine, and logistic regression were used to identify the best MRI predictors of Aβ-positivity. Results The Fazekas scale of WMH (p = 0.02) and CMB scores (p = 0.04) were higher in Aβ (+). The vol-umes of hippocampus, entorhinal cortex, and precuneus were smaller in Aβ (+) (p < 0.05). The third ventricle volume was larger in Aβ (+) (p = 0.002). The logistic regression of ML showed a good accuracy (81.1%) with mini-mental state examination (MMSE) and regional brain volumes. Conclusion The application of ML using the MMSE, third ventricle, and hippocampal volume is helpful in predicting Aβ-positivity with a good accuracy. [ABSTRACT FROM AUTHOR]

Background: Plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis that is associated with adiposity, has been implicated in Alzheimer's disease (AD) pathogenesis. However, whether circulating PAI-1 levels are altered during preclinical AD remains unclear. Objective: To measure plasma PAI-1 levels in cognitively normal cerebrospinal fluid (CSF) AD biomarker positive and biomarker negative participants and to examine the association of plasma PAI-1 levels with CSF AD biomarkers and Mini-Mental State Examination (MMSE) scores. Methods: In this cross-sectional study, plasma PAI-1 levels were measured in 155 cognitively normal (Clinical Dementia Rating, CDR 0) non-obese older adults. 29 men and 26 women were classified as preclinical AD by previously established CSF tau/Aβ42 criteria. All analyses were sex stratified due to reported sex differences in PAI-1 expression. Results: Plasma PAI-1 levels were associated with body mass index (BMI) but not age in men and women. In men, plasma PAI-1 levels and BMI were lower in preclinical AD compared to control. Plasma PAI-1 levels were positively associated with CSF amyloid-β42 (Aβ42) and CSF Aβ42/Aβ40 and negatively associated with CSF tau/Aβ42, while BMI was positively associated with CSF Aβ42 and negatively associated with CSF p-tau181 and CSF tau/Aβ42. In women, plasma PAI-1 levels and BMI were similar between preclinical AD and control and were not associated with CSF AD biomarkers. For men and women, plasma PAI-1 levels and BMI were not associated with MMSE scores. Conclusion: These findings suggest that there are significant sex differences in the systemic metabolic changes seen in the preclinical stage of AD. [ABSTRACT FROM AUTHOR]

The developments in the field of medicine have led to an increase in human lifespan, but with it comes the growth of older population which is followed by an increase in incidence of neurodegenerative diseases such as Alzheimer’s disease. Until recently, the only available therapy for Alzheimer’s disease was symptomatic in nature, such as the cholinesteraze inhibitors (rivastigmine, donepezil, galantamine) and the NMDA receptor antagonist memantine. Current attempts to find the potential disease-modifying therapy are targeting two typical morphological features of the disease, amyloid plaques and tau protein neurofibrillary tangles, which is why they are classified as anti-amyloid and anti-tau therapy. This approach is based on inhibition of beta-amyloid or tau protein synthesis, prevention of their aggregation or promotion of their clearence through use of specific antibodies. One such drug, aducunumab (brand name Aduhelm), has recently been approved by the FDA for treatment of mild Alzheimer’s disease. [ABSTRACT FROM AUTHOR]

Introduction: Cerebrospinal fluid (CSF) biomarker quantification provides physicians with a reliable diagnosis of Alzheimer's disease (AD). However, the relationship between their concentration and disease course has not been clearly elucidated. This work aimed to investigate the clinical and prognostic significance of Aβ40 CSF levels. Methods: A retrospective cohort of 76 patients diagnosed with AD using a decreased Aβ42/Aβ40 ratio was subclassified into hyposecretors (Aβ40 <7,755 pg/mL), normosecretors (Aβ40 7,755–16,715 pg/mL), and hypersecretors (Aβ40 >16,715 pg/mL). Potential differences in AD phenotype, Montreal Cognitive Assessment (MoCA) scores, and Global Deterioration Scale (GDS) stages were assessed. Correlation tests for biomarker concentrations were also performed. Results: Participants were classified as hyposecretors (n = 22, median Aβ40 5,870.500 pg/mL, interquartile range [IQR] 1,431), normosecretors (n = 47, median Aβ40 10,817 pg/mL, IQR 3,622), and hypersecretors (n = 7, 19,767 pg/mL, IQR 3,088). The distribution of positive phosphorylated Tau (p-Tau) varied significantly between subgroups and was more common in the normo- and hypersecretor categories (p = 0.003). Aβ40 and p-Tau concentrations correlated positively (ρ = 0.605, p < 0.001). No significant differences were found among subgroups regarding age, initial MoCA score, initial GDS stage, progression to the dementia stage, or changes in the MoCA score. Conclusion: In this study, we found no significant differences in clinical symptoms or disease progression in AD patients according to their CSF Aβ40 concentration. Aβ40 was positively correlated with p-Tau and total Tau concentrations, supporting their potential interaction in AD pathophysiology. [ABSTRACT FROM AUTHOR]

