Against Alzheimer's Disease Research Articles

Total ginsenoside and Acorus tatarinowii volatile oil co-administration reverses learning memory deficits, reduces Aβ42 and AChE levels, and downregulates the PI3K/Akt/mTOR/Beclin-1 autophagic pathway in APP/PS1 double transgenic mice

Ethnopharmacological RelevanceThe combined application of ginseng and Shichangpu comes from the nootropic prescription—Dingzhi Xiaowan. One of the main effective components of ginseng is saponins. Studies have reported that its total saponins have significant neuroprotective effects, especially in anti-neuro-inflammation and anti-cognitive impairment. Shichangpu is a traditional Chinese medicine commonly used in clinical treatment of mental disorders such as dementia, amnesia, and epilepsy. One of the main active ingredients of Acorus tatarinowii is volatile oil, and research reports that its volatile oil also has a good neuroprotective effect. Previous research by the research team has shown its potential efficacy against Alzheimer's disease (AD). Aim of the studyAt present, the pathogenesis of Alzheimer's disease (AD) is not yet clear and the current treatment methods can only relief the related symptoms of AD. Our previous research found that the volatile oil of Acorus tatarinowii and components of ginsenosides, such as Rd, Rh2 and Rg1 can improve the learning and memory ability of AD mice. However, the effect and mechanism of volatile oil of Acorus tatarinowii combined with total ginsenosides on APP/PS1 double transgenic mice are still unknown. Materials and methodsIn this study, the effects of total ginsenoside and Acorus tatarinowii volatile oil co-administration on behavioral tests, amyloid β 42 (Aβ42) and acetylcholinesterase (AChE) levels, p-Akt, p-mTOR, LC3B, Bcl-2 and p62 expressions were investigated in APP/PS1 double transgenic mice. Furthermore, the PI3K/Akt/mTOR autophagic pathway was also studied and the structure of hippocampal neurons was observed. ResultsThe results showed that co-administrated treatment improved the learning and memory ability of mice in the water maze, passive avoidance and step-down tests, the swimming time and error times were shorten and incubation period was prolonged. And Aβ42 and AChE levels decreased, LC3B and Beclin-1 expressions declined, and number of autophagosomes reduced in the hippocampus of the APP/PS1 double transgenic mice, in contrary, the change of p-Akt, p-mTOR, P62 and Bcl-2 expressions were increased in the co-administrated treated mice compared with the untreated mice. We deduced that co-administrated therapy may firstly upregulate expressions of p-Akt, p-mTOR, P62 and Bcl-2, and then indirectly decrease the expression of LC3B and Beclin-1. ConclusionCollectively, all data indicated that total ginsenoside and Acorus tatarinowii volatile oil co-administration may play an autophagy inhibited role in preventing AD development by the PI3K/Akt/mTOR pathway.

Synthesis of New 3-Arylcoumarins Bearing N-Benzyl Triazole Moiety: Dual Lipoxygenase and Butyrylcholinesterase Inhibitors With Anti-Amyloid Aggregation and Neuroprotective Properties Against Alzheimer's Disease.

A novel series of coumarin derivatives linked to the N-benzyl triazole group were synthesized and evaluated against 15-lipoxygenase (15-LOX), and acetyl- and butyrylcholinesterase (AChE and BuChE) to find the most potent derivative against Alzheimer’s disease (AD). Most of the compounds showed weak to moderate activity against ChEs. Among the most active BuChE and 15-LOX inhibitors, 8l and 8n exhibited an excellent neuroprotective effect, higher than the standard drug (quercetin) on the PC12 cell model injured by H2O2 and significantly reduced aggregation of amyloid Aβ1-42, with potencies of 1.44 and 1.79 times higher than donepezil, respectively. Compound 8l also showed more activity than butylated hydroxytoluene (BHT) as the reference antioxidant agent in reducing the levels of H2O2 activated by amyloid β in BV2 microglial cells. Kinetic and ligand–enzyme docking studies were also performed for better understanding of the mode of interaction between the best BuChE inhibitor and the enzyme. Considering the acceptable BuChE and 15-LOX inhibition activities as well as significant neuroprotection, and anti-amyloid aggregation activities, 8l and 8n could be considered as potential MTDLs for further modification and studies against AD.

Photobiomodulation and visual stimulation against cognitive decline and Alzheimer's disease pathology: A systematic review.

