Beta Deposition Research Articles

Caterpillar Medicinal Mushroom, Cordyceps militaris (Ascomycota), Attenuates Aβ1-42-Induced Amyloidogenesis and Inflammatory Response by Suppressing Amyloid Precursor Protein Progression and p38 MAPK/JNK Activation.

The deposition of amyloid beta (Aβ) is a neuropathological feature of Alzheimer's disease (AD). Cordyceps militaris is an edible medicinal fungus in Asian countries with antioxidative, antiaging, antitumor, and immunomodulatory effects. In this study, we investigated the neuroprotective mechanisms of C. militaris in the brain of Aβ1-42-injected AD mice. An intracerebroventricular injection of Aβ1-42 (total 3 µg/mouse) resulted in neurological damage, including amyloidogenesis and neuroinflammation; however, C. militaris attenuated Aβ1-42-induced amyloidogenesis and inflammatory responses. Oral administration of C. militaris at concentrations of 100 and 200 mg/kg suppressed acetylcholinesterase activity. In addition, C. militaris treatment downregulated amyloid precursor protein levels, with a decrease in β-secretase activity. Moreover, C. militaris significantly enhanced the expression of brain-derived neurotrophic factor. Furthermore, C. militaris-administered groups had inactivated inflammatory responses by downregulation of inducible nitric oxide synthase and cyclooxygenase-2 protein expression. The injection of Aβ1-42 resulted in the activation of p38 MAPK and c-Jun N-terminal kinase, which was rescued by C. militaris. These results suggest that C. militaris has a protective effect against Aβ1-42-induced neurological damage.

The Aβ16-22 hexamer’s aggregation under a co-effect of EGCG compound and low-pH concentration

One of the most common forms of dementia is Alzheimer’s disease (AD), and its relationship with β-amyloid plaques. The deposition of amyloid beta (Aβ) oligomers is proved to be a damage cause for AD patients in which the mechanism of Aβ16-22 fragments is believed to keep an important role in the fibrils’ aggregations due to its’ β-contents. Many previous searches showed that the more β-contents formed the more Aβ-fibrillary conformations created. In a previous study, the Aβ16-22 hexamer configuration under the inhibition of the epigallocatechin-3-gallate (EGCG) compound, which attenuated the production of β-sheet structure formation, was successfully constructed. However, the environment controlled 6Aβ16-22 association change was neglected. So, in this scheme we are motivated to make an atomistic investigation via two molecular dynamic simulations (MD): Aβ16-22 hexamer and EGCG complex, one in normal condition pH = 7.0 and the other in lower one pH = 5.5, respectively. The received data provides evidence to determine, the environmental difference does not change the number of H-bond between EGCG and Aβ fragment in which asserted that EGCG becomes a potential prospect in treating AD. Besides that, the results of simulations by using the DSSP tool of Gromacs package demonstrated that the averaging number of random-coil structure didn’t change too much and received similar values of 24.4 and 24.6, and the decreasing of β-contents under the co-operative interaction of low pH and EGCG inhibitor. The Aβ16-22 free energy has slightly increased from -14,3 kcal.mol-1 to -13,8 kcal.mol-1 when pH concentration is reduced from normal pH = 7.0 to low on pH = 5.5. Finally, the computational results are in agreement with the experimental investigation, our observation adds a physical insight into the picture of the computational aided drug design in Aβ treatment.

The protective effect of early dietary fat consumption on Alzheimer's disease-related pathology and cognitive function in mice.

IntroductionIt has been suggested that obesity may influence Alzheimer's disease (AD) pathogenesis, yet the numerous publications on this topic have inconsistent results and conclusions.MethodsOur study examined the effect of varying the timing of high‐fat diet (HFD) consumption on AD‐related pathology and cognition in transgenic Tg6799 AD mice.ResultsHFD feeding starting at or before 3 months of age, prior to severe AD pathology, had protective effects in AD mice: reduced extracellular amyloid beta (Aβ) deposition, decreased fibrinogen extravasation into the brain parenchyma, and improved cognitive function. However, delaying HFD consumption until 6 months of age, when AD pathology is ubiquitous, reduced these protective effects in AD mice.DiscussionOverall, we demonstrate that the timeline of HFD consumption may play an important role in how dietary fats affect AD pathogenesis and cognitive function.

The global Alzheimer's Association round robin study on plasma amyloid β methods.