Galectin-3 (Gal-3), widely expressed in central nervous system, is a member of the galectin family. Gal-3 can bind a variety of molecules and play a role by regulating downstream signals. Recent advances have suggested that changes in Gal-3 expression in brain tissues, serum and cerebrospinal fluid of patients with Alzheimer's disease (AD) are closely related to the severity of AD. Therefore, GAL-3 is expected to be an important biomarker for the diagnosis and detection of drug efficacy in AD. In this review, we present an updated overview of the current understanding of Gal-3 involvement in AD, which may provide useful references for the clinical diagnosis and treatment of AD in the future. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) represents the most common type of neurodegenerative dementia and is characterized by extracellular amyloid-β (Aβ) deposition, pathologic intracellular tau protein tangles, and neuronal loss. Increasing evidence has been accumulating over the past years, supporting a pivotal role of inflammation in the pathogenesis of AD. Microglia, monocytes, astrocytes, and neurons have been shown to play a major role in AD-associated inflammation. However recent studies showed that the role of both T and B lymphocytes may be important. In particular, B lymphocytes are the cornerstone of humoral immunity, they constitute a heterogenous population of immune cells, being their mature subsets significantly impacted by the inflammatory milieu. The role of B lymphocytes on AD pathogenesis is gaining interest for several reasons. Indeed, the majority of elderly people develop the process of "inflammaging", which is characterized by increased blood levels of proinflammatory molecules associated with an elevated susceptibility to chronic diseases. Epitope-specific alteration pattern of naturally occurring antibodies targeting the amino-terminus and the mid-domain of Aβ in both plasma and cerebrospinal fluid has been described in AD patients. Moreover, a possible therapeutic role of B lymphocytes depletion was recently demonstrated in murine AD models. Interestingly, active immunization against Aβ and tau, one of the main therapeutic strategies under investigation, depend on B lymphocytes. Finally. several molecules being tested in AD clinical trials can modify the homeostasis of B cells. This review summarizes the evidence supporting the role of B lymphocytes in AD from the pathogenesis to the possible therapeutic implications. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory impairment in patients. Erythropoietin (EPO) has been reported to stimulate neurogenesis. This study was conducted to determine the regenerative effects of EPO in an AD model and to assess its underlying mechanism. Recombinant human EPO was intraperitoneally administered to AD mice induced by intracerebroventricular Aβ oligomer injection. Behavioral assessments with novel object recognition test and passive avoidance task showed improvement in memory function of the EPO-treated AD mice compared to that of the saline-treated AD mice (p < 0.0001). An in vivo protein assay for the hippocampus and cortex tissue indicated that EPO treatment modulated neurotransmitters, including dopamine, serotonin, and adrenaline. EPO treatment also restored the activity of serotonin receptors, including 5-HT4R, 5-HT7R, and 5-HT1aR (p < 0.01), at mRNA levels. Furthermore, EPO seemed to exert an anti-inflammatory influence by downregulating TLR4 at mRNA and protein levels (p < 0.05). Finally, an immunohistochemical assay revealed increments of Nestin(+) and NeuN(+) neuronal cells in the CA3 region in the EPO-treated AD mice compared to those in the saline-treated AD mice. The conclusion is that EPO administration might be therapeutic for AD by activating the serotonergic pathway, anti-inflammatory action, and neurogenic characteristics. [ABSTRACT FROM AUTHOR]

Purpose: This paper aims to depict the mechanistic role of vitamin D on dementia prevention, relief of the severity and the complication of the disease. All papers indexed in scientific databases, including Scopus, Elsevier, PubMed, Embase and Google Scholar between 2000 and 2021 were extracted and discussed. To present the mechanistic role of vitamin D in declining the severity of dementia, keywords including dementia, vitamin D, oxidative stress, inflammation, amyloid beta-Peptides were used. Design/methodology/approach: Dementia is a prevalent cognitive disorder worldwide, especially in elderly people, which is accompanied by serious disabilities. Besides genetic, biological and lifestyle factors are involved in the incidence of dementia. An unhealthy diet along with micronutrient deficiencies are among modifiable factors. Vitamin D is one of the important micronutrients in brain health. Besides the involvement in gene expression, bone mineralization, apoptosis, inflammation, skeletal maturation, neurotropic action and hemostasis of phosphate and calcium, vitamin D also exerts neuroprotective effects via genomic and non-genomic pathways. Findings: Vitamin D up-regulates the expression of various genes involved in dementia incidence via various mechanisms. Decreasing oxidative stress and the neuro-inflammatory cytokines levels, regulation of the expression of alternated Proteins including Tau and Amyloid-ß, calcium homeostasis in the central nervous system and also vascular are considered main mechanisms. Originality/value: Considering the importance of diet in preventing dementia, adherence to a healthy diet that provides essential nutrients to brain function seems to be urgent. Controlling serum levels of vitamin D periodically and providing vitamin D by related sources or supplements, if there is a deficiency, is recommended. Future studies are needed to clarify other related mechanisms. [ABSTRACT FROM AUTHOR]

Biomolecular interaction acts a pivotal part in understanding the mechanisms underlying the development of Alzheimer's disease (AD). Herein, we built a biosensing platform to explore the interaction between gelsolin (GSN) and different β-amyloid protein 1-42 (Aβ 1-42) species, including Aβ 1-42 monomer (m-Aβ), Aβ 1-42 oligomers with both low and high levels of aggregation (LLo-Aβ and HLo-Aβ) via dual polarization interferometry (DPI). Real-time molecular interaction process and kinetic analysis showed that m-Aβ had the strongest affinity and specificity with GSN compared with LLo-Aβ and HLo-Aβ. The impact of GSN on inhibiting aggregation of Aβ 1-42 and solubilizing Aβ 1-42 aggregates was evaluated by circular dichroism (CD) spectroscopy. The maintenance of random coil structure of m-Aβ and the reversal of β-sheet structure in HLo-Aβ were observed, demonstrating the beneficial effects of GSN on preventing Aβ from aggregation. In addition, the structure of m-Aβ/GSN complex was analyzed in detail by molecular dynamics (MD) simulation and molecular docking. The specific binding sites and crucial intermolecular forces were identified, which are believed to stabilize m-Aβ in its soluble state and to inhibit the fibrilization of Aβ 1-42. Combined theoretical simulations and experiment results, we speculate that the success of GSN sequestration mechanism and the balance of GSN levels in cerebrospinal fluid and plasma of AD subjects may contribute to a delay in AD progression. This research not only unveils the molecular basis of the interaction between GSN and Aβ 1-42 , but also provides clues to understanding the crucial functions of GSN in AD and drives the development of AD drugs and therapeutic approaches. Gelsolin and Aβ 1-42 with different levels of aggregation are key proteins related to the molecular mechanism of Alzheimer's disease (AD). We studied the real-time binding behaviors between them via dual polarization interferometry (DPI). Their kinetic processes and the key binding sites were further displayed, revealing abundant information about AD from novel viewpoints and covering issues of concern in multiple fields. [Display omitted] • A real-time biosensing platform was built via dual polarization interferometry (DPI) to explore the binding behavior and kinetic aspect between gelsolin (GSN) and different Aβ 1-42 species. • The affinity of Aβ 1-42 monomer and GSN was considerably greater than Aβ 1-42 oligomers with both low and high levels of aggregation. • GSN could reduce amyloid load by inhibiting m-Aβ aggregation and solubilizing Aβ 1-42 aggregates. • The random coil structure, hydrogen bond and hydrophobic region jointly contribute the dominant combination of GSN and Aβ 1-42 monomer. [ABSTRACT FROM AUTHOR]