Given the ineffectiveness of the available drug treatment against Alzheimer disease (AD), light-based therapeutic modalities have been increasingly receiving attention with photobiomodulation (PBM) and, more recently, visual stimulation (VS) being among the most promising approaches. However, the PBM and VS light parameters tested so far, as well as their outcomes, vary a lot with conflicting results being reported. Based on Scopus, PubMed, and Web of Science databases search, this systematic review summarizes, compares, and discusses 43 cell, animal, and human studies of PBM and VS related to cognitive decline and AD pathology. Preclinical work suggests that PBM with 640±30-nm light and VS at 40 Hz attenuates Aβ and Tau pathology and improves neuronal and synaptic plasticity with most studies pointing towards enhancement of degradation/clearance mechanisms in the brain of AD animal models. Despite the gap of the translational evidence for both modalities, the few human studies performed so far support the use of PBM at 810-870 nm light pulsing at 40 Hz for improving brain network connectivity and memory in older subjects and AD patients, while 40 Hz VS in humans seems to improve cognition; further clinical investigation is urgently required to clarify the beneficial impact of PBM and VS in AD patients. This review highlights PBM and VS as promising light-based therapeutic approaches against AD brain neuropathology and related cognitive decline, clarifying the most effective light parameters for further preclinical and clinical testing and use. Light-based brain stimulation produces neural entrainment and reverts neuronal damageBrain PBM and VS attenuate AD neuropathologyPMB and VS are suggested to improve cognitive performance in AD patients and animal modelsLight stimulation represents a promising therapeutic strategy against neurodegeneration.

Neuropsychiatric manifestations in vitamin B12 deficiency.

Vitamin B12 deficiency can have distressing neuropsychiatric symptoms. It can have an etiological role in clinical presentations like depression, anxiety, psychosis, dementia, and delirium, requiring screening of at-risk populations. Few mechanisms that underlie the neuropsychiatric manifestations of B12 deficiency include alteration in one-carbon metabolism, genetic vulnerability, and alteration in folate metabolism. Maintaining a high serum B12 level in elderly can be protective against Alzheimer's disease (AD). In an established AD, its deficiency is associated with higher cognitive decline and risk for delirium. The other mental changes associated with B12 deficiency include apathy, agitation, impaired concentration, insomnia, persecutory delusions, auditory and visual hallucinations, and disorganized thought-process. Besides serum vitamin B12, plasma methylmalonic acid (MMA) and homocysteine helps in diagnosis. The chapter focuses on early recognition and effective treatment of these neuropsychiatric manifestations of vitamin B12 deficiency.

The protective gene dose effect of the APOE ε2 allele on gray matter volume in cognitively unimpaired individuals.

IntroductionHarboring two copies of the apolipoprotein E (APOE) ε2 allele strongly protects against Alzheimer's disease (AD). However, the effect of this genotype on gray matter (GM) volume in cognitively unimpaired individuals has not yet been described.MethodsMulticenter brain magnetic resonance images (MRIs) from cognitively unimpaired ε2 homozygotes were matched (1:1) against all other APOE genotypes for relevant confounders (n = 223). GM volumes of ε2 genotypic groups were compared to each other and to the reference group (APOE ε3/ε3).ResultsCarrying at least one ε2 allele was associated with larger GM volumes in brain areas typically affected by AD and also in areas associated with cognitive resilience. APOE ε2 homozygotes, but not APOE ε2 heterozygotes, showed larger GM volumes in areas related to successful aging.DiscussionIn addition to the known resistance against amyloid‐β deposition, the larger GM volumes in key brain regions may confer APOE ε2 homozygotes additional protection against AD‐related cognitive decline.

What have we learned from past failures of investigational drugs for Alzheimer’s disease?

ABSTRACT Introduction In the last 15 years, huge efforts against Alzheimer’s disease (AD) with drugs targeting β-amyloid (Aβ) and tau have produced poor clinical results. Aducanumab, a recently FDA-approved anti-Aβ monoclonal antibody has been greeted with distrust by most experts, hospitals and insurance companies for its level of efficacy and poor tolerability. Area covered We reviewed literature on tau biology and anti-tau drugs using PubMed, meeting abstracts and ClnicalTrials.gov and discuss what we can learn from past failures of investigational drugs for Alzheimer’s disease, especially anti-Aβ and anti-tau drugs. Expert opinion It is our opinion that previous failures of anti-AD drugs suggest that soluble Aβ and tau are not appropriate drug targets. In addition, pivotal clinical trials of future clinical candidates should avoid major protocol amendments and futility analyses. Study protocols should adopt better measures to protect study blinding and minimise the potential introduction of major biases in the evaluation of the clinical results. Finally, alternative biological targets should be pursued as well as more multimodal approaches to addressing neurodegeneration in AD.

