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Background: Alzheimer's disease (AD) is a progressive neurocognitive disorder. There is no cure for AD. Maintenance on intracellular levels of nicotinamide adenine dinucleotide (NAD+) has been reported to be a promising therapeutic strategy for the treatment of AD. NAD+ precursors that represent candidate targets include nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR)., Objective: This systematic review provides insights into the potential therapeutic value of NAD+ precursors including NMN and NR, for the treatment of AD using preclinical and clinical studies published in the last 5 years., Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) protocol was followed to systematically search the literature using two databases., Results: We found 3 studies that used NMN to treat AD in preclinical murine models. However, human clinical trials using NMN as a therapeutic intervention in AD was not available in the current literature. We also found 4 studies that investigated the potential benefits of NR for the treatment of AD in preclinical models. We also found 2 human clinical trials that showed marked improvements in plasma and neuroimaging biomarkers, and cognitive measures following supplementation with NR., Conclusions: Results of preclinical and clinical studies confirm the potential benefits of NAD+ precursors for the treatment of AD. However, further clinical studies are required to confirm the increasingly important value of NAD+ precursors as effective pharmacological interventions in the clinic.

Background: Alzheimer's disease (AD) is a progressive neurodegenerative pathology that leads to cognitive decline and dementia, particularly in older adults. It disrupts brain structure and function, with neurotoxic amyloid-β (Aβ) plaques being a primary pathological hallmark. Pharmacotherapeutic trials targeting Aβ and other AD pathological features aim to slow disease progression. Functional magnetic resonance imaging (fMRI) is a non-invasive tool that visualizes brain functional activity, aiding in evaluating the efficacy of AD drugs in clinical trials., Objective: This mini-review explores the role of fMRI in evaluating the impact of AD pharmacotherapeutic clinical trials conducted in the past seven years., Methods: Literature was systematically searched using two databases. The risk of bias was assessed with the Revised Cochrane risk-of-bias tool (RoB-2) for randomized clinical trials (RCTs)., Results: Four studies using fMRI to investigate AD drug efficacy were included. Cholinesterase, glutamatergic, and serotonergic drugs showed significant positive effects on brain functional activity, especially within the default mode network. Functional connectivity (FC) changes due to drug intake were linked to cerebellar and cholinergic decline in AD, correlating with improved global cognition and fMRI task performance., Conclusions: Recent RCTs demonstrate fMRI's ability to reveal longitudinal FC pattern changes in response to AD drug treatments across disease stages. Positive FC changes in distinct brain regions suggest potential compensatory mechanisms from drug intake. However, these drugs have limited efficacy, necessitating further research to enhance specific pharmacological interventions for clinical application.

Aim: Quantum dots (QDs) are nanoparticles that have an emerging application as theranostic agents in several neurodegenerative diseases. The advantage of QDs as nanomedicine is due to their unique optical properties that provide high sensitivity, stability and selectivity at a nanoscale range. Objective: To offer renewed insight into current QD research and elucidate its promising application in Alzheimer's disease (AD) diagnosis and therapy. Methods: A comprehensive literature search was conducted in PubMed and Google Scholar databases that included the following search terms: 'quantum dots', 'blood-brain barrier', 'cytotoxicity', 'toxicity' and 'Alzheimer's disease'; PRISMA guidelines were adhered to. Results: Thirty-four publications were selected to evaluate the ability of QDs to cross the blood-brain barrier, potential toxicity and current AD diagnostic and therapeutic applications. Conclusion: QD's unique optical properties and versatility to conjugate to various biomolecules, while maintaining a nanoscale size, render them a promising theranostic tool in AD.

Lipidomics research could provide insights of pathobiological mechanisms in Alzheimer's disease. This study explores a battery of plasma lipids that can differentiate Alzheimer's disease (AD) patients from healthy controls and determines whether lipid profiles correlate with genetic risk for AD. AD plasma samples were collected from the Sydney Memory and Ageing Study (MAS) Sydney, Australia (aged range 75-97 years; 51.2% male). Untargeted lipidomics analysis was performed by liquid chromatography coupled-mass spectrometry (LC-MS/MS). We found that several lipid species from nine lipid classes, particularly sphingomyelins (SMs), cholesterol esters (ChEs), phosphatidylcholines (PCs), phosphatidylethanolamines (PIs), phosphatidylinositols (PIs), and triglycerides (TGs) are dysregulated in AD patients and may help discriminate them from healthy controls. However, when the lipid species were grouped together into lipid subgroups, only the DG group was significantly higher in AD. ChEs, SMs, and TGs resulted in good classification accuracy using the Glmnet algorithm (elastic net penalization for the generalized linear model [glm]) with more than 80% AUC. In general, group lipids and the lipid subclasses LPC and PE had less classification accuracy compared to the other subclasses. We also found significant increases in SMs, PIs, and the LPE/PE ratio in human U251 astroglioma cell lines exposed to pathophysiological concentrations of oligomeric Aβ 42 . This suggests that oligomeric Aβ 42 plays a contributory, if not causal role, in mediating changes in lipid profiles in AD that can be detected in the periphery. In addition, we evaluated the association of plasma lipid profiles with AD-related single nucleotide polymorphisms (SNPs) and polygenic risk scores (PRS) of AD. We found that FERMT2 and MS4A6A showed a significantly differential association with lipids in all lipid classes across disease and control groups. ABCA7 had a differential association with more than half of the DG lipids (52.63%) and PI lipids (57.14%), respectively. Additionally, 43.4% of lipids in the SM class were differentially associated with CLU. More than 30% of lipids in ChE, PE, and TG classes had differential associations with separate genes (ChE-PICALM, SLC24A4, and SORL1; PE-CLU and CR1; TG-BINI) between AD and control group. These data may provide renewed insights into the pathobiology of AD and the feasibility of identifying individuals with greater AD risk.