IntroductionBlood‐based assays to measure brain amyloid beta (Aβ) deposition are an attractive alternative to the cerebrospinal fluid (CSF)–based assays currently used in clinical settings. In this study, we examined different blood‐based assays to measure Aβ and how they compare among centers and assays.MethodsAliquots from 81 plasma samples were distributed to 10 participating centers. Seven immunological assays and four mass‐spectrometric methods were used to measure plasma Aβ concentrations.ResultsCorrelations were weak for Aβ42 while Aβ40 correlations were stronger. The ratio Aβ42/Aβ40 did not improve the correlations and showed weak correlations.DiscussionThe poor correlations for Aβ42 in plasma might have several potential explanations, such as the high levels of plasma proteins (compared to CSF), sensitivity to pre‐analytical sample handling and specificity, and cross‐reactivity of different antibodies. Different methods might also measure different pools of plasma Aβ42. We, however, hypothesize that greater correlations might be seen in future studies because many of the methods have been refined during completion of this study.

Dietary Vitamin B <sub>12</sub> Reduces Amyloid-β Proteotoxicity by Alleviating Oxidative Stress and Mitochondrial Dysfunction

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no effective treatment. Diet, as a modifiable risk factor for AD, could potentially be targeted to slow disease onset and progression. However, complexity of the human diet and indirect effects of the microbiome make it challenging to identify protective nutrients. Multiple factors contribute to AD pathogenesis including amyloid beta (Aβ) deposition, mitochondrial dysfunction, and oxidative stress. Here we used Caenorhabditis elegans to define the impact of diet on Aβ proteotoxicity. We discovered that dietary vitamin B12 alleviated mitochondrial fragmentation, bioenergetic defects, and oxidative stress, delaying Aβ-induced paralysis without affecting Aβ accumulation. Vitamin B12 had this protective effect by acting as a cofactor for methionine synthase rather than as an antioxidant. Vitamin supplementation of B12 deficient adult Aβ animals was beneficial, demonstrating potential for vitamin B12 as a therapy to target pathogenic features of AD triggered by both aging and proteotoxic stress.

Longitudinal evaluation of a novel BChE PET tracer as an early in vivo biomarker in the brain of a mouse model for Alzheimer disease.

Purpose: The increase in butyrylcholinesterase (BChE) activity in the brain of Alzheimer disease (AD) patients and animal models of AD position this enzyme as a potential biomarker of the disease. However, the information on the ability of BChE to serve as AD biomarker is contradicting, also due to scarce longitudinal studies of BChE activity abundance. Here, we report 11C-labeling, in vivo stability, biodistribution, and longitudinal study on BChE abundance in the brains of control and 5xFAD (AD model) animals, using a potent BChE selective inhibitor, [11C]4, and positron emission tomography (PET) in combination with computerised tomography (CT). We correlate the results with in vivo amyloid beta (Aβ) deposition, longitudinally assessed by [18F]florbetaben-PET imaging.Methods: [11C]4 was radiolabelled through 11C-methylation. Metabolism studies were performed on blood and brain samples of female wild type (WT) mice. Biodistribution studies were performed in female WT mice using dynamic PET-CT imaging. Specific binding was demonstrated by ex vivo and in vivo PET imaging blocking studies in female WT and 5xFAD mice at the age of 7 months. Longitudinal PET imaging of BChE was conducted in female 5xFAD mice at 4, 6, 8, 10 and 12 months of age and compared to age-matched control animals. Additionally, Aβ plaque distribution was assessed in the same mice using [18F]florbetaben at the ages of 2, 5, 7 and 11 months. The results were validated by ex vivo staining of BChE at 4, 8, and 12 months and Aβ at 12 months on brain samples.Results: [11C]4 was produced in sufficient radiochemical yield and molar activity for the use in PET imaging. Metabolism and biodistribution studies confirmed sufficient stability in vivo, the ability of [11C]4 to cross the blood brain barrier (BBB) and rapid washout from the brain. Blocking studies confirmed specificity of the binding. Longitudinal PET studies showed increased levels of BChE in the cerebral cortex, hippocampus, striatum, thalamus, cerebellum and brain stem in aged AD mice compared to WT littermates. [18F]Florbetaben-PET imaging showed similar trend of Aβ plaques accumulation in the cerebral cortex and the hippocampus of AD animals as the one observed for BChE at ages 4 to 8 months. Contrarily to the results obtained by ex vivo staining, lower abundance of BChE was observed in vivo at 10 and 12 months than at 8 months of age.Conclusions: The BChE inhibitor [11C]4 crosses the BBB and is quickly washed out of the brain of WT mice. Comparison between AD and WT mice shows accumulation of the radiotracer in the AD-affected areas of the brain over time during the early disease progression. The results correspond well with Aβ accumulation, suggesting that BChE is a promising early biomarker for incipient AD.