CSF protein panels reflecting multiple pathophysiological mechanisms for early and specific diagnosis of Alzheimer’s disease

AbstractBackgroundThe development of disease‐modifying therapies against Alzheimer’s disease (AD) requires biomarker panels that reflect the diverse pathological pathways specifically involved in AD. Here we aimed to identify and validate panels of cerebrospinal fluid (CSF) proteins covering different molecular pathways for early and specific diagnosis of AD.MethodWe measured 665 proteins in 797 CSF samples from patients with mild cognitive impairment with abnormal amyloid (MCI(Aβ+): n=50), AD‐dementia (n=230), non‐AD dementias (n=322; 123 DLB and 199 FTD) and cognitively‐unimpaired controls (n=195; classical AD CSF biomarkers negative) using proximity ligation‐based multiplex immunoassays. Nested and penalized linear modeling were used to identify protein differences (q<0,05) and translatable classification signatures.ResultWe detected highly dysregulated CSF proteins in MCI(Aβ+) or AD compared to controls (112 and 288 proteins respectively, lowest q:1‐15 and 1‐23), as well as between AD and non‐AD dementias (469 proteins; lowest q:1‐29). We confirmed previous findings (e.g., DDAH1, ENO2, PARK7), but we also identified novel proteins especially associated to the prodromal and/or dementia AD stages (e.g., ABL1, SCD4, ENTPD5). Proteins dysregulated in MCI(Aβ+) were primarily related to oxidative stress and energy metabolism, while those specifically dysregulated in later stages of AD dementia were related to cell remodeling, vascular function and immune system. Using penalised generalised linear modeling we identified the minimal number of markers with maximal power to discriminate clinical groups: for MCI(Aβ+) vs. controls: 10‐CSF proteins, AUC:0.99 (95%CI:0.97‐1); for AD vs. controls: 8‐CSF proteins, AUC:0.95 (95%CI:0.92‐0.99) and for AD vs. non‐AD dementias: 9‐CSF proteins, AUC:0.87 (95%CI:0.81‐0.93). The CSF panel discriminating AD from cognitively unimpaired controls was validated in an independent external cohort (n=62, AUC:0.94). Only 3 proteins overlapped across panels, suggesting that the panels with the strongest discriminative power are specific for disease stage and clinical group.ConclusionThis unprecedented large and protein‐rich CSF study indicates that CSF proteome follows a highly dynamic trajectory with distinct CSF profiles associated to different biological processes along the AD continuum. We unveil optimal CSF biomarker panels reflecting the specific multifactorial nature of AD, which can be now translated into customised assays for widespread validation and potential use in heterogeneous diagnostic settings or clinical trials.

BMI1 rs17415557 polymorphism is associated with amyloid-β and rates of cognitive decline in Alzheimer's disease.

Accumulating evidence suggests that BMI1 confers protective effects against Alzheimer's disease (AD). However, the mechanism remains elusive. Given recent pathophysiological evidence, we investigated whether genetic variants in BMI1 is associated with AD biomarkers. We used genetic and AD biomarker data from two independent well-characterized cohorts: Alzheimer's Disease Neuroimaging Initiative (ADNI) and Religious Orders Study and the Rush Memory and Aging Project (ROS/MAP). First, we performed a gene-based association analysis of single-nucleotide polymorphisms (SNPs) in BMI1 with cerebrospinal fluid (CSF) Aβ1-42 levels. Second, we performed longitudinal association analyses of SNPs with cognitive decline rates using linear mixed-effects models. Gene-based genetic association analysis identified SNPs in BMI1 as being significantly associated with CSF Aβ1-42 levels after adjusting for multiple testing using permutation. Participants with minor alleles of BMI1 rs17415557 with the most significant association have increased CSF Aβ1-42 levels, which was interestingly prominent within amyloid-positive participants. Further analysis identified and replicated the minor allele of rs17415557 as being significantly associated with slower cognitive decline rates in AD. Our findings provide fundamental evidence that BMI1 rs17415557 may serve as a protective mechanism related to AD pathogenesis, which supports the results of previous studies linking BMI1 to protection against AD.