Introduction: The accumulation of oxidative stress, neuroinflammation and abnormal aggregation of amyloid β-peptide (Aβ) have been shown to induce synaptic dysfunction and memory deficits in Alzheimer's disease (AD). Cellular depletion of the major endogenous antioxidant Glutathione (GSH) has been linked to cognitive decline and the development of AD pathology. Supplementation with γ-glutamylcysteine (γ-GC), the immediate precursor and the limiting substrate for GSH biosynthesis, can transiently augment cellular GSH levels by bypassing the regulation of GSH homeostasis., Methods: In the present study, we investigated the effect of dietary supplementation of γ-GC on oxidative stress and Aβ pathology in the brains of APP/PS1 mice. The APP/PS1 mice were fed γ-GC from 3 months of age with biomarkers of apoptosis and cell death, oxidative stress, neuroinflammation and Aβ load being assessed at 6 months of age., Results: Our data showed that supplementation with γ-GC lowered the levels of brain lipid peroxidation, protein carbonyls and apoptosis, increased both total GSH and the glutathione/glutathione disulphide (GSH/GSSG) ratio and replenished ATP and the activities of the antioxidant enzymes (superoxide dismutase (SOD), catalase, glutamine synthetase and glutathione peroxidase (GPX)), the latter being a key regulator of ferroptosis. Brain Aβ load was lower and acetylcholinesterase (AChE) activity was markedly improved compared to APP/PS1 mice fed a standard chow diet. Alteration in brain cytokine levels and matrix metalloproteinase enzymes MMP-2 and MMP-9 suggested that γ-GC may lower inflammation and enhance Aβ plaque clearance in vivo. Spatial memory was also improved by γ-GC as determined using the Morris water maze., Conclusion: Our data collectively suggested that supplementation with γ-GC may represent a novel strategy for the treatment and/or prevention of cognitive impairment and neurodegeneration., (Crown Copyright © 2020. Published by Elsevier Ltd. All rights reserved.)

Purpose of Review: The present review aims to address the clinical benefits of using nicotinamide riboside, a precursor to the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD+) as a therapeutic agent to attenuate age-related cognitive decline., Recent Findings: Oral supplementation with nicotinamide riboside can inhibit the accumulation of pathological hallmarks of Alzheimer's disease and improve learning and memory in various murine models for dementia. Nicotinamide riboside can also reduce DNA damage, neuroinflammation, apoptosis, and improved hippocampal synaptic plasticity in diabetic mice, and another Alzheimer's disease mouse model. The cognitive benefits of nicotinamide riboside in Alzheimer's disease models may be modulated in part by upregulation of proliferator-activated-γ coactivator 1α-mediated β-secretase 1(BACE-1) ubiquitination and degradation, preventing Aβ production in the brain. Nicotinamide riboside also maintained blood-brain barrier integrity and maintained the gut microbiota in a mouse model for cerebral small vessel disease and alcohol-induced depression, respectively. Oral nicotinamide riboside has been shown to be bioavailable and well tolerated in humans with limited adverse effects compared to other NAD+ precursors., Summary: Oral nicotinamide riboside may represent a promising stratagem to improve cognitive decline during 'normal' ageing, Alzheimer's disease and other diseases. Results from recent clinical trials are needed to enumerate the preclinical benefits in humans.

Plasma fatty acids have been reported to be dysregulated in mild cognitive impairment (MCI) and Alzheimer's disease (AD), though outcomes are not always consistent, and subject numbers often small. Our aim was to use a meta-analysis and systematic review approach to identify if plasma fatty acid dysregulation would be observed in case control studies of AD and MCI. Six databases were searched for studies reporting quantified levels of fatty acids in MCI and/or AD individuals, relative to cognitively normal controls. Docosahexaenoic (DHA) and vaccenic acids were significantly lower and higher respectively in MCI relative to controls. Total fatty acids were 27.2% lower in AD relative to controls, and this was reflected almost uniformly in all specific fatty acids in AD. Changes to plasma/serum fatty acids were identified in both MCI and AD relative to age and gender matched controls. Differences were greatest in AD, in both total number of fatty acids significantly altered, and the degree of change. Docosahexaenoic acid was lower in both MCI and AD, suggesting that it may be a driver of pathology., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background and Purpose: Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD., Experimental Approach: We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD + precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD + /NADH ratio., Key Results: The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD + to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD + /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ 1-40 levels; and favourable blood-brain barrier-permeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD + was dependent on the electron-withdrawing or electron-donating substituents on the aldehyde- or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electron-donating groups were required for NAD + donation and low cytotoxicity., Conclusions and Implications: The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD + precursors for AD treatment., (© 2020 The British Pharmacological Society.)

Nanoparticle (NP)-based magnetic contrast agents have opened the potential for MRI to be used for early diagnosis of Alzheimer's disease (AD). This article aims to review the current progress of research in this field. A comprehensive literature search was performed based on PubMed, Medline, EMBASE, PsychINFO and Scopus databases using the following terms: 'Alzheimer's disease' AND 'nanoparticles' AND 'Magnetic Resonance Imaging.' 33 studies were included that described the development and utility of various NPs for AD imaging, including their coating, functionalization, MRI relaxivity, toxicity and bioavailability. NPs show immense promise for neuroimaging, due to superior relaxivity and biocompatibility compared with currently available imaging agents. Consistent reporting is imperative for further progress in this field.