Machine learning of brain structural biomarkers for Alzheimer's disease (AD) diagnosis, prediction of disease progression, and amyloid beta deposition in the Japanese population.

IntroductionWe developed machine learning (ML) designed to analyze structural brain magnetic resonance imaging (MRI), and trained it on the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. In this study, we verified its utility in the Japanese population.MethodsA total of 535 participants were enrolled from the Japanese ADNI database, including 148 AD, 152 normal, and 235 mild cognitive impairment (MCI). Probability of AD was expressed as AD likelihood scores (ADLS).ResultsThe accuracy of AD diagnosis was 88.0% to 91.2%. The accuracy of predicting the disease progression in non‐dementia participants over a 3‐year observation was 76.0% to 79.3%. More than 90% of the participants with low ADLS did not progress to AD within 3 years. In the amyloid positron emission tomography (PET)–positive MCI, the hazard ratio of progression was 2.39 with low ADLS, and 5.77 with high ADLS. When high ADLS was defined as N+ and Pittsburgh compound B (PiB) PET positivity was defined as A+, the time to disease progression for 50% of MCI participants was 23.7 months in A+N+, whereas it was 52.3 months in A+N‐.ConclusionThese results support the feasibility of our ML for the diagnosis of AD and prediction of the disease progression.

Cerebrovascular stiffness and flow dynamics in the presence of amyloid and tau biomarkers.

IntroductionThis work investigated the relationship between cerebrovascular disease (CVD) markers and Alzheimer's disease (AD) biomarkers of amyloid beta deposition, and neurofibrillary tau tangles in subjects spanning the AD clinical spectrum.MethodsA total of 136 subjects participated in this study. Four groups were established based on AD biomarker positivity from positron emission tomography (amyloid [A] and tau [T]) and clinical diagnosis (cognitively normal [CN] and impaired [IM]). CVD markers were derived from structural and quantitative magnetic resonance imaging data.ResultsTranscapillary pulse wave delay was significantly longer in controls compared to AT biomarker–confirmed groups (A+/T–/CN P < .001, A+/T+/CN P < .001, A+/T+/IM P = .003). Intracranial low‐frequency oscillations were diminished in AT biomarker–confirmed groups both CN and impaired (A+/T–/CN P = .039, A+/T+/CN P = .007, A+/T+/IM P = .011). A significantly higher presence of microhemorrhages was measured in A+/T+/CN compared to controls (P = .006).DiscussionCerebrovascular markers indicate increased vessel stiffness and reduced vasomotion in AT biomarker–positive subjects during preclinical AD.

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice.

IntroductionMicroglial TYROBP (DAP12) is a network hub and driver in sporadic late‐onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia.MethodsUsing a novel transgenic mouse overexpressing TYROBP in microglia, we observed a decrease of the amyloid burden and an increase of TAU phosphorylation stoichiometry when crossed with APP/PSEN1 or MAPTP301S mice, respectively. Characterization of these mice revealed Tyrobp‐related modulation of apolipoprotein E (Apoe) transcription. We also showed that Tyrobp and Apoe mRNAs were increased in Trem2‐null microglia recruited around either amyloid beta deposits or a cortical stab injury. Conversely, microglial Apoe transcription was dramatically diminished when Tyrobp was absent.ConclusionsOur results provide evidence that TYROBP‐APOE signaling does not require TREM2 and could be an initiating step in establishment of the disease‐associated microglia (DAM) phenotype.

Space-Dependent Glia-Neuron Interplay in the Hippocampus of Transgenic Models of β-Amyloid Deposition.