Anti-Alzheimer's disease potential of Arabian coffee versus Date palm seed extract in male rats.

Coffee is among the most commonly consumed beverage all over the world. Studies have increasingly suggested caffeine and coffee as effective therapeutic interventions against Alzheimer's disease (AD). We have therefore utilized the aluminum chloride rat model for AD to compare the influence of moderately caffeinated (Arabian) and decaffeinated (Date palm seed) coffee on cognitive impairment and pathological events in AD. AD rats given Arabian or Date palm seed coffee were protected against memory impairment and had lower serum levels of the abnormal protein (amyloid-beta; Aβ1-42), the central pathogenic contributor to AD, and transforming growth factor-beta (TGF-β). Interestingly, Date palm seed (decaffeinated) coffee seems to provide more pronounced protection against AD than Arabian (moderately caffeinated) coffee as evidenced by the greater decrease in serum Aβ levels. These results suggest a surprising therapeutic potential of moderate caffeine intake in Arabian coffee to ameliorate AD through decreasing serum Aβ levels. However, Date palm seed (decaffeinated) coffee, rich in flavonoids, appears to provide a better AD-modifying ability through a direct reduction of Aβ production. PRACTICAL APPLICATIONS: Consumption of moderately caffeinated Arabian coffee attenuated AD-induced cognitive impairment via its anti-amyloidogenic potential, decreasing Aβ levels. Moreover, intake of decaffeinated Date seed extract, rich in flavonoids, exerted a superior anti-AD potential through a direct reduction of Aβ production. Both of them were also safe and maintained hepatic and renal functions in a rat model of AlCl3 -induced AD. Further clinical studies are warranted to confirm current results and to recommend the regular drinking of Arabian coffee or Date seed extract as a protective approach to delay AD progression in vulnerable individuals or in early disease stages.

Polydatin protects neuronal cells from hydrogen peroxide damage by activating CREB/Ngb signaling.

Oxidative stress-induced neuronal cell death contributes significantly to the physiological processes of a number of neurological disorders. Polydatin (PD) has been reported to protect against Alzheimer's disease (AD), ischemic stroke and traumatic brain injury. However, the underlying neuroprotective mechanisms remain to be elucidated. The current study suggested that PD activates AKT/cAMP response element-binding protein (CREB) signaling and induces neuroglobin (Ngb) to protect neuronal cells from hydrogen peroxide (H2O2) in vitro. PD inhibited the H2O2-induced neuronal cell death of primary mouse cortical neurons and N2a cells. Functional studies showed that PD attenuated H2O2-induced mitochondrial dysfunction and mitochondrial reactive oxygen species production. Mechanistically, PD was verified to induce the phosphorylation of AKT and CREB and increase the protein level of Ngb. The luciferase assay results showed that Ngb transcriptional activity was activated by CREB, especially after PD treatment. It was further indicated that PD increased the transcription of Ngb by enhancing the binding of CREB to the promoter region of Ngb. Finally, Ngb knockdown largely attenuated the neuroprotective role of PD against H2O2. The results indicated that PD protected neuronal cells from H2O2 by activating CREB/Ngb signaling in neuronal cells, indicating that PD has a neuroprotective effect against neurodegenerative diseases.

Rational design and synthesis of modified natural peptides from Boana pulchella (anura) as acetylcholinesterase inhibitors and antioxidants.

The use of acetylcholinesterase (AChE) inhibitors, antioxidants or multitarget compounds are among the main strategies against Alzheimer's disease (AD). Between AChE inhibitors, those targeting the peripheral anionic site (PAS) are of special interest. Here, we describe the rational design and synthesis of peptide analogs of a natural PAS-targeting sequence that we recently discovered, aiming at increasing its activity against AChE. We also tested their radical scavenging and metal chelating properties. Our design strategy was based on the position-specific, computer-aided insertion of aromatic residues. The analog named as W3 showed a 30-fold higher inhibitory activity than the original sequence and an improved antioxidant activity. W3 is the most potent modified natural peptide against Electrophorus electricus AChE ever reported with an IC50 of 10.42μM (± 1.02). In addition, it showed a radical scavenging activity of 47.00% ± 3.11 at 50μM and 93.47% ± 1.53 at 400μM. Since peptides are receiving increasing interest as drugs, we propose the W3 analog as an attractive sequence for the development of new peptide-based multitarget drugs for AD. Besides, this work sheds light on the importance of the aromatic residues in the modulation of AChE activity and their effect on the radical scavenging activity of a peptide.