Background: Numerous studies have reported on cerebrospinal fluid (CSF) and blood biomarkers of Alzheimer's disease (AD); however, to date, none has compared biomarker patterns across the early-onset subtypes, i.e., early onset sporadic AD (EOsAD) and autosomal dominant AD (ADAD), qualitatively and quantitatively., Objective: To compare the fluid biomarker patterns in early-onset subtypes of AD; EOsAD and ADAD., Methods: Six scientific databases were searched for peer-reviewed research publications. The total number of individuals used in all the meta-analysis were 2,427, comprised of 1,337 patients and 1,090 controls., Results: In the subset of EOsAD cases without APP, PSEN1/PSEN2 mutations, CSF Aβ42 and tau levels were higher when compared to the EOsAD group as a whole. Prevalence of the APOEɛ4 allele was more elevated in EOsAD relative to controls, and not significantly elevated in ADAD cases., Conclusion: Established CSF biomarkers confirmed quantitative differences between variants of EOAD. EOsAD is enriched with APOEɛ4, but the level is not higher than generally reported in late-onset AD. The results prompt further exploration of the etiopathogenesis of EOsAD, which accounts for ∼4-10% of all AD cases, but the reasons for the early onset remain poorly understood.

Background: Cerebral small vessel disease (CSVD) comprises a variety of disorders affecting small arteries and microvessels of the brain, manifesting as white matter hyperintensities (WMHs), cerebral microbleeds (CMBs), and deep brain infarcts. In addition to its contribution to vascular dementia (VaD), it has also been suggested to contribute to the pathogenesis of Alzheimer's disease (AD)., Method: A systematic review of the literature available on Medline, Embase and Pubmed was undertaken, whereby CSVD was divided into WMHs, CMBs and deep brain infarcts. Biomarkers of AD pathology in the cerebrospinal fluid or plasma, or positron emission tomographic imaging for amyloid and/or tau deposition were used for AD pathology., Results: A total of 4117 articles were identified and 41 articles met criteria for inclusion. These consisted of 17 articles on vascular risk factors for clinical AD, 21 articles on Aβ pathology and 15 articles on tau pathology, permitting ten meta-analyses. CMBs or lobar CMBs were associated with pooled relative risk (RR) of AD at 1.546, (95%CI 0.842-2.838, z = 1.41 p = 0.160) and 1.526(95%CI 0.760-3.063, z = 1.19, p = 0.235) respectively, both non-significant. Microinfarcts were associated with significantly increased AD risk, with pooled odds ratio OR at 1.203(95%CI 1.014-1.428, 2.12 p = 0.034). Aβ pathology was significantly associated with WMHs in AD patients but not in normal age-matched controls. The pooled β (linear regression) for total WMHs with CSF Aβ42 in AD patients was -0.19(95%CI -0.26-0.11, z = 4.83 p = 0.000) and the pooled r (correlation coefficient) for WMHs and PiB in the normal population was -0.10 (95%CI -0.11-0.30, 0.93 p = 0.351). CMBs were significantly associated with Aβ pathology in AD patients. The pooled standardized mean difference (SMD) was -0.453, 95%CI -0.697- -0.208, z = 3.63 p = 0.000. There was no significant relationship between the incidence of lacunes and levels of CSFAβ, with a pooled β of 0.057 (95%CI -0.050-0.163, z = 1.05 p = 0.295). No significant relationship was found between CMBs and the levels of CSFt-tau/CSFp-tau in AD patients (-0.014, 95%CI -0.556-0.529, z = 0.05 p = 0.960; -0.058, 95%CI -0.630-0.515, z = 0.20 p = 0.844) and cortical CMBs and CSF p-tau in the normal population (0.000, 95%CI -0.706-0.706, z = 0.00 p = 0.999)., Conclusions: Some CSVD markers were significantly associated with clinical AD pathology and may be associated with Aβ/tau pathology. WMHs and microinfarcts were associated with increased risk of AD. It remains unclear whether they precede or follow AD pathology., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) is characterized by multiple pathological hallmarks, including β-amyloid aggregation, oxidative stress, and metal dys-homeostasis. In the absence of treatments addressing its multi-factorial pathology, we designed novel multi-functional adamantane-based semicarbazones and hydrazones (1-12) targeting AD hallmarks. Of these, 2-pyridinecarboxaldehyde (N-adamantan-1-yl)benzoyl-4-amidohydrazone (10) was identified as the lead compound, which demonstrated: (1) pronounced iron chelation efficacy; (2) attenuation of CuII-mediated β-amyloid aggregation; (3) low cytotoxicity; (4) inhibition of oxidative stress; and (5) favorable characteristics for effective blood-brain barrier permeation. Structure-activity relationships revealed that pyridine-derived hydrazones represent a promising pharmacophore for future design strategies due to their ability to bind critical FeII pools. Collectively, the unique multi-functional activity of these agents provides a novel therapeutic strategy for AD treatment.

Purpose of Review: The current review discusses the biology and metabolism of the essential pyridine nucleotide nicotinamide adenine dinucleotide (NAD+) in the central nervous system. We also review recent work suggesting important neuroprotective effects that may be associated with the promotion of NAD+ levels through NAD+ precursors against Alzheimer's disease., Recent Findings: Perturbations in the physiological homoeostatic state of the brain during the ageing process can lead to impaired cellular function, and ultimately leads to loss of brain integrity and accelerates cognitive and memory decline. Increased oxidative stress has been shown to impair normal cellular bioenergetics and enhance the depletion of the essential nucleotides NAD+ and ATP. NAD+ and its precursors have been shown to improve cellular homoeostasis based on association with dietary requirements, and treatment and management of several inflammatory and metabolic diseases in vivo. Cellular NAD+ pools have been shown to be reduced in the ageing brain, and treatment with NAD+ precursors has been hypothesized to restore these levels and attenuate disruption in cellular bioenergetics., Summary: NAD+ and its precursors may represent an important therapeutic strategy to maintain optimal cellular homoeostatic functions in the brain. NAD+ precursors are available in a variety of foods and may be translated to the clinic in the form of supplements.