This review is focused on the description and discussion of the alterations of astrocytes and microglia interplay in models of Alzheimer’s disease (AD). AD is an age-related neurodegenerative pathology with a slowly progressive and irreversible decline of cognitive functions. One of AD’s histopathological hallmarks is the deposition of amyloid beta (Aβ) plaques in the brain. Long regarded as a non-specific, mere consequence of AD pathology, activation of microglia and astrocytes is now considered a key factor in both initiation and progression of the disease, and suppression of astrogliosis exacerbates neuropathology. Reactive astrocytes and microglia overexpress many cytokines, chemokines, and signaling molecules that activate or damage neighboring cells and their mutual interplay can result in virtuous/vicious cycles which differ in different brain regions. Heterogeneity of glia, either between or within a particular brain region, is likely to be relevant in healthy conditions and disease processes. Differential crosstalk between astrocytes and microglia in CA1 and CA3 areas of the hippocampus can be responsible for the differential sensitivity of the two areas to insults. Understanding the spatial differences and roles of glia will allow us to assess how these interactions can influence the state and progression of the disease, and will be critical for identifying therapeutic strategies.

Correlation of protein tau and amyloid beta aggregates neuroinflammation and oxidative stress in 5xFAD and P301S mice

AbstractBackgroundThe deposition of protein tau (Tau) and amyloid beta (Aβ) aggregates during Alzheimer disease (AD) is accompanied by other processes, mostly controlled by glial activation. Despite numerous attempts, there is little information on the role of these processes in the disease mechanism. Exact mapping and correlation of pathological changes would give information that could help reveal underlying causes for the onset of the disease. We set off to longitudinally investigate and correlate disease related processes in the brains of 5xFAD and P301S mice models.MethodNeuroinflammation and oxidative stress in P301S and 5xFAD transgenic (tg) mice were monitored longitudinally by PET‐CT imaging and compared to age‐matched healthy controls (WT). PET imaging using [18F]DPA‐714, [18F]FSPG, [18F]florbetaben, and [18F]EFAPEM1 was performed to assess levels of neuroinflammation, oxidative stress, Aβ load (5xFAD mice) and Tau aggregates (P301S) load, respectively. Uptake in the cortex (CTX) was presented as SUV or SUVr when a reference region was available. IHC staining of brain slices for Aβ, Tau deposits, neuroinflammation and oxidative stress is currently in progress.ResultPET‐CT studies showed increase of levels of Tau deposits at 8 month‐old P301S mice and Aβ levels at 6, 8 and 10 month‐old 5xFAD mice. For 5xFAD mice, [18F]DPA‐714 and [18F]FSPG uptake followed the trend of Aβ deposition, peaking at 8 months. Compared to WT mice, four‐fold increase in [18F]DPA‐714 (p&lt;0.0001) and three‐fold increase in [18F]FSPG (p=0.0019) SUV was observed, suggesting protein deposits‐induced increase in inflammation and oxidative stress. Surprisingly, neuroinflammation and oxidative stress did not follow the trend of Tau deposition in P301S mice.ConclusionLongitudinal deposition of Aβ and Tau was in accordance with reported ex vivo data for the two animal models. Neuroinflammation and oxidative stress correspond well with the levels of Aβ, longitudinally. The two processes also occur in P301S mice brain but correspond poorly with Tau deposition. These results suggest that either Aβ and Tau aggregates affect neuroinflammation and oxidative stress differently, or that neuroinflammation and oxidative stress are independent processes. Further studies are in progress to confirm the observed data.

Linking central auditory deficits to cognitive decline in mice with amyloid deposition

AbstractBackgroundAlzheimer’s disease (AD) is a form of dementia that is characterized by the progressive loss of cognitive capacity, including the loss of executive functions and memory. There is growing evidence suggesting that hearing loss and dementia are tightly linked, with recent studies showing that hearing loss is independently associated with accelerated cognitive decline. However, the neural mechanisms linking hearing loss to AD‐related pathologies and subsequent cognitive decline remain unknown.MethodWe will test the hypothesis that amyloid pathology impacts feedforward sensory processing in primary auditory cortex (A1). We performed in vivo two‐photon calcium imaging in awake, head‐fixed APPswe/PS1dE9 (APP/PS1) mice to investigate how AD pathology impacts central auditory processing. APP/PS1 mice express chimeric mouse/human amyloid precursor protein (APP) and mutant presinilin‐1 (PS1). These transgenes target neurons of the central nervous system and lead to the rapid accumulation of soluble amyloid beta and subsequent plaque deposition in cortical and hippocampal areas. Our study uses the fine‐scale tonotopic arrangement of excitatory neurons in A1 as an assay for feedforward sensory integration. With two‐photon calcium imaging, we have the spatial and temporal resolution to monitor the activity of hundreds of neurons simultaneously with single‐cell resolution.ResultPreliminary data collected from 11 mice (7 APP+, 4 WT) suggests clear differences in the processing of feedforward sensory information, namely differences in the tonotopic arrangement of neurons in A1 between WT and APP/PS1 mice.ConclusionFuture work will investigate how AD pathology affects sensorimotor learning. Learning rates will be monitored in APP/PS1 mice trained on a go/no‐go stimulus recognition task. To probe the neural computations that are critical for the selection of auditory cues during behavior, excitatory networks in A1 will be monitored using two‐photon calcium imaging while animals perform the task. This study hopes to elucidate neural mechanisms of how amyloid beta pathology impacts central auditory processing, and thus, mechanistically link hearing loss, AD‐related pathologies and cognitive impairments.