Deciphering the AChE-binding mechanism with multifunctional tricyclic coumarin anti-Alzheimer's agents using biophysical and bioinformatics approaches and evaluation of their modulating effect on Amyloidogenic peptide assembly

Investigating the drug-AChE binding mechanism is vital in understanding its cogent use in medical practice against Alzheimer's disease (AD). The production and accumulation of oligomers of β-amyloid is a central event in the neuropathology of AD. Beside the inhibition of assembly process, modulation of the aggregation process of these proteins towards minimally toxic pathways may be a possible therapeutic strategy for AD. Hence, the present study aims to examine the effect of multifunctional fused tricyclic 7-hydroxy 4-methyl coumarin analogs (HMC1–5) on the self-induced aggregation of β-amyloid using Thioflavin T (ThT) assay, scanning electron microscopic study, AlamarBlue and immune blotting assays and also the binding mechanism with AChE by fluorescence emission, conformational, molecular docking and molecular dynamic simulation studies under physiological pH 7.4. The ThT assay, FE-SEM study, cell line and western blots establish that the HMC1–5 molecules could irreversibly disrupt preformed Aβ42 fibrils, accelerate the aggregates into micro size co-assembled structures, and effectively eliminate the cytotoxicity of Aβ1–42. Fluorescence emission studies indicating a strong binding affinity between HMC1–5 and AChE with the binding constants of 1.04 × 105, 3.57 × 104, 1.97 × 104, 3.07 × 104 and 2.95 × 104 M−1, respectively and binding sites number found to be 1. CD studies disclosed a partial unfolding in the secondary structure of AChE upon binding with HMC1–5. Docking analysis inferred that the HMC1–5 were bound through hydrophobic and hydrophilic interactions to the AChE active site. Molecular dynamics simulations emphasized the stability of AChE-HMC1–5 complexes throughout the 100 ns simulations, and the local conformational changes of the residues of AChE validate the stability of complexes. These results provide new and unique complementary approach for modulating the biological effects of the Aβ aggregates by coumarin analogs and new insights for further in vivo investigations as novel anti AD agents.

Structural characterization of polysaccharide purified from Hericium erinaceus fermented mycelium and its pharmacological basis for application in Alzheimer's disease: Oxidative stress related calcium homeostasis

The purified polysaccharides from Hericium erinaceus fermented mycelium entitled with PHEB was analyzed and it was mainly composed of six glycosidic bonds. It has been confirmed to show the relieving activity against Alzheimer's Disease (AD)- just as behaviors of B6C3-Tg (APPswePSEN1d E9)/Nju double transgenic [Genotype: (Appswe)T, (Psen1) T] (APP/PS1) mice. Six-week PHEB administration significantly improved the cognitive behavior of mice. Brain injury, amyloid beta deposition and tau hyperphosphorylation were alleviated in PHEB-treated AD mice without changes in other tissues. PHEB alleviated the oxidative stress in brains of AD mice via regulation the Nrf2 and its downstream kinase, which further improved the cholinergic system function. Proteomics and bioinformatics analysis showed that the therapeutic effect of PHEB is achieved by regulating calcium homeostasis mediated by oxidative stress. Furthermore, PHEB regulated the CaMK II/IV to achieve the calcium homeostasis in brains; and ultimately to show the anti-AD property.

Hippocampal CysLT1R overexpression or activation accelerates memory deficits, synaptic dysfunction, and amyloidogenesis in young APP/PS1 transgenic mice.

BackgroundOur previous studies demonstrated that cysteinyl leukotrienes receptor 1 (CysLT1R) knockout, pharmacological blockade, or hippocampus knockdown produced beneficial effects against Alzheimer’s disease (AD); however, whether CysLT1R upregulation has deleterious effects on AD remains elusive.MethodsIn this study, we investigated the changes in behaviors, hippocampal amyloidogenesis, and synapse plasticity after CysLT1R overexpression by microinfusion of the lentiviral vector, containing its coding sequence of mouse (LV-CysLT1R), into the bilateral dentate gyri (DG) of the hippocampus or CysLT1R activation by repeated systemic administration of its agonist YM-17690 (0.1 mg/kg, once a day, i.p., for 28 d).ResultsThe behavior data showed that overexpression of CysLT1R in hippocampal DG or administration of YM-17690 deteriorated behavioral performance in Morris water maze (MWM), Y-maze tests, and novel object recognition (NOR) in young APP/PS1 mice. The further studies showed that these treatments significantly destroyed synaptic function, as evidenced by impaired hippocampal long-term potentiation (LTP), decreased spine density, low number of synapses, and decreased postsynaptic protein (PSD95), and promoted the generation of amyloid β (Aβ) through increased expression of BACE1 and PS1 in the hippocampus of young APP/PS1 mice.ConclusionsTogether, our results indicate that CysLT1R upregulation accelerates memory impairment in young APP/PS1 mice, which is associated with promoting synaptic dysfunction and amyloidogenesis in the hippocampus.