The brain is highly enriched in lipids, and an intensive study of these lipids may be informative, not only of normal brain function but also of changes with age and in disease. In recent years, the development of highly sensitive mass spectrometry platforms and other high-throughput technologies has enabled the discovery of complex changes in the entire lipidome. This lipidomics approach promises to be a particularly useful tool for identifying diagnostic biomarkers for early detection of age-related neurodegenerative disease, such as Alzheimer's disease (AD), which has till recently been limited to protein- and gene-centric approaches. This review highlights known lipid changes affecting the AD brain and presents an update on the progress of lipid biomarker research in AD. Important considerations for designing large-scale lipidomics experiments are discussed to help standardize findings across different laboratories, as well as challenges associated with moving toward clinical application., (Copyright © 2017 the Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)

Alzheimer's disease (AD) is the leading cause of dementia in the elderly and is characterized by progressive cognitive and memory deficits. The pathological hallmarks of AD include extracellular senile plaques and intracellular neurofibrillary tangles. Although several mechanisms have been used to explain the underlying pathogenesis of AD, current treatment regimens remain inadequate. The neuroprotective effects of the polyphenolic stilbene resveratrol (3,5,4'-trihydroxy-trans-stilbene) have been investigated in several in vitro and in vivo models of AD. The current review discusses the multiple potential mechanisms of action of resveratrol on the pathobiology of AD. Moreover, due to the limited pharmacokinetic parameters of resveratrol, multiple strategies aimed at increasing the bioavailability of resveratrol have also been addressed.

Purpose of Review: Alzheimer's disease is the most common cause of dementia. There are still no disease modifying treatments that can cure or slow disease progression. Recently, Alzheimer's disease researchers have attempted to improve early detection and diagnostic criteria for Alzheimer's disease, with the rationale that treatment of disease, or even prevention, may be more successful during the early preclinical stages of Alzheimer's disease when neurodegenerative damage is not as widespread. As the brain has a high lipid content, lipidomics may offer novel insights into the underlying pathogenesis of Alzheimer's disease. This review reports on recent developments in the relatively unexplored field of lipidomics in Alzheimer's disease, including novel biomarkers and pathomechanisms of Alzheimer's disease., Recent Findings: Numerous biomarker panels involving phospholipids and sphingolipids have been proposed, indicating perturbed lipid metabolism in early stages of Alzheimer's disease. Future strategies targeting these metabolic changes through dietary supplementation could have therapeutic benefits in at-risk individuals., Summary: Dysregulated lipid metabolism could reflect pathological changes in synaptic function and neuronal membranes, leading to cognitive decline. However, extensive validation in large independent cohorts is required before lipid biomarkers can be used clinically to assess Alzheimer's disease risk and progression.

Objective: Accumulating evidence suggests that the eye can be used in the assessment of early on-set Alzheimer's disease (AD). The eye offers a natural window to the brain through the retina. The retina and brain share common developmental origins and patho-physiological origins and mechanisms, having been sequestered from it during early development, but retaining its connections with the brain via the optic nerve. Therefore, it is well understood that neurological abnormalities have a direct profound impact on the retina. Recent studies suggest an array of physiological and pathological changes in the retina in dementia and specifically in AD. There are also reports on imaging the two hallmark proteins of the disease, extracellular amyloid beta peptides and intracellular hyper phosphorylated tau protein, as a proxy to neuroimaging., Results: In this review, we summarise retinal structural, functional and vascular changes reported to be associated with AD. We also review techniques employed to image these two major hall mark proteins of AD and their relevance for early detection of AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Neurodegenerative diseases, namely Alzheimer's disease and Parkinson's disease represent a deleterious impact worldwide. Despite extensive preclinical and clinical research in neurodegenerative disorders, therapeutic strategies aimed at the prevention and chronic treatment of neurodegenerative conditions have not been successfully translated to the clinic. Therefore, the identification of novel pharmacological intervention derived from natural products is warranted. Nobiletin and tangeretin are important citrus flavonoids derived from the peel and other parts of Citrus L. genus, and have been shown to exhibit neuroprotective effects in several in vitro and in vivo studies. Apart from there antioxidant and anti-inflammatory effects, nobiletin and tangeretin have been shown to attenuate cholinergic deficits, reduce the abnormal accumulation of neurotoxic amyloid-beta peptides, reverse N-methyl- D-aspartate (NMDA) receptor hypofunction, ameliorate ischemic injury, inhibit hyperphosphorylation of tau protein, enhance neprilysin levels, modulate several signaling cascades, and protect against 1-methyl-4-phenylpyridinium (MPP(+)) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity. Taken together, these naturally occurring phytochemicals may represent beneficial drug candidates for the treatment and prevention of Alzheimer's and Parkinson's disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Tannic acid (TA) is a naturally occurring plant-derived polyphenol found in several herbaceous and woody plants, including legumes, sorghum, beans, bananas, persimmons, rasberries, wines and a broad selection of teas. Clinically, TA has strong antioxidant/free radical scavenging, antiinflammatory, anti-viral/bacterial, and anti-carcinogenic properties. While the aetiology of Alzheimer's disease (AD) remains unclear, this complex multifactorial neurodegenerative disorder remains the most common form of dementia, and is a growing public health concern worldwide. The neuroprotective effects of TA against AD have been shown in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that TA is also a natural inhibitor of β-secretase (BACE1) activity and protein expression. BACE1 is the primary enzyme responsible for the production and deposition of Aβ peptide. TA also destabilises neurotoxic amyloid beta (Aβ) fibrils in vitro. Apart from its effects on the Aβ cascade, TA can also inhibit the in vitro aggregation of tau peptide, a core component of intracellular neurofibrillary tangles (NFTs). This review summarizes the relevance of TA and TA-related vegetable extracts (tannins) in the pathogenesis of AD and its enzymatic targets. It also highlights the significance of TA as an important lead compound against AD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Alzheimer disease (AD) is one of the most common forms of dementia in the elderly. Several reports have suggested neurotoxic effects of amyloid beta protein (Aβ) and role of oxidative stress in AD. Figs are rich in fiber, copper, iron, manganese, magnesium, potassium, calcium, vitamin K, and are a good source of proanthocyanidins and quercetin which demonstrate potent antioxidant properties. We studied the effect of dietary supplementation with 4% figs grown in Oman on the memory, anxiety, and learning skills in APPsw/Tg2576 (Tg mice) mice model for AD. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4 months and after 15 months using the Morris water maze test, rota-rod test, elevated plus maze test, and open-field test. Tg mice that were fed a control diet without figs showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial, position discrimination learning ability, and motor coordination compared to the wild-type control mice on the same diet, and Tg mice fed on 4% fig diet supplementation for 15 months. Our results suggest that dietary supplementation of figs may be useful for the improvement of cognitive and behavioral deficits in AD.