Alzheimer’s disease (AD) is a neurodegenerative disease responsible for almost half of all dementia cases in the world and progressively increasing. The etiopathology includes heritability, genetic factors, aging, nutrition, but sex hormones play a relevant role. Animal models demonstrated that testosterone (T) exerted a neuroprotective effect reducing the production of amyloid-beta (Aβ), improving synaptic signaling, and counteracting neuronal death. This study aims to evaluate the impact of T deprivation and T administration in humans on the onset of dementia and AD. A search was conducted on MEDLINE and Scopus for the “androgen deprivation therapy” and “testosterone therapy” with “dementia” and “Alzheimer’s.” Studies lasting twenty years with low risk of bias, randomized clinical trial, and case-controlled studies were considered. Twelve articles on the effect of androgen deprivation therapy (ADT) and AD and seventeen on T therapy and AD were retrieved. Men with prostate cancer under ADT showed a higher incidence of dementia and AD. The effect of T administration in hypogonadal men with AD and cognitive impairment has evidenced some positive results. The majority of studies showed the T administration improved memory and cognition in AD while others did not find any benefit. Although some biases in the studies are evident, T therapy for AD patients may represent an essential clinical therapy to reduce dementia incidence and AD progression. However, more specific case-controlled trials on the effect of androgens therapy in men and women to reducing the onset of AD are necessary. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Amyloid‐β protein (Aβ) is a fatal cause of Alzheimer's disease, which can trigger a series of cytotoxicity by the abnormal aggregation of Aβ in human brain. The strategies for inhibition and disaggregation of Aβ fibrillation are mostly based on the interaction between monomers, oligomers, fibrils, and materials. This review summarizes recent researches of materials and regulation of interactions for inhibiting Aβ aggregation and disaggregating Aβ fibrils. The materials have been reviewed and divided into several kinds according to molecular type. And the regulation of interactions between materials and Aβ protein mainly focuses on covalent interaction, non‐covalent interaction and photoactivated effect based on covalent and non‐covalent interaction. In this review, the photodynamic effect and photothermal effect on regulation of Aβ aggregation are summarized in detail. In the end, the challenges and outlook of the application prospects on the strategies for inhibition and disaggregation of Aβ fibrillation are estimated. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is the most common cause of neurodegeneration. It is characterized by deposits of amyloid beta (Aβ) plaques and impaired memory. Microglia are associated with AD. They are activated in the AD brain and AD models. However, the exact role of microglia has not been established. We thus investigated the role of microglia in AD models using a primary culture and an ex-vivo assay. We showed that oligomerized Aβ is toxic to neurons in the primary culture. In the ex-vivo assay, a microglial cell line removed amyloid plaques in the brain of 5XFAD (AD model) mice. To verify if microglia can be protective for the neuron, we co-cultured neurons with primary microglia and treated them with Aβ. The loss of neurons, induced by amyloid toxicity, was attenuated by co-cultured microglia. Taken together, our data suggest that microglia promote neuronal survival by phagocytic clearance of Aβ in AD models. [ABSTRACT FROM AUTHOR]

Alzheimer's disease is a neurodegenerative condition that causes changes in memory and cognition, in addition to behavioral disorders, and most commonly affects the elderly. Several studies in the literature have presented therapeutic measures in an attempt to interfere with the pathogenic mechanisms of the disease and to mitigate its clinical manifestations. Some factors, such as excitotoxicity, cholinergic dysfunctions, oxidative stress, tau protein hyperphosphorylation, changes in amyloid-beta peptide metabolism, herpes viruses, apolipoprotein E, glycogen synthase kinase 3, insulin resistance, and the endocannabinoid system seem to be related to pathophysiology of Alzheimer's disease. Given this, a literature review was carried out to address the molecular mechanisms associated with the pathophysiological hypotheses previously mentioned, aiming to better understanding their underlying causes and contributing to possible pharmacological strategies about treatment of the disease. [ABSTRACT FROM AUTHOR]

Background: Focused ultrasound (FUS)-mediated blood–brain barrier (BBB) opening has shown efficacy in removal of amyloid plaque and improvement of cognitive functions in preclinical studies, but this is rarely reported in clinical studies. This study was conducted to evaluate the safety, feasibility and potential benefits of repeated extensive BBB opening. Methods: In this open-label, prospective study, six patients with Alzheimer's disease (AD) were enrolled at Severance Hospital in Korea between August 2020 and September 2020. Five of them completed the study. FUS-mediated BBB opening, targeting the bilateral frontal lobe regions over 20 cm3, was performed twice at three-month intervals. Magnetic resonance imaging, 18F-Florbetaben (FBB) positron emission tomography, Caregiver-Administered Neuropsychiatric Inventory (CGA-NPI) and comprehensive neuropsychological tests were performed before and after the procedures. Results: FUS targeted a mean volume of 21.1 ± 2.7 cm3 and BBB opening was confirmed at 95.7% ± 9.4% of the targeted volume. The frontal-to-other cortical region FBB standardized uptake value ratio at 3 months after the procedure showed a slight decrease, which was statistically significant, compared to the pre-procedure value (− 1.6%, 0.986 vs1.002, P = 0.043). The CGA-NPI score at 2 weeks after the second procedure significantly decreased compared to baseline (2.2 ± 3.0 vs 8.6 ± 6.0, P = 0.042), but recovered after 3 months (5.2 ± 5.8 vs 8.6 ± 6.0, P = 0.89). No adverse effects were observed. Conclusions: The repeated and extensive BBB opening in the frontal lobe is safe and feasible for patients with AD. In addition, the BBB opening is potentially beneficial for amyloid removal in AD patients. [ABSTRACT FROM AUTHOR]

Amyloid‐β (Aβ) aggregates are one of biomarkers of Alzheimer's disease (AD). It is well known that Aβ aggregates display neurotoxicty or cytotoxicity to neurons. Thus, degrading Aβ aggregates is crucial for exploring the treatment of AD. Moreover, the excessive production of HOCl in the AD brain is an important feature of the disease. Herein, a novel compound MB‐O based on methylene blue (MB) skeleton was designed and synthesized. The probe MB‐O can specifically react with HOCl, releasing the fluorophore MB with strong fluorescence intensity increase. More importantly, the released MB is capable of degrading Aβ aggregates under red light irradiation. [ABSTRACT FROM AUTHOR]

