Extracellular Amyloid-beta Research Articles

The analysis of whether CRISPR-Cas9 is the way forward for Alzheimers disease treatment

Alzheimer's disease (AD) is a progressive and irreversible neurological condition which according to WHO affects more than 55 million individuals globally and is the leading cause of dementia and thereby poses a significant burden on healthcare systems worldwide. AD progresses through stages of mild cognitive impairment to severe dementia and is characterised by the accumulation of extracellular amyloid-beta plaques and neurofibrillary tangles concentrated with tau proteins in neocortical structures and the temporal lobe. Gene-editing technology such as the most prevalent CRISPR-Cas9 provides prospects for the treatment of AD by enabling precise modifications of the genetic mutations associated with the disease. This review explores the potential of CRISPR-Cas9 to revolutionise treatment by targeting and rectifying mutated genes but also examines the current state of Alzheimers treatment. This paper examines recent advancements in preclinical studies and highlights the successes in reducing amyloid-beta plaques and tau neurofibrillary tangles, the pathological features of AD. By evaluating current CRISPR-Cas9 research and other treatments for AD, I aim to provide insight into its potential as a transformative gene therapy approach whilst evaluating its limitations.

NCMP-06. GENOTYPE AND SEX IMPACT MEMORY FUNCTION AFTER BRAIN IRRADIATION

Abstract PURPOSE/OBJECTIVE Cognitive changes are a serious complication that can occur after brain radiotherapy. There is a need to better understand which individuals are more susceptible to develop strategies to preserve their function. The apolipoprotein E type 4 allele (APOEe4) APOE4 is the most prevalent genetic risk factor for Alzheimer Disease. We hypothesized that APOE genotype influences memory function after a subtherapeutic dose of whole brain irradiation in male and female mice. MATERIALS/METHODS Age-matched adult female and male mice engineered with either human APOE3 or APOE4 gene knocked-in were randomized to no treatment or whole brain irradiation (0 Gy or 5 Gy x 2), then evaluated with longitudinal neurobehavioral tests of learning, memory, pain threshold and anxiety. We performed immunohistochemical analyses of mouse brain sections at 1 month and at 4 months post-radiation to quantify extracellular amyloid beta plaques and other neuropathologic hallmarks associated with neurodegeneration. RESULTS Neurobehavioral testing identified significant sex and genotype-dependent changes in memory and anxiety measures developing longitudinally after brain irradiation. At baseline (unirradiated), APOE4 mice (male and female) performed worse on multiple memory measures. However after irradiation, sex and genotype each independently impacted multiple neurobehavioral function tests and also interacted with each other to significantly influence the timing and magnitude of changes in memory function. ApoE4 significantly impacted the toxicity of radiation in a sex-dependent manner. Neuropathologic analyses including amyloid beta plaque deposition and ApoE levels are ongoing. CONCLUSIONS After brain irradiation of relatively moderate dose, neurobehavioral performance including memory are impacted in a genotype and sex-dependent manner and dynamically over time. In addition to suggesting important sex-dependent differences in memory vulnerability, these data point to new opportunities for personalizing care for patients receiving brain irradiation.

Isotope Encoded chemical Imaging Identifies Amyloid Plaque Age Dependent Structural Maturation, Synaptic Loss, and Increased Toxicity.