Alzheimer's Disease (AD) is a progressive neurodegenerative disorder characterized by extracellular plaques containing abnormal Amyloid Beta (Aβ) aggregates, intracellular neurofibrillary tangles containing hyperphosphorylated tau protein, microglia-dominated neuroinflammation, and impairments in synaptic plasticity underlying cognitive deficits. Therapeutic strategies for the treatment of AD are currently limited. In this study, we investigated the effects of dietary supplementation of 4% pomegranate extract to a standard chow diet on neuroinflammation, and synaptic plasticity in APPsw/Tg2576 mice brain. Treatment with a custom mixed diet (pellets) containing 4% pomegranate for 15 months ameliorated the loss of synaptic structure proteins, namely PSD-95, Munc18-1, and SNAP25, synaptophysin, phosphorylation of Calcium/Calmodulin Dependent Protein Kinase IIα (p-CaMKIIα/ CaMKIIα), and phosphorylation of Cyclic AMP-Response Element Binding Protein (pCREB/CREB), inhibited neuroinflammatory activity, and enhanced autophagy, and activation of the phophoinositide-3-kinase-Akt-mammalian target of rapamycin signaling pathway. These neuroprotective effects were associated with reduced β-site cleavage of Amyloid Precursor Protein in APPsw/Tg2576 mice. Therefore, long-term supplementation with pomegranates can attenuate AD pathology by reducing inflammation, and altering APP-dependent processes.

Rhodiola rosea L. (roseroot) is a common member of the family Crassulaceae, known as one of the most important popular medicinal plants in the northern region of Europe. The roots of R. rosea possess a wide range of pharmacological activities such as antioxidant, antiinflammatory, anticancer, cardioprotective, and neuroprotective effects that are because of the presence of different phytochemicals such as phenols and flavonoids. In addition, the presence of salidroside, rosavins, and p-tyrosol are responsible for its beneficial effects for the treatment of on depression, fatigue, and cognitive dysfunction. A plethora of studies report that R. rosea has potent neuroprotective effects through the suppression of oxidative stress, neuroinflammation, and excitotoxicity in brain tissues and antagonism of oncogenic p21-activated kinase. However, to our knowledge, no review articles have been published addressing the neuroprotective effects of R. rosea. Therefore, the present article aims at critically reviewing the available literature on the beneficial effects of R. rosea on as a therapeutic strategy for the treatment of Alzheimer's disease and other neurodegenerative diseases where oxidative stress plays a major role in disease development and progression. We also discuss the cultivation, phytochemistry, clinical impacts, and adverse effects of R. rosea to provide a broader insight on the therapeutic potential for this plant., (Copyright © 2016 John Wiley & Sons, Ltd.)

According to the epidemiological reports published by the World Health Organization, the proportion of elderly people (over 60 years) will increase from 11% to 22% by 2050 worldwide. This increase will be associated with a growing rate of morbidity and mortality of age-related diseases. Mental and neurodegenerative diseases are important health problems in elderly people. Therefore, recent research has been focused on finding effective neuroprotective agents with low adverse effects. Over the last two decades, much attention has been drawn to plant-derived bioactive compounds as novel therapeutic agents for treatment of neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). Among them, flavonoid chemical class is known as one of the most bioactive and non-toxic phytochemicals, which are widely found in different herbal medicines and edible plants. Fisetin is one of the most common and bioactive flavonoids which possesses potential neuroprotective effects. Fisetin also enhances learning and memory, decreases neuronal cell death, and suppresses oxidative stress. The present paper aims to critically evaluate the available literature regarding the beneficial effects of fisetin on neurodegenerative diseases, especially AD and PD. In addition, we provide information regarding the chemistry, sources, bioavailability and clinical impacts of fisetin to provide a broad spectrum for the use of this compound as a new approach to the treatment of AD and PD.