Comparative Transcriptome Analysis of the Expression of Antioxidant and Immunity Genes in the Spleen of a Cyanidin 3-O-Glucoside-Treated Alzheimer's Mouse Model.

Cyanidin 3-O-glucoside (C3G) is a well-known antioxidant found as a dietary anthocyanin in different fruits and vegetables. It has protective and therapeutic effects on various diseases. It can reduce neuronal death from amyloid-beta (Aβ)-induced toxicity and promote the inhibition of Aβ fibrillization. Antioxidant and immune modulation might play a critical role in the properties of C3G against Alzheimer’s disease (AD) and other diseases. However, limited studies have been performed on the mechanism involved in the effect of C3G through transcriptome analysis. Thus, the objective of this study was to perform comparative transcriptome analysis of the spleen to determine gene expression profiles of wild-type mice (C57BL/6J Jms), an Alzheimer’s mouse model (APPswe/PS1dE9 mice), and a C3G-treated Alzheimer’s mouse model. Differentially expressed antioxidant, immune-related, and AD pathways genes were identified in the treated group. The validation of gene expression data via RT-PCR studies further supported the current findings. Six important antioxidant genes (S100a8, S100a9, Prdx2, Hp, Mpst, and Prxl2a) and a high number of immune-related genes were found to be upregulated in the treatment groups, suggesting the possible antioxidant and immunomodulatory mechanisms of C3G, respectively. Further studies are strongly recommended to elucidate the precise role of these essential genes and optimize the therapeutic function of C3G in AD and other disease conditions.

Integrative brain transcriptome analysis links complement component 4 and HSPA2 to the APOE \u03b52 protective effect in Alzheimer disease

Mechanisms underlying the protective effect of apolipoprotein E (APOE) ε2 against Alzheimer disease (AD) are not well understood. We analyzed gene expression data derived from autopsied brains donated by 982 individuals including 135 APOE ɛ2/ɛ3 carriers. Complement pathway genes C4A and C4B were among the most significantly differentially expressed genes between ɛ2/ɛ3 AD cases and controls. We also identified an APOE ε2/ε3 AD-specific co-expression network enriched for astrocytes, oligodendrocytes and oligodendrocyte progenitor cells containing the genes C4A, C4B, and HSPA2. These genes were significantly associated with the ratio of phosphorylated tau at position 231 to total Tau but not with amyloid-β 42 level, suggesting this APOE ɛ2 related co-expression network may primarily be involved with tau pathology. HSPA2 expression was oligodendrocyte-specific and significantly associated with C4B protein. Our findings provide the first evidence of a crucial role of the complement pathway in the protective effect of APOE ε2 for AD.

Two New Diterpenoids from Biscogniauxia sp. and Their Activities.

Two new diterpenoids, including a seco-isopimarane type (1) and an abietane type (2), were isolated from Biscogniauxia sp. (71-10-1-1). Their structures, including absolute configurations, were elucidated by NMR spectroscopic analyses, X-ray crystallography, 13C chemical shifts calculations, and ECD calculations. This is the first report of diterpenoids from Biscogniauxia sp. Furthermore, short-term memory enhancement against Alzheimer’s disease (AD), anti-inflammatory, and cytotoxic activities of 1–2 were also evaluated. The results showed that compound 1 exhibited short-term memory enhancement activity against AD.

DSCR1 upregulation enhances dural meningeal lymphatic drainage to attenuate amyloid pathology of Alzheimer's disease.