In Alzheimer's disease (AD), amyloid-β (Aβ) generation and upstream β-secretase 1 (BACE1) expression appear to be driven by oxidative stress via c-Jun N-terminal kinase (JNK), p38, and Interferon-Induced, Double-Stranded RNA-Activated Protein Kinase (PKR). In addition, inflammatory molecules, including lipopolysaccharide (LPS), induce genes central to Aβ genesis, such as BACE1, via nuclear factor-κB (NFκB). However, additional triggers of Aβ generation remain poorly understood and might represent novel opportunities for therapeutic intervention. Based on mechanistic studies and elevated ectopic oxidatively damaged DNA (oxoDNA) levels in preclinical AD, mild cognitive impairment, and AD patients, we hypothesize oxoDNA contributes to β-amyloidosis starting from the earliest stages of AD through multiple pathways. OxoDNA induces mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), thereby sensitizing the brain to oxidative stress-induced JNK activation and BACE1 transcription. It also induces myeloid differentiation primary response 88 (MyD88) and activates protein kinase CK2, thereby increasing NFκB activation and BACE1 induction. OxoDNA increases oxidative stress via nuclear factor erythroid 2-related factor 2 (Nrf2) ectopic localization, likely augmenting JNK-mediated BACE1 induction. OxoDNA likely also promotes β-amyloidosis via absent in melanoma 2 (AIM2) induction. Falsifiable predictions of this hypothesis include that deoxyribonuclease treatment should decrease Aβ and possibly slow cognitive decline in AD patients. While formal testing of this hypothesis remains to be performed, a case report has found deoxyribonuclease I treatment improved a severely demented AD patient's Mini-Mental Status Exam score from 3 to 18 at 2 months. There is preliminary preclinical and clinical evidence suggesting that ectopic oxidatively damaged DNA may act as an inflammatory damage-associated molecular pattern contributing to Aβ generation in AD, and deoxyribonuclease I should be formally evaluated to test whether it can decrease Aβ levels and slow cognitive decline in AD patients. [ABSTRACT FROM AUTHOR]

Recent studies indicate a crucial role for neuronal glycogen storage and degradation in memory formation. We have previously identified alpha‐amylase (α‐amylase), a glycogen degradation enzyme, located within synaptic‐like structures in CA1 pyramidal neurons and shown that individuals with a high copy number variation of α‐amylase perform better on the episodic memory test. We reported that neuronal α‐amylase was absent in patients with Alzheimer's disease (AD) and that this loss corresponded to increased AD pathology. In the current study, we verified these findings in a larger patient cohort and determined a similar reduction in α‐amylase immunoreactivity in the molecular layer of hippocampus in AD patients. Next, we demonstrated reduced α‐amylase concentrations in oligomer amyloid beta 42 (Aβ42) stimulated SH‐SY5Y cells and neurons derived from human‐induced pluripotent stem cells (hiPSC) with PSEN1 mutation. Reduction of α‐amylase production and activity, induced by siRNA and α‐amylase inhibitor Tendamistat, respectively, was further shown to enhance glycogen load in SH‐SY5Y cells. Both oligomer Aβ42 stimulated SH‐SY5Y cells and hiPSC neurons with PSEN1 mutation showed, however, reduced load of glycogen. Finally, we demonstrate the presence of α‐amylase within synapses of isolated primary neurons and show that inhibition of α‐amylase activity with Tendamistat alters neuronal activity measured by calcium imaging. In view of these findings, we hypothesize that α‐amylase has a glycogen degrading function within synapses, potentially important in memory formation. Hence, a loss of α‐amylase, which can be induced by Aβ pathology, may in part underlie the disrupted memory formation seen in AD patients. [ABSTRACT FROM AUTHOR]

'Indane′ and its analogues indene, 1‐indenone, and 1,3‐indandione present an attractive biological profile for the rational development of therapeutic molecules. The indane/ indene moieties contain aromatic benzene ring fused with an aliphatic cyclopentane/ cyclopentene ring, which provides a rigid bicyclic ring‐framework enriched with diverse chemical properties. The multifarious possibilities for varying the substituent pattern on these fused ring systems enable the extensive appraisal of structure‐activity relationship analysis of rationally designed therapeutic molecules deliberated at their molecular targets. Indane analogues serve as useful scaffolds for the development of efficacious pharmaceuticals and commercial drugs, including Indinavir, Sulindac, and donepezil; whereas the pharmacophores based on indane moiety such as Aminoindanes and Indanedione contribute towards the development of neuroleptics and neuroprotective molecules. Similarly, the Indane‐carboxamide derivatives present a robust candidature as CGRP receptor antagonists, while substituted Indane and its analogue Indene present a privileged profile for the development of anticancer therapeutics by targeting the multifaceted oncologic pathways. Besides, the indane natural product scaffolds serve as perspective drug candidates with marked therapeutic properties. The present review summarizes the medicinal chemistry aspects of indane nucleus and its analogues as anticancer, anti‐inflammatory, and neuroprotective agents for the coherent development of impending therapeutics. [ABSTRACT FROM AUTHOR]

Although bis‐α‐amino acids have been used to synthesize dimer models of aggregative peptides involved in neurodegenerative diseases, tris‐α‐amino acids are employed to a lesser extent for trimer models. The reported tris‐α‐amino acids substituted on the 1,3,5‐positions of an aromatic ring are not suitable for mimicking trimers due to their low flexibility and high planarity. Here, we design and synthesize two new alkyl bridged‐tris‐α‐amino acids with Fmoc protecting groups as new flexible linkers for trimer models. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is one of the most common of the multifactorial diseases and is characterized by a range of abnormal molecular processes, such as the accumulation of extracellular plaques containing the amyloid‐β (Aβ) peptides and dyshomeostasis of copper in the brain. In this study, we have investigated the effect of CuII on the aggregation of Aβ1–40 and Aβ4–40, representing the two most prevalent families of Aβ peptides, that is, the full length and N‐truncated peptides. Both families are similarly abundant in healthy and AD brains. For either of the studied peptides, substoichiometric CuII concentrations accelerated aggregation, whereas superstoichiometric CuII inhibited fibril formation, likely by stabilizing the oligomers. The addition of either Aβ4–40 or substoichiometric CuII affected the aggregation profile of Aβ1–40, by yielding shorter and thicker fibrils; amorphous aggregates were formed in the presence of a molar excess of CuII. The similarity of these two effects can be attributed to the increase in the positive charge on the Aβ N terminus, caused both by CuII complexation and N truncation at position 4. Our findings provide a better understanding of the biological Aβ aggregation process as these two Aβ species and CuII coexist and interact under physiological conditions. [ABSTRACT FROM AUTHOR]