Resveratrol (3,4',5-trihydroxystilbene) is a naturally occurring phytochemical present in red wine, grapes, berries, chocolate and peanuts. Clinically, resveratrol has exhibited significant antioxidant, anti-inflammatory, anti-viral, and anti-cancer properties. Although resveratrol was first isolated in 1940, it was not until the last decade that it was recognised for its potential therapeutic role in reducing the risk of neurodegeneration, and Alzheimer's disease (AD) in particular. AD is the primary cause of progressive dementia. Resveratrol has demonstrated neuroprotective effects in several in vitro and in vivo models of AD. Apart from its potent antioxidant and anti-inflammatory roles, evidence suggests that resveratrol also facilitates non-amyloidogenic breakdown of the amyloid precursor protein (APP), and promotes removal of neurotoxic amyloid beta (Aβ) peptides, a critical step in preventing and slowing down AD pathology. Resveratrol also reduces damage to neuronal cells via a variety of additional mechanisms, most notably is the activation of NAD(+)-dependent histone deacetylases enzymes, termed sirtuins. However in spite of the considerable advances in clarifying the mechanism of action of resveratrol, it is unlikely to be effective as monotherapy in AD due to its poor bioavailability, biotransformation, and requisite synergism with other dietary factors. This review summarizes the relevance of resveratrol in the pathophysiology of AD. It also highlights why resveratrol alone may not be an effective single therapy, and how resveratrol coupled to other compounds might yet prove an effective therapy with multiple targets.

Alzheimer's disease (AD) is the most common neurodegenerative disorder and the leading cause of age-related dementia worldwide. Several models for AD have been developed to provide information regarding the initial changes that lead to degeneration. Transgenic mouse models recapitulate many, but not all, of the features of AD, most likely because of the high complexity of the pathology. In this context, the validation of a wild-type animal model of AD that mimics the neuropathological and behavioral abnormalities is necessary. In previous studies, we have reported that the Chilean rodent Octodon degus could represent a natural model for AD. In the present work, we further describe the age-related neurodegeneration observed in the O. degus brain. We report some histopathological markers associated with the onset progression of AD, such as glial activation, increase in oxidative stress markers, neuronal apoptosis and the expression of the peroxisome proliferative-activated receptor γ coactivator-1α (PGC-1α). With these results, we suggest that the O. degus could represent a new model for AD research and a powerful tool in the search for therapeutic strategies against AD., (© 2014 International Society of Neuropathology.)

Alzheimer's disease is a debilitating age-related disorder characterized by distinct pathological hallmarks, such as progressive memory loss and cognitive impairment. During the last few years, several cellular signaling pathways have been associated with the pathogenesis of Alzheimer's disease, such as Notch, mTOR and Wnt. However, the potential factors that modulate these pathways and novel molecular mechanisms that might account for the pathogenesis of Alzheimer's disease or for therapy against this disease are still matters of intense research. Teneurins are members of a unique protein system that has recently been proposed as a novel and highly conserved regulatory signaling system in the vertebrate brain, so far related with neurite outgrowth and neuronal matching. The similitude in structure and function of teneurins with other cellular signaling pathways, suggests that they may play a critical role in Alzheimer's disease, either through the modulation of transcription factors due to the nuclear translocation of the teneurins intracellular domain, or through the activity of the corticotrophin releasing factor (CRF)-like peptide sequence, called teneurin C-terminal associated peptide. Moreover, the presence of Ca(2+)-binding motifs within teneurins structure and the Zic2-mediated Wnt/β-catenin signaling modulation, allows hypothesize a potential crosslink between teneurins and the Wnt signaling pathway, particularly. Herein, we aim to highlight the main characteristics of teneurins and propose, based on current knowledge of this family of proteins, an interesting review of their potential involvement in Alzheimer's disease., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Alzheimer's disease (AD) is a neurodegenerative disorder associated with increased oxidative stress and neuroinflammation. Markers of increased protein, lipid and nucleic acid oxidation and reduced activities of antioxidant enzymes have been reported in AD plasma. Amyloid plaques in the AD brain elicit a range of reactive inflammatory responses including complement activation and acute phase reactions, which may also be reflected in plasma. Previous studies have shown that human AD plasma may be cytotoxic to cultured cells. We investigated the effect of pooled plasma (n = 20 each) from healthy controls, individuals with amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD) on cultured microglial cells. AD plasma and was found to significantly decrease cell viability and increase glycolytic flux in microglia compared to plasma from healthy controls. This effect was prevented by the heat inactivation of complement. Proteomic methods and isobaric tags (iTRAQ) found the expression level of complement and other acute phase proteins to be altered in MCI and AD plasma and an upregulation of key enzymes involved in the glycolysis pathway in cells exposed to AD plasma. Altered expression levels of acute phase reactants in AD plasma may alter the energy metabolism of glia.

