Pathological Features Of Alzheimer's Disease Research Articles

Astrocyte activation imaging with 11C-acetate and amyloid PET in mild cognitive impairment due to Alzheimer pathology.

Neuroinflammation is a well-known feature of early Alzheimer disease (AD) yet astrocyte activation has not been extensively evaluated with in vivo imaging in mild cognitive impairment (MCI) due to amyloid plaque pathology. Unlike neurons, astrocytes metabolize acetate, which has potential as a glial biomarker in neurodegeneration in response to AD pathologic features. Since the medial temporal lobe (MTL) is a hotspot for AD neurodegeneration and inflammation, we assessed astrocyte activity in the MTL and compared it to amyloid and cognition. We evaluate spatial patterns of in vivo astrocyte activation and their relationships to amyloid deposition and cognition in a cross-sectional pilot study of six participants with MCI and five cognitively normal participants. We measure 11C-acetate and 18F-florbetaben amyloid standardized uptake values ratios (SUVRs) and kinetic flux compared to the cerebellum on PET, with MRI and neurocognitive testing. MTL 11C-acetate SUVR was significantly elevated in MCI compared to cognitively normal participants (P = 0.03; Cohen d = 1.76). Moreover, MTL 11C-acetate SUVR displayed significant associations with global and regional amyloid burden in MCI. Greater MTL 11C-acetate retention was significantly related with worse neurocognitive measures including the Montreal Cognitive Assessment (P = 0.001), word list recall memory (P = 0.03), Boston naming test (P = 0.04) and trails B test (P = 0.04). While further validation is required, this exploratory pilot study suggests a potential role for 11C-acetate PET as a neuroinflammatory biomarker in MCI and early AD to provide clinical and translational insights into astrocyte activation as a pathological response to amyloid.

Sunday Driver Mediates Multi-Compartment Golgi Outposts Defects Induced by Amyloid Precursor Protein.

Golgi defects including Golgi fragmentation are pathological features of Alzheimer’s disease (AD). As a pathogenic factor in AD, amyloid precursor protein (APP) induces Golgi fragmentation in the soma. However, how APP regulates Golgi outposts (GOs) in dendrites remains unclear. Given that APP resides in and affects the movements of GOs, and in particular, reverses the distribution of multi-compartment GOs (mcGOs), we investigated the regulatory mechanism of mcGO movements in the Drosophila larvae. Knockdown experiments showed that the bidirectional mcGO movements were cooperatively controlled by the dynein heavy chain (Dhc) and kinesin heavy chain subunits. Notably, only Dhc mediated APP’s regulation of mcGO movements. Furthermore, by loss-of-function screening, the adaptor protein Sunday driver (Syd) was identified to mediate the APP-induced alteration of the direction of mcGO movements and dendritic defects. Collectively, by elucidating a model of bidirectional mcGO movements, we revealed the mechanism by which APP regulates the direction of mcGO movements. Our study therefore provides new insights into AD pathogenesis.

Bis(8‐hydroxyquinoline) Ligands: Exploring their Potential as Selective Copper‐Binding Agents for Alzheimer's Disease

AbstractAmyloid‐β (Aβ) aggregation, metal ion dyshomeostasis, and oxidative stress are pathological features of Alzheimer's disease (AD). Aβ and metal ions form metal‐Aβ complex species that influence the aggregation of Aβ and, in particular, redox metal ions such as Cu lead to the production of reactive oxygen species (ROS). To target metal coordination to Aβ and the reactivities of Cu−Aβ, metal chelating agents must extract Cu2+ from Aβ in AD pathological conditions. Bis(8‐hydroxyquinoline) ligands can extract Cu2+ from Aβ and therefore inhibit the Cu‐induced Aβ aggregation and the aerobic oxidation of ascorbate. In particular, N‐butyl‐2,2‐imino‐bis(8‐hydroxyquinoline) can selectively target Cu−Aβ reactivities in the presence of Zn2+ such as in AD brain patients. The ligands can release Cu in intracellular environments in the presence of a large excess of glutathione, contributing to restore Cu homeostasis.

Examination of BDNF Treatment on BACE1 Activity and Acute Exercise on Brain BDNF Signaling.

Perturbations in metabolism results in the accumulation of beta-amyloid peptides, which is a pathological feature of Alzheimer’s disease. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) is the rate limiting enzyme responsible for beta-amyloid production. Obesogenic diets increase BACE1 while exercise reduces BACE1 activity, although the mechanisms are unknown. Brain-derived neurotropic factor (BDNF) is an exercise inducible neurotrophic factor, however, it is unknown if BDNF is related to the effects of exercise on BACE1. The purpose of this study was to determine the direct effect of BDNF on BACE1 activity and to examine neuronal pathways induced by exercise. C57BL/6J male mice were assigned to either a low (n = 36) or high fat diet (n = 36) for 10 weeks. To determine the direct effect of BDNF on BACE1, a subset of mice (low fat diet = 12 and high fat diet n = 12) were used for an explant experiment where the brain tissue was directly treated with BDNF (100 ng/ml) for 30 min. To examine neuronal pathways activated with exercise, mice remained sedentary (n = 12) or underwent an acute bout of treadmill running at 15 m/min with a 5% incline for 120 min (n = 12). The prefrontal cortex and hippocampus were collected 2-h post-exercise. Direct treatment with BDNF resulted in reductions in BACE1 activity in the prefrontal cortex (p < 0.05), but not the hippocampus. The high fat diet reduced BDNF content in the hippocampus; however, the acute bout of exercise increased BDNF in the prefrontal cortex (p < 0.05). These novel findings demonstrate the region specific differences in exercise induced BDNF in lean and obese mice and show that BDNF can reduce BACE1 activity, independent of other exercise-induced alterations. This work demonstrates a previously unknown link between BDNF and BACE1 regulation.