In vitro Cu(Aβ1–x)‐induced ROS production has been extensively studied. Conversely, the ability of N‐truncated isoforms of Aβ to alter the Cu‐induced ROS production has been overlooked, even though they are main constituents of amyloid plaques found in the human brain. N‐Truncated peptides at the positions 4 and 11 (Aβ4–x and Aβ11–x) contain an amino‐terminal copper and nickel (ATCUN) binding motif (H2N‐Xxx‐Zzz‐His) that confer them different coordination sites and higher affinities for CuII compared to the Aβ1–x peptide. It has further been proposed that the role of Aβ4–x peptide is to quench CuII toxicity in the brain. However, the role of CuI coordination has not been investigated to date. In contrast to CuII, CuI coordination is expected to be the same for N‐truncated and N‐intact peptides. Herein, we report in‐depth characterizations and ROS production studies of Cu (CuI and CuII) complexes of the Aβ4–16 and Aβ11–16N‐truncated peptides. Our findings show that the N‐truncated peptides do produce ROS when CuI is present in the medium, albeit to a lesser extent than the unmodified counterpart. In addition, when used as competitor ligands (i.e. in the presence of Aβ1–16), the N‐truncated peptides are not able to fully preclude Cu(Aβ1–16)‐induced ROS production. [ABSTRACT FROM AUTHOR]

Metal dysregulation, oxidative stress, protein modification, and aggregation are factors strictly interrelated and associated with neurodegenerative pathologies. As such, all of these aspects represent valid targets to counteract neurodegeneration and, therefore, the development of metal‐binding compounds with other properties to combat multifactorial disorders is definitely on the rise. Herein, the synthesis and in‐depth analysis of the first hybrids of carnosine and 8‐hydroxyquinoline, carnoquinolines (CarHQs), which combine the properties of the dipeptide with those of 8‐hydroxyquinoline, are reported. CarHQs and their copper complexes were characterized through several techniques, such as ESI‐MS and NMR, UV/Vis, and circular dichroism spectroscopy. CarHQs can modulate self‐ and copper‐induced amyloid‐β aggregation. These hybrids combine the antioxidant activity of their parent compounds. Therefore, they can simultaneously scavenge free radicals and reactive carbonyl species, thanks to the phenolic group and imidazole ring. These results indicate that CarHQs are promising multifunctional candidates for neurodegenerative disorders and they are worthy of further studies. [ABSTRACT FROM AUTHOR]

Purpose: [18F]FDG-PET and [11C]PIB-PET are validated as neurodegeneration and amyloid biomarkers of Alzheimer's disease (AD). We used a PET staging system based on the 2018 NIA-AA research framework to compare the proportion of amyloid positivity (A+) and hypometabolism ((N)+) in cases of mild probable AD, amnestic mild cognitive impairment (aMCI), and healthy controls, incorporating an additional classification of abnormal [18F]FDG-PET patterns and investigating the co-occurrence of such with A+, exploring [18F]FDG-PET to generate hypotheses in cases presenting with clinical-biomarker "mismatches." Methods: Elderly individuals (N = 108) clinically classified as controls (N = 27), aMCI (N = 43) or mild probable AD (N = 38) were included. Authors assessed their A(N) profiles and classified [18F]FDG-PET neurodegenerative patterns as typical or non-typical of AD, performing re-assessments of images whenever clinical classification was in disagreement with the PET staging (clinical-biomarker "mismatches"). We also investigated associations between "mismatches" and sociodemographic and educational characteristics. Results: AD presented with higher rates of A+ and (N)+. There was also a higher proportion of A+ and (N)+ individuals in the aMCI group in comparison to controls, however without statistical significance regarding the A staging. There was a significant association between amyloid positivity and AD (N)+ hypometabolic patterns typical of AD. Non-AD (N)+ hypometabolism was seen in all A− (N)+ cases in the mild probable AD and control groups and [18F]FDG-PET patterns classified such individuals as "SNAP" and one as probable frontotemporal lobar degeneration. All A− (N)− cases in the probable AD group had less than 4 years of formal education and lower socioeconomic status (SES). Conclusion: The PET-based staging system unveiled significant A(N) differences between AD and the other groups, whereas aMCI and controls had different (N) staging, explaining the cognitive impairment in aMCI. [18F]FDG-PET could be used beyond simple (N) staging, since it provided alternative hypotheses to cases with clinical-biomarker "mismatches." An AD hypometabolic pattern correlated with amyloid positivity. Low education and SES were related to dementia in the absence of biomarker changes. [ABSTRACT FROM AUTHOR]

The nuclear coactivator binding domain (NCBD) of transcriptional co‐regulator CREB‐binding protein (CBP) is an example of conformationally malleable proteins that can bind to structurally unrelated protein targets and adopt distinct folds in the respective protein complexes. Here, we show that the folding landscape of NCBD contains an alternative pathway that results in protein aggregation and self‐assembly into amyloid fibers. The initial steps of such protein misfolding are driven by intermolecular interactions of its N‐terminal α‐helix bringing multiple NCBD molecules into contact. These oligomers then undergo slow but progressive interconversion into β‐sheet‐containing aggregates. To reveal the concealed aggregation potential of NCBD we used a chemically synthesized mirror‐image d‐NCBD form. The addition of d‐NCBD promoted self‐assembly into amyloid precipitates presumably due to formation of thermodynamically more stable racemic β‐sheet structures. The unexpected aggregation of NCBD needs to be taken into consideration given the multitude of protein–protein interactions and resulting biological functions mediated by CBP. [ABSTRACT FROM AUTHOR]

Purpose: Memantine is an approved drug for the treatment of Alzheimer's disease (AD). Autophagy, lysosome dysfunction, and sigma receptors have possible roles in the pathophysiology of AD. Therefore, we aimed to investigate the contribution of sigma receptors and lysosome inhibition to the neuroprotective effects of memantine against amyloid-beta (Aβ)-induced neurotoxicity in SH-SY5Y cells. Methods: We determined the neuroprotective effects of memantine (2.5 µM), dizocilpine (MK801, as a selective N-methyl-D-aspartate (NMDA) receptor antagonist) (5 μM) against Aβ25– 35 (2 μg/μL)-induced neurotoxicity. We used chloroquine (10, 20, and 40 μM) as a lysosome inhibitor and BD-1063 (1, 10, and 30 μM) as a selective sigma receptor antagonist. The MTT assay was used to measure the neurotoxicity in the SH-SY5Y cells. Data were analyzed using the one-way ANOVA. Results: Memantine (2.5 µM), dizocilpine (5 µM), chloroquine (10 and 20 µM) and BD-1063 (1, 10 and 30 µM) decreased the neurotoxic effects of Aβ on the SH-SY5Y cells. However, chloroquine (40 µM) increased the neurotoxic effects of Aβ. Cell viability in the cells treated with memantine + Aβ + chloroquine (10, 20, and 40 μM) was significantly lower than the memantine + Aβ-treated group. Moreover, cell viability in the memantine + Aβ group was higher than the memantine + Aβ + BD-1063 (10 and 30 μM) groups. Conclusion: The lysosomal and sigma receptors may contribute to the neuroprotective mechanism of memantine and other NMDA receptor antagonists. Moreover, the restoration of lysosomes function and the modulation of sigma receptors are potential targets in the treatment of AD. [ABSTRACT FROM AUTHOR]