It is of critical importance to our understanding of Alzheimer's disease (AD) pathology to determine how key pathological factors are interconnected and implicated in nerve cell death, clinical symptoms, and disease progression. The formation of extracellular beta-amyloid (Aβ) plaques is the major pathological hallmark of AD and Aβ has been suggested to be a critical inducer of AD, driving disease pathogenesis. Exactly how Aβ plaque formation begins and how ongoing plaque deposition proceeds and initiates subsequent neurotoxic mechanisms is not well understood. The primary aim of our research is to elucidate the biochemical processes underlying early Aβ plaque formation in brain tissue. We recently introduced a chemical imaging paradigm based on mass spectrometry imaging (MSI) and metabolic isotope labelling to follow stable isotope labelling kinetics (iSILK) in vivo to track the in vivo build-up and deposition of Aβ. Herein, knock-in Aβ mouse models (App NL-F ) that develop Aβ pathology gradually are metabolically labeled with stable isotopes. This chemical imaging approach timestamps amyloid plaques during the period of initial deposition allowing the fate of aggregating Aβ species from before and during the earliest events of plaque pathology through plaque maturation to be tracked. To identify the molecular and cellular response to plaque maturation, we integrated iSILK with single plaque transcriptomics performed on adjacent tissue sections. This enabled changes in gene expression to be tracked as a function of plaque age (as encoded in the Aβ peptide isotopologue pattern) distinct from changes due to the chronological age or pathological severity. This approach identified that plaque age correlates negatively with gene expression patterns associated with synaptic function as early as in 10-month-old animals but persists into 18 months. Finally, we integrated hyperspectral confocal microscopy into our multiomic approach to image amyloid structural isomers, revealing a positive correlation between plaque age and amyloid structural maturity. This analysis identified three categories of plaques, each with a distinct impact on the surrounding microenvironment. Here, we identified that older, more compact plaques were associated with the most significant synapse loss and toxicity. These data show how isotope-encoded MS imaging can be used to delineate Aβ toxicity dynamics in vivo. Moreover, we show for the first time a functional integration of dynamic MSI, structural plaque imaging and whole genome-wide spatial transcriptomics at the single plaque level. This multiomic approach offers an unprecedented combination of temporal and spatial resolution enabling a description of the earliest events of precipitating amyloid pathology and how Aβ modulates synaptotoxic mechanisms.

Disrupted mitochondrial response to nutrients is a presymptomatic event in the cortex of the APPSAA knock-in mouse model of Alzheimer's disease.

Reduced brain energy metabolism, mammalian target of rapamycin (mTOR) dysregulation, and extracellular amyloid beta (Aβ) oligomer (xcAβO) buildup are some well-known Alzheimer's disease (AD) features; how they promote neurodegeneration is poorly understood. We previously reported that xcAβOs inhibit nutrient-induced mitochondrial activity (NiMA) in cultured neurons. We now report NiMA disruption in vivo. Brain energy metabolism and oxygen consumption were recorded in heterozygous amyloid precursor protein knock-in (APPSAA) mice using two-photon fluorescence lifetime imaging and multiparametric photoacoustic microscopy. NiMA is inhibited in APPSAA mice before other defects are detected in these Aβ-producing animals that do not overexpress APP or contain foreign DNA inserts into genomic DNA. Glycogen synthase kinase 3 (GSK3β) signals through mTORC1 to regulate NiMA independently of mitochondrial biogenesis. Inhibition of GSK3β with TWS119 stimulates NiMA in cultured human neurons, and mitochondrial activity and oxygen consumption in APPSAA mice. NiMA disruption in vivo occurs before plaques, neuroinflammation, and cognitive decline in APPSAA mice, and may represent an early stage in human AD. Amyloid beta blocks communication between lysosomes and mitochondria in vivo. Nutrient-induced mitochondrial activity (NiMA) is disrupted long before the appearance of Alzheimer's disease (AD) histopathology in heterozygous amyloid precursor protein knock-in (APPSAA/+) mice. NiMA is disrupted long before learning and memory deficits in APPSAA/+ mice. Pharmacological interventions can rescue AD-related NiMA disruption in vivo.

Abstract P132: Sex Differences in Cerebrovascular Dysfunction in the APP/PS1 TgF344-AD Rat Model of Alzheimer's Disease