Purpose of Review: Alzheimer's disease is a complex multifactorial age-related neurodegenerative disorder. Current transgenic animal models do not fully recapitulate human Alzheimer's disease at the molecular, cellular and behavioural levels. This review aims to address the clinical relevance of using 'physiologically' aged rats, dogs and Octodon degus, as more representative 'natural' ecologically valid models to elucidate mechanistic aspects of Alzheimer's disease, and for the development of therapeutic agents to attenuate age-related cognitive decline., Recent Findings: Aged rats, dogs and O. degus decline cognitively and ultimately develop Alzheimer's disease-like symptoms in response to the natural ageing process. Aged rats provide a tractable and popular model to examine the neurobiological basis underlying cognitive decline with age, but they do not develop Alzheimer's disease pathology. Progressive accumulation of abnormal amyloid-beta in extracellular plaques and surrounding cerebral vasculature is a common feature in human Alzheimer's disease, aged canine model and most nonhuman primates. Interestingly, the O. degus develops amyloid-beta deposits, neurofibrillary tangles containing hyperphosphorylated tau protein, altered cholinergic transmission and cognitive deficits analogous to those observed in Alzheimer's disease. Natural animal models better represent the full pathophysiology of Alzheimer's disease and are not only a viable alternative to transgenic models, but also are arguably the preferable model., Summary: 'Natural' models are useful to elucidate the neurobiological basis of Alzheimer's disease and develop effective therapeutic strategies that can be translated into human clinical trials.

Objective: Transgenic (Tg) mice, which possess an amyloid precursor protein (APP) gene mutation, develop extracellular amyloid β (Aβ) deposition in the brain, and severe memory and behavioral deficits with age. These mice serve as an important animal model for testing the efficacy of novel drug candidates for the treatment and management of symptoms of Alzheimer's disease (AD). Several reports have suggested that oxidative stress is the underlying cause of Aβ neurotoxicity in AD. Pomegranates contain very high levels of antioxidants and several medicinal properties that may be useful for improving quality of life in individuals with AD. The aim of this study was to investigate the effect of dietary supplementation of Omani pomegranate extract on memory, anxiety, and learning skills in an AD mouse model possessing the double Swedish APP mutation (APPsw/Tg2576)., Methods: The experimental groups of APP-Tg mice from the age of 4 mo were fed a custom mixed diet (pellets) containing 4% pomegranate. We assessed spatial memory and learning ability, psychomotor coordination, and anxiety-related behavior in Tg and wild-type mice at the age of 4 to 5 mo and 18 to 19 mo using the Morris water maze test, rotarod performance test, elevated plus-maze test, and open field test., Results: APPsw/Tg2576 mice that were fed a standard chow diet without pomegranates showed significant memory deficits, increased anxiety-related behavior, and severe impairment in spatial learning ability, position discrimination learning ability, and motor coordination compared with the wild-type mice on the same diet, at the age of 18 to 19 mo. In contrast, APPsw/Tg2576 mice that were fed a diet containing 4% pomegranates showed significant improvements in memory, learning, locomotor function, as well as reduction in anxiety, compared with APPsw/Tg2576 mice fed the standard chow diet., Conclusion: Our results suggest that dietary supplementation with pomegranates may slow the progression of cognitive and behavioral impairments in AD., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Accumulating evidence has suggested the involvement of oxidative stress in the pathogenesis of Alzheimer's disease (AD). The main endogenous antioxidant, glutathione (GSH), has been shown to decline with ageing and in several age-related degenerative diseases, including AD. Potential options for replenishing GSH levels as a therapeutic target to treat these conditions include the administration of GSH itself, and low toxicity forms of the limiting amino acid for GSH synthesis; cysteine. However, passive GSH uptake is limited due to an unfavourable concentration gradient between the plasma and cytosol. Similarly, cysteine prodrugs have demonstrated limited efficacy to elevate depleted GSH levels in several in vivo and in vitro models of disease. It has been suggested that the decline in GSH levels in AD, may be associated with down regulation of GSH homeostasis rather than substrate limitation. Cellular GSH homeostasis is regulated by non-allosteric feedback inhibition exerted by GSH on glutamate cysteine ligase (GCL), which is responsible for the synthesis of the GSH precursor γ-glutamylcysteine (GGC). In conditions involving down regulated GSH homeostasis, GGC serves as a crucialrate-limiting substrate for GSH synthetase, the main enzyme responsible for condensing glycine with GGC to form the final thiol tripeptide, GSH. In this review, we focus on the therapeutic potential of GGC to elevate cellular GSH levels. We also discuss the efficacy of GGC prodrugs which would be taken up and converted by the unregulated GS to GSH, and the administration of modified GSH compounds, such as GSH esters that could potentially overcome the concentration gradient that prohibits passive GSH uptake, in AD.

Numerous studies suggest energy failure and accumulative intracellular waste play a causal role in the pathogenesis of several neurodegenerative disorders and Alzheimer's disease (AD) in particular. AD is characterized by extracellular amyloid deposits, intracellular neurofibrillary tangles, cholinergic deficits, synaptic loss, inflammation and extensive oxidative stress. These pathobiological changes are accompanied by significant behavioral, motor, and cognitive impairment leading to accelerated mortality. Currently, the potential role of several metabolic pathways associated with AD, including Wnt signaling, 5' adenosine monophosphate-activated protein kinase (AMPK), mammalian target of rapamycin (mTOR), Sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1), and peroxisome proliferator-activated receptor gamma co-activator 1-α (PGC-1α) have widened, with recent discoveries that they are able to modulate several pathological events in AD. These include reduction of amyloid-β aggregation and inflammation, regulation of mitochondrial dynamics, and increased availability of neuronal energy. This review aims to highlight the involvement of these new set of signaling pathways, which we have collectively termed "anti-ageing pathways", for their potentiality in multi-target therapies against AD where cellular metabolic processes are severely impaired.