Polydopamine (PD) and melanin species are chemically complex systems, the formation and properties of which are incompletely understood. Inspired by the role of functional amyloids in melanin biosynthesis, this paper examines the influences of the supramolecular structure of amyloids on oxidative polymerization of dopamine. Kinetic analyses on the formation of PD species in the presence of hen egg white lysozyme (HEWL) fibers or soluble HEWL revealed that both forms gave rise to the total quantity of PD species, but the rate of their formation could be accelerated only by the amyloid form. PD species formed with HEWL fibers showed a morphology of bundled fibers, whereas those with soluble HEWL had a mesh‐like structure. Amyloid fibers of recombinant Pmel17 had properties similar to those of HEWL fibers in modulating PD formation. The results presented here suggest how nature designs functionality with an amyloid structure and can help understand and engineer chemistries of other functional amyloids. [ABSTRACT FROM AUTHOR]

It has been reported that many molecules could inhibit the aggregation of Aβ (amyloid‐β) through suppressing either primary nucleation, secondary nucleation, or elongation processes. In order to suppress multiple pathways of Aβ aggregation, we screened 23 small molecules and found two types of inhibitors with different inhibiting mechanisms based on chemical kinetics analysis. Trp‐glucose conjugates (AS2) could bind with fibril ends while natural products (D3 and D4) could associate with monomers. A cocktail of these two kinds of molecules achieved co‐inhibition of various fibrillar species and avoid unwanted interference. [ABSTRACT FROM AUTHOR]

The amyloid formation of the folded segment of a variant of Exenatide (a marketed drug for type‐2 diabetes mellitus) was studied by electronic circular dichroism (ECD) and NMR spectroscopy. We found that the optimum temperature for E5 protein amyloidosis coincides with body temperature and requires well below physiological salt concentration. Decomposition of the ECD spectra and its barycentric representation on the folded‐unfolded‐amyloid potential energy surface allowed us to monitor the full range of molecular transformation of amyloidogenesis. We identified points of no return (e.g.; T=37 °C, pH 4.1, cE5=250 μm, cNaCl=50 mm, t>4–6 h) that will inevitably gravitate into the amyloid state. The strong B‐type far ultraviolet (FUV)‐ECD spectra and an unexpectedly strong near ultraviolet (NUV)‐ECD signal (Θ≈275–285 nm) indicate that the amyloid phase of E5 is built from monomers of quasi‐elongated backbone structure (φ≈−145°, ψ≈+145°) with strong interstrand Tyr↔Trp interaction. Misfolded intermediates and the buildup of "toxic" early‐stage oligomers leading to self‐association were identified and monitored as a function of time. Results indicate that the amyloid transition is triggered by subtle misfolding of the α‐helix, exposing aromatic and hydrophobic side chains that may provide the first centers for an intermolecular reorganization. These initial clusters provide the spatial closeness and sufficient time for a transition to the β‐structured amyloid nucleus, thus the process follows a nucleated growth mechanism. [ABSTRACT FROM AUTHOR]

Mounting evidence supports the role of amyloidogenesis, oxidative stress, and metal dyshomeostasis in the development of neurodegenerative disorders. Parkinson's Disease is characterized by α‐synuclein (αSyn) accumulation and aggregation in brain regions, also promoted by Cu2+. αSyn is modified by reactive carbonyl species, including acrolein (ACR). Notwithstanding these findings, the interplay between ACR, copper, and αSyn has never been investigated. Therefore, we explored more thoroughly the effects of ACR on αSyn using an approach based on LC‐MS/MS analysis. We also evaluated the influence of Cu2+ on the protein carbonylation and how the ACR modification impacts the Cu2+ binding and the production of Reactive Oxygen Species (ROS). Finally, we investigated the effects of ACR and Cu2+ ions on the αSyn aggregation by dynamic light scattering and fluorescence assays. Cu2+ regioselectively inhibits the modification of His50 by ACR, the carbonylation lowers the affinity of His50 for Cu2+ and ACR inhibits αSyn aggregation both in the presence and in the absence of Cu2+. [ABSTRACT FROM AUTHOR]

The properties of eumelanin‐like particles (EMPs) and pheomelanin‐like particles (PMPs) in regulating the process of amyloid formation of amyloid‐beta 42 (Aβ42) were examined. EMPs and PMPs are effective both in interfering with amyloid aggregation of Aβ42 and in remodeling matured Αβ42 fibers. The results suggest that some (but not all) molecular species consisting of melanin‐like particles (MPs) are responsible for their inhibiting property toward amyloid formation, and the influence is likely manifested by long‐range interactions. Incubating preformed Aβ42 fibers with catechols or MPs leads to the formation of mesh‐like, interconnected Aβ42 fibers encapsulated with melanin‐like material. MPs are kinetically more effective than catechol monomers in this process, and a detailed investigation reveals that 4,5‐dihydroxyindole, a major intermediate in the formation of melanin‐like species, and its derivatives are mainly responsible for remodeling amyloid fibers. [ABSTRACT FROM AUTHOR]

Background & Objective: It has been shown that glial activation has important role in the pathophysiology of Alzheimer’s disease. S100B is an astrocyte specific factor with deleterious effects on the neuronal and non-neuronal cells in the central nervous system. Arundic acid is an agent that inhibits the secretion and production of S100B in astrocytes. Therefore, we aimed to evaluate the contribution of S100B in the cyto-protective effects of Arundic acid against beta-amyloid in 1321N1 astrocyte cell culture. Materials & Methods: Human astrocyte cells (1321N1) were treated with beta-amyloid (200 μM) and / or Arundic acid (50 μM) for 24 hours. Cell viability was measured using the MTT (3, 4, 5- dimethylthiazole-2, 5-diphenyl tetrazolium bromide) method. The S100B protein level was measured by the ELISA method. Results: Beta-amyloid treatment reduced cell survival compared to the control-treated groups. In contrast, the addition of Arundic acid to beta-amyloid suppressed the beta-amyloid-induced cell death. Beta-amyloid also increased the S100B protein level. However, Arundic acid prevented the rise of S100B protein level induced by beta-amyloid. Conclusion: The reduction of S100B protein secretion may be involved in the protective effects of Arundic acid against the beta-amyloid induced Glio-toxicity in the astrocyte culture. [ABSTRACT FROM AUTHOR]