Alzheimer's Disease (AD) is the primary cause of dementia and is characterized by extracellular beta-amyloid plaques and intracellular hyperphosphorylated tau-containing neurofibrillary tangles in the brain. Emerging evidence suggests that cerebrovascular dysfunction is associated with AD. Although two-thirds of AD patients are female, sex differences in transgenic AD models have been largely ignored. The present study investigated sex differences in cerebrovascular dysfunction and potential mechanisms in AD using a TgF344-AD rat model. The APP/PS1 TgF344-AD (AD) rats serve as a preferred model to study AD since they recapitulate the complete repertoire of AD-like pathologies in humans. We previously longitudinally characterized cerebral hemodynamics in male TgF344 AD rats at 3, 4, 6, and 14 months, and reported that 4-month-old AD males displayed early signs of impaired cerebral blood flow (CBF) autoregulation and reduced functional hyperemia, two months earlier than memory loss, which was co-occurred with the appearance of plaques. These deficits progressed with advancing age. The present study used 13-14 months of female TgF344-AD (AD) and F344 (WT) rats. We found that AD females also displayed impaired learning and memory function in the eight-arm swim and open field tests as seen in males. Amyloid plaques were prominent in the hippocampus and cortex of female AD brains at a similar level in males, while no plaques were observed in WT brains. Functional hyperemic responses to whisker stimulation were markedly impaired in female AD rats. Further, we found evidence of astrocyte activation and microgliosis in female AD brains using immunohistochemistry and western blots. The astrocytes and microglial activation formed clusters around amyloid plaques. The direct contact between astrocytic endfeet and penetrating arterioles was markedly reduced in AD animals. Moreover, the blood-brain barrier (BBB) was disrupted in AD animals as the tight junction marker ZO1 was significantly reduced in AD brains. These results demonstrate cerebrovascular dysfunction contributes to loss of cognitive function in both male and female APP/PS1 TgF344-AD rats and is associated with impaired functional hyperemia, loss of astrocytic endfeet on penetrating arterioles, BBB breakdown, neuroinflammation related to amyloid plaques. They also indicate that the female TgF344-AD rat is appropriate for studying age-related influences of sex hormones on AD.

Sex-dependent effects of amyloidosis on functional network hub topology is associated with downregulated neuronal gene signatures in the APPswe/PSEN1dE9 double transgenic mouse.

Extracellular beta-amyloid (Aβ) is thought to cause impairments in brain-wide functional connectivity, although mechanisms linking Aβ to broader functional network processing remain elusive. In the present study, we evaluated the effects of Aβ on fear memory and functional connectome measures in male and female mice. Middle-aged (9-11mo) double transgenic APP-PS1 mice and age and sex-matched controls were tested on a fear conditioning protocol and then imaged at 11.1 Tesla. Brains were harvested and processed for analysis of Aβ plaques and Iba1 immunolabeling in neocortical areas, hippocampus, and basolateral amygdala. Additional RNA sequencing data from separate age, strain, and sex-matched mice were analyzed for differentially expressed genes (DEGs) and weighted gene co-expression networks. In both male and female mice, we observed increased functional connectivity in a dorsal striatal/amygdala network as a result of Aβ. Increased functional connectivity within this network was matched by increases in APP gene expression, Aβ and Iba1 immunolabeling, and an upregulated cluster of DEGs involved in the immune response. Conversely, the network measure representing node hubness, eigenvector centrality, was increased in prefrontal cortical brain regions, but only in female APP-PS1 mice. This female-specific effect of amyloid was associated with down-regulation of a cluster of DEGs involved in cortical and striatal GABA transmission, anxiogenic responses, and motor activity, in female APP-PS1 mice, but not males. Our results contribute to a growing literature linking between Aβ, immune activation, and functional network connectivity. Furthermore, our results reveal outcomes of Aβ on gene expression patterns in female mice that may contribute to amyloidosis-induced dysregulation of non-cognitive circuitry.

The relationship between hypoxia and Alzheimer's disease: an updated review.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases, and the most prevalent form of dementia. The main hallmarks for the diagnosis of AD are extracellular amyloid-beta (Aβ) plaque deposition and intracellular accumulation of highly hyperphosphorylated Tau protein as neurofibrillary tangles. The brain consumes more oxygen than any other organs, so it is more easily to be affected by hypoxia. Hypoxia has long been recognized as one of the possible causes of AD and other neurodegenerative diseases, but the exact mechanism has not been clarified. In this review, we will elucidate the connection between hypoxia-inducible factors-1α and AD, including its contribution to AD and its possible protective effects. Additionally, we will discuss the relationship between oxidative stress and AD as evidence show that oxidative stress acts on AD-related pathogenic factors such as mitochondrial dysfunction, Aβ deposition, inflammation, etc. Currently, there is no cure for AD. Given the close association between hypoxia, oxidative stress, and AD, along with current research on the protective effects of antioxidants against AD, we speculate that antioxidants could be a potential therapeutic approach for AD and worth further study.