Association of plasma YKL‐40 with brain amyloidosis, memory performance, and sex in subjective memory complainers

AbstractBackgroundNeuroinflammation – a crucial early pathomechanistic alteration of Alzheimer's disease (AD) – may represent either a detrimental or a compensatory mechanism or both, based on the disease stage. YKL‐40, a glycoprotein highly expressed in human glia cells, is a candidate biomarker to in vivo track glial‐related neuroinflammation in AD. Few studies explored, in cognitively healthy individuals, the potential influence of key biological factors – age, sex, Apolipoprotein E (APOE) ε4 allele – on YKL‐40 plasma concentrations as well as its association with other AD pathophysiological mechanisms and cognitive scores.MethodWe assessed the cross‐sectional and longitudinal impact of relevant biological factors – sex, age, APOE ε4 allele – on YKL‐40. Moreover, we explored the cross‐sectional and longitudinal association of YKL‐40 with: 1) global/regional brain amyloid beta (Aβ) deposition using Aβ‐positron emission tomography (PET) imaging; 2) synaptic loss, using [18F]‐fluorodeoxyglucose‐PET ([18F]‐FDG‐PET); 3) neurodegeneration using magnetic resonance imaging (MRI), i.e. hippocampal, entorhinal cortex, and basal forebrain volumes. We also sought for the potential association between YKL‐40 and the degree of cognitive performance. The study was performed in the INSIGHT‐preAD cohort (N=314, M=114, F=200, aged 70 to 85), a large observational monocentric French academic cohort (Pitié‐Salpêtrière University Hospital, Paris) of individuals with subjective memory complaints (SMC), a condition at risk for AD. We used mixed models with interaction of YKL‐40 with time.ResultMen displayed higher YKL‐40 concentrations than women at each time point investigated (b=0.171, t=2.434, P=0.015). YKL‐40 presented an age‐associated increase at each time point investigated (b=0.029, t=3.004, P=0.003). YKL‐40 was negatively associated with baseline Aβ deposition, at both global (b=‐0.025, t=‐1.992, P=0.047) and regional level. Besides, one‐year increase of YKL‐40 concentration was positively associated with memory performance, longitudinally (b=0.308, z=2.280, P=0.023). YKL‐40 showed no effect on synaptic loss or neurodegeneration.ConclusionPlasma YKL‐40 concentrations present an age‐associated increase with men showing higher levels than women, irrespective of the time point, thus indicating a potential sexual dimorphism in neuroinflammation. Moreover, the association of higher YKL‐40 concentrations with lower overall/regional cross‐sectional Aβ deposition and higher memory scores over time indicates a non‐clinical detrimental/potential protective effect of glia activation on incipient brain amyloidosis and synaptic network homeostasis.

Subtle executive deficits are associated with higher brain amyloid burden and lower cortical volume in subjective cognitive decline: the FACEHBI cohort

To determine whether lower performance on executive function tests in subjective cognitive decline (SCD) individuals are associated with higher levels of brain amyloid beta (Aβ) deposition and regional volumetric reduction in areas of interest for Alzheimer’s disease (AD). 195 individuals with SCD from the FACEHBI study were assessed with a neuropsychological battery that included the following nine executive function tests: Trail Making Test A and B (TMTA, TMTB), the Rule Shift Cards subtest of BADS, the Automatic Inhibition subtest of the Syndrom Kurz Test (AI-SKT), Digit Span Backwards and Similarities from WAIS-III, and the letter, semantic, and verb fluency tests. All subjects underwent an 18F-Florbetaben positron emission tomography (FBB-PET) scan to measure global standard uptake value ratio (SUVR), and a magnetic resonance imaging (MRI). A multiple regression analysis, adjusted for age, was carried out to explore the association between global SUVR and performance on executive tests. Then, on those tests significantly associated with amyloid burden, a voxel-based morphometry (VBM) analysis was carried out to explore their correlates with grey matter volume. Multiple regression analysis revealed a statistically significant association between Aβ deposition and performance on one of the executive tests (the AI-SKT). Moreover, VBM analysis showed worse AI-SKT scores were related to lower volume in bilateral hippocampus and left inferior frontal regions. In conclusion, in SCD individuals, worse automatic inhibition ability has been found related to higher cerebral Aβ deposition and lower volume in the hippocampus and frontal regions. Thus, our results may contribute to the early detection of AD in individuals with SCD.