Nanoparticles have great potential to be used in various biomedical applications, including therapy or diagnosis of amyloid‐related diseases. The physical and chemical properties of iron oxide superparamagnetic nanoparticles (MNPs) functionalized with different amino acids (AAs), namely, with lysine (Lys), glycine (Gly), or tryptophan (Trp), have been characterized. The cytotoxicity of nanoparticles and their effect on amyloid fibrillization of lysozymes in vitro was also verified. The AA‐MNPs under study are nontoxic to human SHSY5Y neuroblastoma cells. Moreover, the AA‐MNPs were able to significantly inhibit lysozyme amyloid fibrillization and destroy amyloid fibrils. Kinetic studies revealed that the presence of AA‐MNPs affected lysozyme fibrillization, namely, the lag phase and steady‐state phase of the growth curves. The most effective activities were observed for Trp‐MNPs, which revealed the importance of aromatic rings in the structure of AAs used as coating agents. The obtained results indicate the possible application of these AA‐MNPs in the treatment of amyloid diseases associated with lysozyme or other amyloidogenic proteins. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that disparate pathways from systemic metabolism to retinoic acid/vitamin A signaling can contribute to Alzheimer's disease (AD) pathobiology. Retinol binding protein 4 (RBP4) is an adipocyte-secreted hormone (adipokine) that regulates insulin signaling and is also a key transporter of retinoic acid and its derivatives. While earlier studies found alterations in the brain and cerebrospinal fluid (CSF) levels of RBP4 in later stages of AD, it is not known if circulating RBP4 is altered in preclinical AD or if it can be a useful biomarker for cognitive decline and dementia. In this study, we used ELISA to measure plasma RBP4 levels in cognitively normal individuals (Clinical Dementia Rating, CDR 0). Subjects with preclinical AD were identified by previously established CSF criteria (preclinical AD: 20 men, 18 women; control: 45 men, 73 women). Plasma RBP4 levels were similar between preclinical AD and control subjects in men (preclinical AD: 30.0±7.4 μg/mL; control: 30.0±8.7 μg/mL; p = 0.97) and women (preclinical AD 30.9±7.9 μg/mL; control: 31.7±8.5 μg/mL; p = 0.72). Additionally, RBP4 levels were not related to body mass index or CSF AD biomarkers levels of amyloid-β42, tau, or phosphorylated tau. Baseline plasma RBP4 levels were not associated with the incidence of CDR ≥0.5, all-cause dementia, or AD diagnosis. Collectively, these results do not support peripheral RBP4 as a clinical biomarker or therapeutic target in the early stages of AD. [ABSTRACT FROM AUTHOR]

Abstract: Because mice and rats do not naturally develop Alzheimer's disease, genetically modified animals are required to study this pathology. This striking difference in terms of disease onset could be due to three alterations in the murine sequence (R5G, Y10F and H13R) of the amyloid‐β peptide with respect to the human counterpart. Whether the metal‐ion binding properties of the murine peptide are at the origin of such different amyloidogenicity of the two peptides is still an open question. Herein, the main zinc binding site to the murine amyloid‐β at physiological pH has been determined through the combination of several spectroscopic and analytical methods applied to a series of six peptides with one or two of the key mutations. These results have been compared with the zinc binding site encountered in the human peptide. A coordination mechanism that demonstrates the importance of the H13R and R5G mutations in the different zinc environments present in the murine and human peptides is proposed. The nature of the minor zinc species present at physiological pH is also suggested for both peptides. Finally, the biological relevance and fallouts of the differences determined in zinc binding to human versus murine amyloid‐β are also discussed. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a severe neurodegenerative disorder for which the exact etiology is largely unknown. An increasingly recognized and investigated notion is the pathogenic role of mitochondrial dysfunction in AD. We assessed mitochondrial oxidative-phosphorylation (OXPHOS) enzyme activities in the APPswe/PS1ΔE9 mouse model from 4.5 to 14 months of age. We show an age-dependent decrease in mitochondrial complex-II activity starting at 9 months in APP/PS1 mice. Other enzymes of the OXPHOS do not show any alterations. Since amyloid-β (Aβ) plaques are already present from 4 months of age, mitochondrial dysfunction likely occurs downstream of Aβ pathology in this mouse model. [ABSTRACT FROM AUTHOR]

The Amyloid β peptide (Aβ) is a main component of senile plaques in Alzheimer's disease. Currently, NADPH oxidase (NOX) and mitochondria are considered as primary sources of ROS induced by Aβ. However, the contribution of NOX and mitochondria to Aβ-induced ROS generation has not been well defined. To delineate the relative involvement of NOX and mitochondria in Aβ-induced ROS generation and neuronal death in mouse cortical cultures, we examined the effect of NOX inhibitors, apocynin and AEBSF, and the mitochondria-targeted antioxidants (MTAs), mitotempol and mitoquinone, on Aβ-induced ROS generation and neuronal deaths. Cell death was assessed by measuring lactate dehydrogenase efflux in bathing media at 24 and 48 hrs after exposure to Aβ1-42. Aβ1-42 induced dose- and time-dependent neuronal deaths in cortical cultures. Treatment with 20 μM Aβ1-42 markedly and continuously increased not only the DHE fluorescence (intracellular ROS signal), but also the DHR123 fluorescence (mitochondrial ROS signal) up to 8 hrs. Treatment with apocynin or AEBSF selectively suppressed the increase in DHE fluorescence, while treatment with mitotempol selectively suppressed the increase in DHR123 fluorescence. Each treatment with apocynin, AEBSF, mitotempol or mitoquinone significantly attenuated the Aβ1-42-induced neuronal deaths. However, any combined treatment with apocynin/AEBSF and mitotempol/mitoquinone failed to show additive effects. These findings indicate that 20 μM Aβ1-42 induces oxidative neuronal death via inducing mitochondrial ROS as well as NOX activation in mixed cortical cultures, but combined suppression of intracellular and mitochondrial ROS generation fail to show any additive neuroprotective effects against Aβ neurotoxicity. [ABSTRACT FROM AUTHOR]