Multiple Roles of Apolipoprotein E4 in Oxidative Lipid Metabolism and Ferroptosis During the Pathogenesis of Alzheimer’s Disease

Alzheimer’s disease (AD) is the most prevalent neurodegenerative disease worldwide and has a great socio-economic impact. Modified oxidative lipid metabolism and dysregulated iron homeostasis have been implicated in the pathogenesis of this disorder, but the detailed pathophysiological mechanisms still remain unclear. Apolipoprotein E (APOE) is a lipid-binding protein that occurs in large quantities in human blood plasma, and a polymorphism of the APOE gene locus has been identified as risk factors for AD. The human genome involves three major APOE alleles (APOE2, APOE3, APOE4), which encode for three subtly distinct apolipoprotein E isoforms (APOE2, APOE3, APOE4). The canonic function of these apolipoproteins is lipid transport in blood and brain, but APOE4 allele carriers have a much higher risk for AD. In fact, about 60% of clinically diagnosed AD patients carry at least one APOE4 allele in their genomes. Although the APOE4 protein has been implicated in pathophysiological key processes of AD, such as extracellular beta-amyloid (Aβ) aggregation, mitochondrial dysfunction, neuroinflammation, formation of neurofibrillary tangles, modified oxidative lipid metabolism, and ferroptotic cell death, the underlying molecular mechanisms are still not well understood. As for all mammalian cells, iron plays a crucial role in neuronal functions and dysregulation of iron homeostasis has also been implicated in the pathogenesis of AD. Imbalances in iron homeostasis and impairment of the hydroperoxy lipid-reducing capacity induce cellular dysfunction leading to neuronal ferroptosis. In this review, we summarize the current knowledge on APOE4-related oxidative lipid metabolism and the potential role of ferroptosis in the pathogenesis of AD. Pharmacological interference with these processes might offer innovative strategies for therapeutic interventions.

Investigating Stem Cell Therapy for Alzheimer's Disease: A Promising Approach

Alzheimer's disease (AD) is a neurodegenerative disorder, a form of dementia commonly affecting people 40-65. Growing more prevalent in society, approximately 6.2 million Americans aged 65 and older live with AD. AD is a progressive, long-term neurological disorder that worsens cognitive skills, memory, and communication abilities leading to a performative decline in daily tasks. Characterized by the accumulation of extracellular amyloid beta (Aβ) plaque and neurofibrillary tangles (NFTs) of tau in the central nervous system, these account for synapse loss and neuronal death in the brain. Unfortunately, even with its detrimental impacts, clinical trials of therapeutic drugs are still to be tested and not available to the public. Current research on stem cell transplantation has been shown to alleviate neuropathologies and is explored as a prospective treatment for AD. This literature review assesses the important uses of stem cell therapy for AD patients to provide a new clinical approach for future treatment. Further clinical research should be conducted on the long-term outcomes of stem cell therapy for deeper analysis of its therapeutic effects for AD.

Brain Slice Derived Nerve Fibers Grow along Microcontact Prints and are Stimulated by Beta-Amyloid(42).

Alzheimer's disease is characterized by extracellular beta-amyloid plaques, intraneuronal tau neurofibrillary tangles and excessive neurodegeneration. The mechanisms of neuron degeneration and the potential of these neurons to form new nerve fibers for compensation remain elusive. The present study aimed to evaluate the impact of beta-amyloid and tau on new formations of nerve fibers from mouse organotypic brain slices connected to collagen-based microcontact prints. Organotypic brain slices of postnatal day 8-10 wild-type mice were connected to established collagen-based microcontact prints loaded with polyornithine to enhance nerve fiber outgrowth. Human beta-amyloid(42) or P301S mutated aggregated tau was co-loaded to the prints. Nerve fibers were immunohistochemically stained with neurofilament antibodies. The physiological activity of outgrown neurites was tested with neurotracer MiniRuby, voltage-sensitive dye FluoVolt, and calcium-sensitive dye Rhod-4. Immunohistochemical staining revealed newly formed nerve fibers extending along the prints derived from the brain slices. While collagen-only microcontact prints stimulated nerve fiber growth, those loaded with polyornithine significantly enhanced nerve fiber outgrowth. Beta-amyloid(42) significantly increased the neurofilament-positive nerve fibers, while tau had only a weak effect. MiniRuby crystals, retrogradely transported along these newly formed nerve fibers, reached the hippocampus, while FluoVolt and Rhod-4 monitored electrical activity in newly formed nerve fibers. Our data provide evidence that intact nerve fibers can form along collagen-based microcontact prints from mouse brain slices. The Alzheimer's peptide beta-amyloid(42) stimulates this growth, hinting at a neuroprotective function when physiologically active. This "brain-on-chip" model may offer a platform for screening bioactive factors or testing drug effects on nerve fiber growth.