An Isoquinolinium Dual Inhibitor of Cholinesterases and Amyloid β Aggregation Mitigates Neuropathological Changes in a Triple-Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder affecting millions of people worldwide. The underlying pathologic mechanisms of AD are unclear. Over the decades, the development of single target agent did not lead to any successful treatment for AD. A multitarget agent that could tackle more than one AD phenotype may be helpful as a treatment strategy. Cholinesterases (ChEs) including acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), are currently the drug targets with approved treatments. Moreover, amyloid beta (Aβ) deposition is a hallmark of AD that receives considerable attention. Herein, 9Q, a previously reported dual target inhibitor dealing with cholinergic dysfunction and amyloid deposition for AD treatment, has undergone thorough investigations. In vitro studies revealed that 9Q exhibited over 80% inhibition of ChE activity at 100 μM and more than 30% inhibition of Aβ aggregation at 1 mM concentration. Moreover 9Q was able to penetrate the blood-brain barrier (BBB) and enhance the cerebral acetylcholine level in triple transgenic AD (3xTg-AD) mice. Following one month treatment with 9Q, the amyloid burden and the cognitive deficits in 3xTg-AD mice were significantly ameliorated. It was observed that 9Q treatment mitigated synapse dysfunction, decreased amyloidogenic APP processing, and reduced the tau pathology in 3xTg-AD mice. Taken together, our results suggested that dual inhibition of cholinesterases and Aβ aggregation could be a promising approach in AD treatment.

Two new acylated triterpenoidal saponins from Gleditsia caspica Desf. and the effect of its saponin content on LPS-induced cognitive impairment in mice

• Two new triterpenoid saponins were isolated from Gleditsia caspica Desf. • Structures of saponins were determined using spectral and chemical means. • MEGC and SFGC were able to significantly improve memory and learning in mice dose dependently. Two bisdismosidic triterpenoidal saponins, caspicaoside A 1 (1) and caspicaoside B 1 (2) , were isolated from Gleditsia caspica fruit methanolic extract. The structures of 1 and 2 were determined using chemical and spectral techniques. Gleditsia caspica fruit methanolic extract (MEGC) and its saponin containing fraction (SFGC) at the two dose levels 45 and 90 mg/kg b.wt. were studied comparatively for their effect on LPS-induced cognitive impairment in mice using Ginkgo biloba (100 mg/kg b.wt.) as a standard drug. Neurobehavioral tests (Morris Water Maze and Novel Object Recognition tests) were conducted to prove that MEGC and SFGC at the two levels were able to significantly improve memory and learning in mice dose dependently. Also, the two test drugs were able to significantly decrease the levels of proinflammatory cytokines (Tumor necrosis factor alpha and Interleukin 1-beta) in addition to reducing the extra-cellular deposition of amyloid beta 42 in a dose dependent manner.

The role of slow wave sleep in the development of dementia and its potential for preventative interventions

The increasing incidence rate of dementia underlines the necessity to identify early biomarkers of imminent cognitive decline. Recent findings suggest that cognitive decline and the pathophysiology of Alzheimer's disease are closely linked to disruptions in slow wave sleep (SWS) – the deepest sleep stage. SWS is essential for memory functions and displays a potentially causal and bidirectional link to the accumulation of amyloid beta deposition. Accordingly, improving SWS in older adults – especially when at risk for dementia – might slow down the rate of cognitive decline. Recent work suggests that SWS can be improved by specifically targeting the electrophysiological peaks of the slow waves with acoustic stimulation. In older adults, this approach is still fairly new and accompanied by challenges posed by the specific complexity of their sleep physiology, like lower amplitude slow waves and fragmented sleep architecture. We suggest an approach that tackles these issues and attempts to re-instate a sleep physiology that resembles a younger, healthier brain. With enough SWS of high quality, metabolic clearance and memory functions could benefit and help slowing the process of cognitive aging. Ultimately, acoustic stimulation to enhance SWS could serve as a cost-effective, non-invasive tool to combat cognitive decline.