Sleep deprivation is a common complaint in modern societies. Insufficient sleep has increased the risk of catching neurodegenerative diseases such as Alzheimer's. Several studies have indicated that restricted sleep increases the level of deposition of ß-amyloid and formation of neurofibrillary tangles, the major brain microstructural hallmarks for Alzheimer disease. The mechanisms by which sleep deprivation affects the pathology of Alzheimer disease has not yet been fully and definitively identified. However, risk factors like apolipoprotein E risk alleles, kinases and phosphatases dysregulation, reactive oxygen species, endoplasmic reticulum damages, glymphatic system dysfunctions and orexinergic system inefficacy have been identified as the most important factors which mediates between the two conditions. In this review, these factors are briefly discussed. [ABSTRACT FROM AUTHOR]

Abstract: Inhibition of abnormal protein self‐aggregation is an attractive strategy against amyloidogenic diseases, but has found limited success due to the complexity of protein self‐assembly, the absence of fully reproducible aggregation assays, and the scarce knowledge of the inhibition mechanisms by small molecules. In this context, catechol‐containing compounds may lead to covalent adducts with amyloid fibrils that interfere with the aggregation process. In particular, the covalent adduct formed between the oxidized form of (+)‐taxifolin and an β‐amyloid (Aβ42) suggests the involvement of a specific recognition motif that enables the chemical reaction with Aβ42. In this study, we have examined the mechanisms implicated in the aza‐Michael addition of the o‐quinone species of (+)‐taxifolin with Aβ42 fibrils. The results support the binding of (+)‐taxifolin to the hydrophobic groove delimited by the edges defined by Lys16 and Glu22 residues in the fibril. The chemical reaction proceeds through the nucleophilic attack of the deprotonated amino group of a Lys16 residue in a process activated by the interaction between the o‐quinone ring with a vicinal Lys16 residue, as well as by a water‐assisted proton transfer, which is the rate‐limiting step of the reaction. This specific inhibition mechanism, which may explain the enhanced anti‐aggregating activity of oxidized flavonoids compared to fresh compounds, holds promise for developing disease‐modifying therapies. [ABSTRACT FROM AUTHOR]

Abstract: Transition metal ions often interact with disordered proteins. The affinity is high enough to compete with structured proteins, but the catalytic activity of the metal centre is often out of control and, therefore, potentially dangerous for cells. An example is a single copper ion interacting with the amyloid‐β (Aβ) peptide and triplet dioxygen, an interaction that is fundamental in producing reactive oxygen species in neurodegeneration. High‐throughput modelling of the Cu‐Aβ‐O2 system was performed with the aim of providing a tool to dissect the structural features that characterise dangerous Cu‐based catalysts in neurodegeneration. This study showed that the production of superoxide is a process with low‐energy intermediate species, once a small population of high‐energy CuI‐Aβ complex is formed. This population is enhanced when Cu bridges two different peptides in 1:1 Cu:Aβ dimers. Despite the bias for high‐energy reduced reactant species, the reduction of CuII‐Aβ product by superoxide can also occur, in addition to that by ascorbate, because the structural disorder produces a small population of oxidant species characterised by unstable CuII coordination, coexisting with the most abundant reductant species, characterised by stable CuII coordination. [ABSTRACT FROM AUTHOR]

β-Amyloid peptide (Aβ) is the main component of senile plaques in patients with Alzheimer's disease, and is known to be a main pathogenic factor of the disease. Recent evidence indicates that activation of NADPH oxidase (NOX) in microglia or astrocytes may be a source of Aβ-induced reactive oxygen species (ROS). We investigated the role of neuronal NOX in Aβ-induced neuronal death in mouse mixed cortical cultures. Cell death was assessed by measuring lactate dehydrogenase efflux to bathing media 24 or 48 hr after exposure to Aβ25-35, a fragment of Aβ with an equivalent neurotoxic effect. Aβ25-35 induced neuronal death in concentration- and time- dependent manners with apoptotic features. Neuronal death was significantly attenuated, not only by anti-apoptotic drugs, such as z-VAD-fmk and cycloheximide, but also by antioxidants, such as trolox, ascorbic acid, and epigallocatethin gallate. We also demonstrated that treatment with 20 μM Aβ25-35 increased fluorescent signals in mixed cortical cultures, but produced only weak signals in pure astrocyte cultures in the presence of 2′,7′-dichlorofluorescin diacetate (DCF-DA), an indicator for intracellular ROS. Increased DCF-DA fluorescence was markedly inhibited, not only by trolox, but also by selective NOX inhibitors, such as apocynin and AEBSF. Western blot analyses revealed that Aβ25-35 increased the expression of gp91phox, a main subunit of NOX in cells. The above antioxidants, apocynin, and AEBSF significantly attenuated neuronal death induced by Aβ25-35. Furthermore, the gp91phox-specific siRNA-based knockdown of NOX significantly inhibited neuronal death. These results suggest that activation of neuronal NOX is involved in Aβ25-35-induced neuronal death. [ABSTRACT FROM AUTHOR]

The role of aromatic and nonaromatic amino acids in amyloid formation has been elucidated by calculating interaction energies between β-sheets in amyloid model systems using density functional theory (B3LYP-D3/6-31G*). The model systems were based on experimental crystal structures of two types of amyloids: (1) with aromatic amino acids, and (2) without aromatic amino acids. Data show that these two types of amyloids have similar interaction energies, supporting experimental findings that aromatic amino acids are not essential for amyloid formation. However, different factors contribute to the stability of these two types of amyloids. In the former, the presence of aromatic amino acids significantly contributes to the strength of interactions between side chains; interactions between aromatic and aliphatic side chains are the strongest, followed by aromatic-aromatic interactions, while aliphatic-aliphatic interactions are the weakest. In the latter, that is, the amyloids without aromatic residues, stability is provided by interactions of aliphatic side chains with the backbone and, in some cases, by hydrogen bonds. [ABSTRACT FROM AUTHOR]

γ-Secretase is a four-component membrane-embedded aspartyl protease involved in the final cleavage step of the amyloid precursor protein (APP) to generate the amyloid-β (Aβ) peptide. Different amino-acid lengths of Aβ peptide can be produced by this enzyme, of which the oligomerization and aberrant accumulation of the product containing 42 amino acids (Aβ42) has been associated with the development and formation of amyloid-β plaques in the brain of Alzheimer's disease (AD) patients. Herein, we review some of the most important topics associated with the structure and activity of γ-secretase and the factors that alter the substrate cleavage pattern, critical to the formation of the different isoforms of the amyloid-β peptides. [ABSTRACT FROM AUTHOR]