Crystal Violet Selectively Detects Aβ Oligomers but Not Fibrils In Vitro and in Alzheimer's Disease Brain Tissue.

Deposition of extracellular Amyloid Beta (Aβ) and intracellular tau fibrils in post-mortem brains remains the only way to conclusively confirm cases of Alzheimer's Disease (AD). Substantial evidence, though, implicates small globular oligomers instead of fibrils as relevant biomarkers of, and critical contributors to, the clinical symptoms of AD. Efforts to verify and utilize amyloid oligomers as AD biomarkers in vivo have been limited by the near-exclusive dependence on conformation-selective antibodies for oligomer detection. While antibodies have yielded critical evidence for the role of both Aβ and tau oligomers in AD, they are not suitable for imaging amyloid oligomers in vivo. Therefore, it would be desirable to identify a set of oligomer-selective small molecules for subsequent development into Positron Emission Tomography (PET) probes. Using a kinetics-based screening assay, we confirm that the triarylmethane dye Crystal Violet (CV) is oligomer-selective for Aβ42 oligomers (AβOs) grown under near-physiological solution conditions in vitro. In postmortem brains of an AD mouse model and human AD patients, we demonstrate that A11 antibody-positive oligomers but not Thioflavin S (ThioS)-positive fibrils colocalize with CV staining, confirming in vitro results. Therefore, our kinetic screen represents a robust approach for identifying new classes of small molecules as candidates for oligomer-selective dyes (OSDs). Such OSDs, in turn, provide promising starting points for the development of PET probes for pre-mortem imaging of oligomer deposits in humans.

Particulate matter constituents trigger the formation of extracellular amyloid β and Tau -containing plaques and neurite shortening in vitro

Air pollution is an environmental factor associated with an increased risk of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, characterized by decreased cognitive abilities and memory. The limited models of sporadic Alzheimer’s disease fail to replicate all pathological hallmarks of the disease, making it challenging to uncover potential environmental causes. Environmentally driven models of Alzheimer’s disease are thus timely and necessary. We used live-cell confocal fluorescent imaging combined with high-resolution stimulated emission depletion (STED) microscopy to follow the response of retinoic acid-differentiated human neuroblastoma SH-SY5Y cells to nanomaterial exposure. Here, we report that exposure of the cells to some particulate matter constituents reproduces a neurodegenerative phenotype, including extracellular amyloid beta-containing plaques and decreased neurite length. Consistent with the existing in vivo research, we observed detrimental effects, specifically a substantial reduction in neurite length and formation of amyloid beta plaques, after exposure to iron oxide and diesel exhaust particles. Conversely, after exposure to engineered cerium oxide nanoparticles, the lengths of neurites were maintained, and almost no extracellular amyloid beta plaques were formed. Although the exact mechanism behind this effect remains to be explained, the retinoic acid differentiated SH-SY5Y cell in vitro model could serve as an alternative, environmentally driven model of neurodegenerative diseases, including Alzheimer’s disease.

Polar lipids modify Alzheimer's Disease pathology by reducing astrocyte pro-inflammatory signaling through platelet-activating factor receptor (PTAFR) modulation.