Alzheimer's disease (AD) is characterised by extracellular amyloid deposits, neurofibrillary tangles, synaptic loss, inflammation and extensive oxidative stress. Polyphenols, which include resveratrol, epigallocatechin gallate and curcumin, have gained considerable interest for their ability to reduce these hallmarks of disease and their potential to slow down cognitive decline. Although their antioxidant and free radical scavenging properties are well established, more recently polyphenols have been shown to produce other important effects including anti-amyloidogenic activity, cell signalling modulation, effects on telomere length and modulation of the sirtuin proteins. Brain accessible polyphenols with multiple effects on pathways involved in neurodegeneration and ageing may therefore prove efficacious in the treatment of age-related diseases such as AD, although the evidence for this so far is limited. This review aims to explore the known effects of polyphenols from various natural and synthetic sources on brain ageing and neurodegeneration, and to examine their multiple mechanisms of action, with an emphasis on the role that the sirtuin pathway may play and the implications this may have for the treatment of AD., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Purpose of Review: Alzheimer's disease has long been primarily considered a disease of gray matter. However, convergent evidence has suggested that white matter abnormalities are also important components of Alzheimer's disease. We undertook a review of the recent findings of Alzheimer's disease related white matter aberrations identified in patients with Alzheimer's disease and using in-vitro and in-vivo models, and discuss the potential causes of white matter damage in Alzheimer's disease. In doing so, we aim to provide a renewed insight into white matter changes in Alzheimer's disease and related dementias., Recent Findings: Neuroimaging studies have found that patients with preclinical Alzheimer's disease have widespread white matter abnormalities at a stage similar to those reported in Alzheimer's disease, whereas gray matter structures were relatively intact. In addition, demyelination of the white matter is reported to occur prior to the presence of amyloid-β plaques and neurofibrillary tangles in the presymptomatic stages of Alzheimer's disease. Furthermore, in a mouse model of Alzheimer's disease, axonal disease due to impaired axonal transport was shown to precede and drive downstream production and aggregation of amyloid β peptides., Summary: White matter abnormalities not only represent an early neuropathological event in Alzheimer's disease but may also play an important role in the pathogenesis and diagnosis of Alzheimer's disease.

Nature has gifted mankind with a plethora of flora-bearing fruits, vegetables and nuts. The diverse array of bioactive nutrients present in these natural products plays a pivotal role in prevention and cure of various neurodegenerative diseases, such as Alzheimer's disease (AD), Parkinson's disease and other neuronal dysfunctions. Accumulated evidence suggests that naturally occurring phyto-compounds, such as polyphenolic antioxidants found in fruits, vegetables, herbs and nuts, may potentially hinder neurodegeneration, and improve memory and cognitive function. Nuts such as walnut have also demonstrated neuroprotective effect against AD. The molecular mechanisms behind the curative effects rely mainly on the action of phytonutrients on distinct signalling pathways associated with protein folding and neuroinflammation. The neuroprotective effects of various naturally occurring compounds in AD is evaluating in this review.

Purpose of Review: Sirtuins are a family of enzymes highly conserved in evolution and involved in mechanisms known to promote healthy ageing and longevity. This review aims to discuss recent advances in understanding the role of sirtuins, in particular mammalian SIRT1, in promoting longevity and its potential molecular basis for neuroprotection against cognitive ageing and Alzheimer's disease pathology., Recent Findings: Accumulative increase in oxidative stress during ageing has been shown to decrease SIRT1 activity in catabolic tissue, possibly by direct inactivation by reactive oxygen. SIRT1 overexpression prevents oxidative stress-induced apoptosis and increases resistance to oxidative stress through regulation of the FOXO family of forkhead transcription factors. In addition, resveratrol strongly stimulates SIRT1 deacetylase activity in a dose-dependent manner by increasing its binding affinity to both the acetylated substrate and NAD(+). Recently, SIRT1 has been shown to affect amyloid production through its influence over the ADAM10 gene. Upregulation of SIRT1 can also induce the Notch pathway and inhibit mTOR signalling., Summary: Recent studies have revealed some of the mechanisms and pathways that are associated with the neuroprotective effects of SIRT1.

Alzheimer's disease (AD) is the most common origin of dementia in the elderly. Although the cause of AD remains unknown, several factors have been identified that appear to play a critical role in the development of this debilitating disorder. In particular, amyloid precursor protein (APP), tau hyperphosphorylation, and the secretase enzymes, have become the focal point of recent research. Over the last two decades, several transgenic and non-transgenic animal models have been developed to elucidate the mechanistic aspects of AD and to validate potential therapeutic targets. Transgenic rodent models over-expressing human β-amyloid precursor protein (β-APP) and mutant forms of tau have become precious tools to study and understand the pathogenesis of AD at the molecular, cellular and behavioural levels, and to test new therapeutic agents. Nevertheless, none of the transgenic models of AD recapitulate fully all of the pathological features of the disease. Octodon degu, a South American rodent has been recently found to spontaneously develop neuropathological signs of AD in old age. This review aims to address the limitations and clinical relevance of transgenic rodent models in AD, and to highlight the potential for O. degu as a natural model for the study of AD neuropathology.

Oxidative imbalance is a prominent feature in Alzheimer's disease and ageing. Increased levels of reactive oxygen species (ROS) can result in disordered cellular metabolism due to lipid peroxdation, protein-cross linking, DNA damage and the depletion of nicotinamide adenine dinucleotide (NAD(+)). NAD(+) is a ubiquitous pyridine nucleotide that plays an essential role in important biological reactions., from ATP production and secondary messenger signaling, to transcriptional regulation and DNA repair. Chronic oxidative stress may be associated with NAD(+) depletion and a subsequent decrease in metabolic regulation and cell viability. Hence, therapies targeted toward maintaining intracellular NAD(+) pools may prove efficacious in the protection of age-dependent cellular damage, in general, and neurodegeneration in chronic central nervous system inflammatory diseases such as Alzheimer's disease, in particular.