Highly developed meningeal lymphatics remove waste products from the brain. Disruption of meningeal lymphatic vessels in a mouse model of amyloid pathology (5XFAD) accelerates the accumulation of amyloid plaques in the meninges and brain, and causes learning and memory deficits, suggesting that clearance of toxic wastes by lymphatic vessels plays a key role in neurodegenerative diseases. Here, we discovered that DSCR1 (Down syndrome critical region 1, known also as RCAN1, regulator of calcineurin 1) facilitates the drainage of waste products by increasing the coverage of dorsal meningeal lymphatic vessels. Furthermore, upregulation of DSCR1 in 5XFAD mice diminishes Aβ pathology in the brain and improves memory defects. Surgical ligation of cervical lymphatic vessels afferent to dcLN blocks the beneficial effects of DSCR1 on Aβ accumulation and cognitive function. Interestingly, intracerebroventricular delivery of AAV1-DSCR1 to 5XFAD mice is sufficient to rebuild the meningeal lymphatic system and re-establish cognitive performance. Collectively, our data indicate that DSCR1 facilitates the growth of dorsal meningeal lymphatics to improve drainage efficiency and protect against Alzheimer's disease (AD) pathologies, further highlighting that improving meningeal lymphatic function is a feasible treatment strategy for AD. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Curiosity-Based Interventions Increase Everyday Functioning Score But Not Serum BDNF Levels in a Cohort of Healthy Older Adults.

An enriched environment is effective in stimulating learning and memory in animal models as well as in humans. Environmental enrichment increases brain-derived neurotrophic factor (BDNF) in aged rats and reduces levels of Alzheimer-related proteins in the blood, including amyloid-β (Aβ) peptides and misfolded toxic forms of tau. To address whether stimulation of curiosity, which is a form of enrichment, may provide a buffer against Alzheimer’s disease (AD), we measured levels of biomarkers associated with AD at baseline and after a 6-week intervention in older adults (>65 years of age) randomized to one of three different intervention conditions. Specifically, in this pilot study, we tested the effectiveness of a traditional, structured learning environment compared to a self-motivated learning environment designed to stimulate curiosity. There were no significant differences from baseline to post-intervention in any of the groups for Aβ42/Aβ40 ratio or t-tau (total-tau) plasma levels. Serum BDNF levels decreased significantly in the control group. Interestingly, individuals who had the lowest serum BDNF levels at baseline experienced significantly higher increases in BDNF over the course of the 6-week intervention compared to individuals with higher serum BDNF levels at baseline. As expected, older individuals had lower MoCA scores. Years of education correlated negatively with Aβ levels, suggesting a protective effect of education on levels of this toxic protein. ECog scores were negatively correlated with BDNF levels, suggesting that better performance on the ECog questionnaire was associated with higher BDNF levels. Collectively, these findings did not suggest that a 6-week cognitive training intervention focused on curiosity resulted in significant alterations in blood biomarkers but showed interesting correlations between cognitive scores and BDNF levels, further supporting the role of this trophic factor in brain health in older adults.

Neuroprotective Efficacy of Apple Cider Vinegar on Zinc-High Fat Diet-Induced Mono Amine Oxidase Alteration in Murine Model of AD

Objective: Monoamine Oxidase (MAO), which catalyzes the oxidative deamination of amines present in the brain and peripheral tissues, is involved in the metabolism of monoamines and is vital for cognition. This study was designed to examine the protective effect of Apple Cider Vinegar (ACV) on MAO and amine neurotransmitters such as dopamine (DA), serotonin (5-HT), non-adrenaline (NA) levels. Method: In this experiment, out of five groups, three groups of animals were pretreated with one of the test drugs each i.e., Chrysin (10 mg/kg), ACV (0.7% v/v) and Rivastigmine (2.5 mg/kg) along with Zn with high fat diet (HFD) for 3 months and the rest two groups were that of control and disease induced. After the treatment period, mice were examined for MAO-A & B, DA, 5-HT and NA level estimation. Results: The results showed that Zn with HFD had induced a significant increase (p < 0.01, p < 0.001) in MAO-A & B levels and a significant decrease (p < 0.001) in the levels of 5-HT, DA, and NA. Pretreatment of test drugs with Zn with HFD caused a restoration activity and a significant decrease (p < 0.01, p < 0.05) in MAO-A & B levels and a significant increase (p < 0.05, p < 0.01, p < 0.001) in the level of DA, 5HT and NA as compared to the Zn treated group. Amongst all three test drugs mentioned above, the ACV-treated group showed the most improvement during pretreatment. Conclusions: The findings suggest that ACV, might prove to be a beneficial nutraceutical & provide a protective effect against Alzheimer’s disease (AD)-like neurological diseases.