Pro-inflammatory processes triggered by the accumulation of extracellular amyloid beta (Aβ) peptides are a well-described pathology in Alzheimer's disease (AD). Activated astrocytes surrounding Aβ plaques contribute to inflammation by secreting proinflammatory factors. While astrocytes may phagocytize Aβ and contribute to Aβ clearance, reactive astrocytes may also increase Aβ production. Therefore, identifying factors that can attenuate astrocyte activation and neuroinflammation and how these factors influence pro-inflammatory pathways is important for developing therapeutic and preventive strategies in AD. Here, we identify the platelet-activating factor receptor (PTAFR) pathway as a key mediator of astrocyte activation. Intriguingly, several polar lipids (PLs) have exhibited anti-inflammatory protective properties outside the central nervous system through their inhibitory effect on the PTAFR pathway. Thus, we additionally investigated whether different PLs also exert inhibitory effects on the PAF pathway in astrocytes and whether their presence influences astrocytic pro-inflammatory signaling and known AD pathologies in vitro. PLs from salmon and yogurt were extracted using novel food-grade techniques and their fatty acid profile was determined using LC/MS. The effect of PLs on parameters such as astrocyte activation and generation of oxygen species (ROS) was assessed. Additionally, effects of the secretome of astrocytes treated with these polar lipids on aged neurons was measured. We show that PLs obtained from salmon and yogurt lower astrocyte activation, the generation of reactive oxygen species (ROS), and extracellular Aβ accumulation. Cell health of neurons exposed to the secretome of astrocytes treated with salmon-derived PLs and Aβ was less affected than those treated with astrocytes exposed to Aβ only. Our results highlight a novel underlying mechanism, why consuming PL-rich foods such as fish and dairy may reduce the risk of developing dementia and associated disorders.

Discovery of Small Molecule Glycolytic Stimulants for Enhanced ApoE Lipidation in Alzheimer's Disease Cell Model.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by pathophysiological deposits of extracellular amyloid beta (Aβ) peptides and intracellular neurofibrillary tangles of tau. The central role of Aβ in AD pathology is well-established, with its increased deposition attributed mainly to its decreased cerebral clearance. Here, it is noteworthy that apolipoprotein E (ApoE), the most significant risk factor for AD, has been shown to play an isoform-specific role in clearing Aβ deposits (ApoE2 > ApoE3 > ApoE4), owing mainly to its lipidation status. In addition to the pathophysiological Aβ deposits, AD is also characterized by abnormal glucose metabolism, which is a distinct event preceding Aβ deposition. The present study established, for the first time, a possible link between these two major AD etiologies, with glucose metabolism directly influencing ApoE lipidation and its secretion by astrocytes expressing human ApoE4. Specifically, glucose dose-dependently activated liver X receptor (LXR), leading to elevated ABCA1 and ABCG1 protein levels and enhanced ApoE lipidation. Moreover, co-treatment with a glycolytic inhibitor significantly inhibited this LXR activation and subsequent ApoE lipidation, further supporting a central role of glucose metabolism in LXR activation leading to enhanced ApoE lipidation, which may help against AD through potential Aβ clearance. Therefore, we hypothesized that pharmacological agents that can target cellular energy metabolism, specifically aerobic glycolysis, may hold significant therapeutic potential against AD. In this context, the present study also led to the discovery of novel, small-molecule stimulants of astrocytic glucose metabolism, leading to significantly enhanced lipidation status of ApoE4 in astrocytic cells. Three such newly discovered compounds (lonidamine, phenformin, and berberine), owing to their promising cellular effect on the glycolysis-ApoE nexus, warrant further investigation in suitable in vivo models of AD.

Early amyloid-induced changes in microglia gene expression in male APP/PS1 mice.

Alzheimer's disease (AD) is a progressive neurodegenerative disease and the most common cause of dementia, characterized by deposition of extracellular amyloid-beta (Aβ) aggregates and intraneuronal hyperphosphorylated Tau. Many AD risk genes, identified in genome-wide association studies (GWAS), are expressed in microglia, the innate immune cells of the central nervous system. Specific subtypes of microglia emerged in relation to AD pathology, such as disease-associated microglia (DAMs), which increased in number with age in amyloid mouse models and in human AD cases. However, the initial transcriptional changes in these microglia in response to amyloid are still unknown. Here, to determine early changes in microglia gene expression, hippocampal microglia from male APPswe/PS1dE9 (APP/PS1) mice and wild-type littermates were isolated and analyzed by RNA sequencing (RNA-seq). By bulk RNA-seq, transcriptomic changes were detected in hippocampal microglia from 6-months-old APP/PS1 mice. By performing single-cell RNA-seq of CD11c-positive and negative microglia from 6-months-old APP/PS1 mice and analysis of the transcriptional trajectory from homeostatic to CD11c-positive microglia, we identified a set of genes that potentially reflect the initial response of microglia to Aβ.