Mangosteen Pericarp and Its Bioactive Xanthones: Potential Therapeutic Value in Alzheimer's Disease, Parkinson's Disease, and Depression with Pharmacokinetic and Safety Profiles.

Alzheimer’s disease (AD), Parkinson’s disease (PD), and depression are growing burdens for society globally, partly due to a lack of effective treatments. Mangosteen (Garcinia mangostana L.,) pericarp (MP) and its xanthones may provide therapeutic advantages for these disorders. In this review, we discuss potential therapeutic value of MP-derived agents in AD, PD, and depression with their pharmacokinetic and safety profiles. MP-derived agents have shown multifunctional effects including neuroprotective, antioxidant, and anti-neuroinflammatory actions. In addition, they target specific disease pathologies, such as amyloid beta production and deposition as well as cholinergic dysfunction in AD; α-synuclein aggregation in PD; and modulation of monoamine disturbance in depression. Particularly, the xanthone derivatives, including α-mangostin and γ-mangostin, exhibit potent pharmacological actions. However, low oral bioavailability and poor brain penetration may limit their therapeutic applications. These challenges can be overcome in part by administering as a form of MP extract (MPE) or using specific carrier systems. MPE and α-mangostin are generally safe and well-tolerated in animals. Furthermore, mangosteen-based products are safe for humans. Therefore, MPE and its bioactive xanthones are promising candidates for the treatment of AD, PD, and depression. Further studies including clinical trials are essential to decipher their efficacy, and pharmacokinetic and safety profiles in these disorders.

Proteomic Profiling of Extracellular Vesicles Derived from Cerebrospinal Fluid of Alzheimer's Disease Patients: A Pilot Study.

Pathological hallmarks of Alzheimer’s disease (AD) are deposits of amyloid beta (Aβ) and hyper-phosphorylated tau aggregates in brain plaques. Recent studies have highlighted the importance of Aβ and tau-containing extracellular vesicles (EVs) in AD. We therefore examined EVs separated from cerebrospinal fluid (CSF) of AD, mild cognitive impairment (MCI), and control (CTRL) patient samples to profile the protein composition of CSF EV. EV fractions were separated from AD (n = 13), MCI (n = 10), and CTRL (n = 10) CSF samples using MagCapture Exosome Isolation kit. The CSF-derived EV proteins were identified and quantified by label-free and tandem mass tag (TMT)-labeled mass spectrometry. Label-free proteomics analysis identified 2546 proteins that were significantly enriched for extracellular exosome ontology by Gene Ontology analysis. Canonical Pathway Analysis revealed glia-related signaling. Quantitative proteomics analysis, moreover, showed that EVs expressed 1284 unique proteins in AD, MCI and CTRL groups. Statistical analysis identified three proteins—HSPA1A, NPEPPS, and PTGFRN—involved in AD progression. In addition, the PTGFRN showed a moderate correlation with amyloid plaque (rho = 0.404, p = 0.027) and tangle scores (rho = 0.500, p = 0.005) in AD, MCI and CTRL. Based on the CSF EV proteomics, these data indicate that three proteins, HSPA1A, NPEPPS and PTGFRN, may be used to monitor the progression of MCI to AD.

Alzheimer’s disease and the genetics of neuroprotection

As the world’s leading form of age-related dementia, Alzheimer’s disease (AD) is a devastating neurological disorder associated with severe emotional and economic burdens. Despite years of research, the underlying mechanism behind this disease remains unclear. The current prevailing theory relies on the deposition of toxic amyloid beta (Aβ), which promotes the formation of phosphorylated tau tangles, and together these damaging changes drive the loss of neurons. Much of AD development can be attributed to genetic influences, including pathogenic variants of β-amyloid precursor protein, presenilins 1 and 2, and the presence of apolipoprotein 4. However, there are other subtle, yet significant variations within our genome that contribute to protecting us against AD. Variants of the phospholipase Cγ2 and toll-like receptor 4 genes have been associated with reduced risk of developing AD, as well as increased longevity of patients. These neuroprotective variants can guide the development of future therapeutic interventions for AD, as current strategies have proven lackluster.