A Comprehensive Mini Review on the Natural Product Bacopa monnieri for the Management of Alzheimer’s Disease

Abstract: Central nervous system disorders are expected to profoundly impact the global healthcare needs of the human community in this era. Senile decay of neurons is (Alzheimers Disease) AD. The hallmark of the pathophysiology of AD disease has two pivotal features: extracellular beta-amyloid deposition and intracellular tau hyperphosphorylation. New medicine-based psychoactive treatments have met with modest effectiveness due to the multifactorial nature of these diseases. As a result, there is an increasing need for new products that can address various receptors and enhance behavioral abilities independently or in tandem with traditional medications. Herbal products focused on conventional expertise have recently been widely popular in developed and developing countries. Ayurveda is a medical science that deals with the treatment of diseases using naturally occurring plant products. Ayurveda claims to have a large number of neuroprotective herbs. This review discusses the pharmacological effects and therapeutic properties of In vivo, In vitro, In silico and human clinical trials of (Bacopa monnieri) BM against AD.

Perineuronal net deglycosylation associates with tauopathy-induced gliosis and neurodegeneration.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by clinical symptoms of memory and cognitive deficiencies. Postmortem evaluation of AD brain tissue shows proteinopathy that closely associate with the progression of this dementing disorder, including the accumulation of extracellular beta amyloid (Aβ) and intracellular hyperphosphorylated tau (pTau) with neurofibrillary tangles (NFTs). Current therapies targeting Aβ have limited clinical efficacy and life-threatening side effects and highlight the need for alternative treatments targeting pTau and other pathophysiologic mechanisms driving AD pathogenesis. The brain's extracellular matrices (ECM), particularly perineuronal nets (PNNs), play a crucial role in brain functioning and neurocircuit stability, and reorganization of these unique PNN matrices has been associated with the progression of AD and accumulation of pTau in humans. We hypothesize that AD-associated changes in PNNs may in part be driven by the accumulation of pTau within the brain. In this work, we investigated whether the presence of pTau influenced PNN structural integrity and PNN chondroitin sulfate-glycosaminoglycan (CS-GAG) compositional changes in two transgenic mouse models expressing tauopathy-related AD pathology, PS19 (P301S) and Tau4RTg2652 mice. We show that PS19 mice exhibit an age-dependent loss of hippocampal PNN CS-GAGs, but not the underlying aggrecan core protein structures, in association with pTau accumulation, gliosis, and neurodegeneration. The loss of PNN CS-GAGs were linked to shifts in CS-GAG sulfation patterns to favor the neuroregenerative isomer, 2S6S-CS. Conversely, Tau4RTg2652 mice exhibit stable PNN structures and normal CS-GAG isomer composition despite robust pTau accumulation, suggesting a critical interaction between neuronal PNN glycan integrity and neighboring glial cell activation. Overall, our findings provide insights into the complex relationship between PNN CS-GAGs, pTau pathology, gliosis, and neurodegeneration in mouse models of tauopathy, and offer new therapeutic insights and targets for AD treatment.

Nanotechnology for microglial targeting and inhibition of neuroinflammation underlying Alzheimer’s pathology

BackgroundAlzheimer's disease (AD) is considered to have a multifactorial etiology. The hallmark of AD is progressive neurodegeneration, which is characterized by the deepening loss of memory and a high mortality rate in the elderly. The neurodegeneration in AD is believed to be exacerbated following the intercoupled cascades of extracellular amyloid beta (Aβ) plaques, uncontrolled microglial activation, and neuroinflammation. Current therapies for AD are mostly designed to target the symptoms, with limited ability to address the mechanistic triggers for the disease. In this study, we report a novel nanotechnology based on microglial scavenger receptor (SR)-targeting amphiphilic nanoparticles (NPs) for the convergent alleviation of fibril Aβ (fAβ) burden, microglial modulation, and neuroprotection.MethodsWe designed a nanotechnology approach to regulate the SR-mediated intracellular fAβ trafficking within microglia. We synthesized SR-targeting sugar-based amphiphilic macromolecules (AM) and used them as a bioactive shell to fabricate serum-stable AM–NPs via flash nanoprecipitation. Using electron microscopy, in vitro approaches, ELISA, and confocal microscopy, we investigated the effect of AM–NPs on Aβ fibrilization, fAβ-mediated microglial inflammation, and neurotoxicity in BV2 microglia and SH-SY5Y neuroblastoma cell lines.ResultsAM–NPs interrupted Aβ fibrilization, attenuated fAβ microglial internalization via targeting the fAβ-specific SRs, arrested the fAβ-mediated microglial activation and pro-inflammatory response, and accelerated lysosomal degradation of intracellular fAβ. Moreover, AM–NPs counteracted the microglial-mediated neurotoxicity after exposure to fAβ.ConclusionsThe AM–NP nanotechnology presents a multifactorial strategy to target pathological Aβ aggregation and arrest the fAβ-mediated pathological progression in microglia and neurons.Graphical

HLH-30/TFEB modulates autophagy to improve proteostasis in Aβ transgenic Caenorhabditis elegans.

Alzheimer's disease (AD) is a complex neurodegenerative disease that affects elderly individuals, characterized by senile plaques formed by extracellular amyloid beta (Aβ). Autophagy dysfunction is a manifestation of protein homeostasis imbalance in patients with AD, but its relationship with Aβ remains unclear. Here, we showed that in Aβ transgenic Caenorhabditis elegans, Aβ activated the TOR pathway and reduced the nuclear entry of HLH-30, leading to autophagy dysfunction characterized by autophagosome accumulation. Then, utilizing RNA-seq, we investigated the regulatory mechanisms by which HLH-30 modulates autophagy in C. elegans. We found that HLH-30 elevated the transcript levels of v-ATPase and cathepsin, thus enhancing lysosomal activity. This led to an increase in autophagic flux, facilitating more pronounced degradation of Aβ. Moreover, HLH-30 reduced the level of ROS induction by Aβ and enhanced the antioxidant stress capacity of the worms through the gsto-1 gene. Additionally, we identified two HLH-30/TFEB activators, saikosaponin B2 and hypericin, that improved autophagic flux, thereby enhancing protein homeostasis in C. elegans. Overall, our findings suggested that HLH-30/TFEB plays a key role in modulating autophagy and can be considered a promising drug target for AD treatments.

Inhibitory Impacts of Fulvic Acid-Coated Iron Oxide Nanoparticles on the Amyloid Fibril Aggregations.

Alzheimer's disease is considered as multi-factor diseases, the main hallmarks of which are extracellular amyloid-beta and intracellular tau protein aggregations, leading to neural death. With this in mind, most of the studies have been focused on eliminating these aggregations. Fulvic acid is one of the polyphenolic compounds which exhibits strong anti-inflammation and anti-amyloidogenic effects. On the other hand, iron oxide nanoparticles are able to reduce/eliminate the amyloid aggregations. Here in, the effect of fulvic acid-coated iron-oxide nanoparticles on the commonly used in-vitro model for amyloid aggregation studies, i. e., lysozyme from chicken egg white was investigated. The chicken egg white lysozyme forms the amyloid aggregation under acidic pH and high heat. The average size of nanoparticles was 10.7±2.7 nm. FESEM, XRD, and FTIR confirmed that fulvic acid was coated onto the surface of the nanoparticles. The inhibitory effects of the nanoparticles were verified by Thioflavin T assay, CD, and FESEM analysis. Furthermore, the toxicity of the nanoparticles on the neuroblastoma SH-SY5Y was assessed through MTT assay. Our results indicate that these nanoparticles efficiently inhibit amyloid aggregation formation, while exhibiting no in-vitro toxicity. This data shed light on the anti-amyloid activity of the nanodrug; paving the way for future drug development for treating Alzheimer's disease.