Classification of patients with Alzheimer\u2019s disease using the arterial pulse spectrum and a multilayer-perceptron analysis

Cerebrovascular atherosclerosis has been identified as a prominent pathological feature of Alzheimer’s disease (AD); the link between vessel pathology and AD risk may also extend to extracranial arteries. This study aimed to determine the effectiveness of using arterial pulse-wave measurements and multilayer perceptron (MLP) analysis in distinguishing between AD and control subjects. Radial blood pressure waveform (BPW) and finger photoplethysmography signals were measured noninvasively for 3 min in 87 AD patients and 74 control subjects. The 5-layer MLP algorithm employed evaluated the following 40 harmonic pulse indices: amplitude proportion and its coefficient of variation, and phase angle and its standard deviation. The BPW indices differed significantly between the AD patients (6247 pulses) and control subjects (6626 pulses). Significant intergroup differences were found between mild, moderate, and severe AD (defined by Mini-Mental-State-Examination scores). The hold-out test results indicated an accuracy of 82.86%, a specificity of 92.31%, and a 0.83 AUC of ROC curve when using the MLP-based classification between AD and Control. The identified differences can be partly attributed to AD-induced changes in vascular elastic properties. The present findings may be meaningful in facilitating the development of a noninvasive, rapid, inexpensive, and objective method for detecting and monitoring the AD status.

The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein.

The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer's disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism/processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology. We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon ll. A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production. These findings suggest that in the absence of MBP, there is a marked reduction of nonamyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

Amyloid pathology arrangements in Alzheimer\u2019s disease brains modulate in vivo seeding capability

Amyloid-β (Aβ) misfolding is one of the hallmark pathological features of Alzheimer’s disease (AD). AD can manifest with diverse symptomatology including variable rates of cognitive decline, duration of clinical disease, and other detrimental changes. Several reports suggest that conformational diversity in misfolded Aβ is a leading factor for clinical variability in AD, analogous to what it has been described for prion strains in prion diseases. Notably, prion strains generate diverse patterns of misfolded protein deposition in the brains of affected individuals. Here, we tested the in vivo prion-like transmission features of four AD brains displaying particular patterns of amyloidosis. AD brains induced different phenotypes in recipient mice, as evaluated by their specific seeding activity, as well as the total amount of Aβ deposited surrounding vascular structures and the reactivity of amyloid pathology to thioflavin S. Our results support the notion that AD-subtypes are encoded in disease-associated Aβ. Further research exploring whether AD include a spectrum of different clinical conditions or syndromes may pave the way to personalized diagnosis and treatments.

Olmesartan Prevents Oligomerized Amyloid β (Aβ)-Induced Cellular Senescence in Neuronal Cells.

Alzheimer's disease (AD) is a neurodegenerative disease with high morbidity. The deposition of oligomerized amyloid β (Aβ) is the pathological feature of AD. The Aβ-caused neuronal oxidative stress and cellular senescence play an important role in the development and progression of AD. Olmesartan is a novel angiotensin receptor blocker with promising antihypertensive properties and has recently been reported to exert anti-inflammatory and antioxidative stress effects. Blood pressure control using Angiotensin receptor blockers has shown multiple benefits in Alzheimer's disease models. In the present study, the effect of Olmesartan on oligomerized amyloid β (Aβ)-induced cellular senescence was investigated in cultured M17 neuronal cells. Our results show that Olmesartan treatment significantly ameliorates oligomerized Aβ-elevated ROS and MDA levels, as well as the induced senescent cells number. At the molecular level, Olmesartan inhibits the elevated expression of senescence biomarkers (p16 and p21). Furthermore, Olmesartan potently reversed the increased K382 acetylation of p53 and the downregulation of SIRT1. Moreover, we show that the effect of Olmesartan against cell senescence and deacetylation of p53 was abolished by inhibition of SIRT1, either by using nicotinamide or by transfection with SIRT1 siRNA. In conclusion, Olmesartan prevents oligomerized Aβ-induced cellular senescence in neuronal cells by downregulating p16 and p21 through a SIRT1 dependent deacetylation of p53; our finding indicates that Olmesartan has a protective effect in Aβ-induced neurotoxicity.

Impact of Tau on Neurovascular Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is a chronic neurodegenerative disorder and the most prevalent cause of dementia. The main cerebral histological hallmarks are represented by parenchymal insoluble deposits of amyloid beta (Aβ plaques) and neurofibrillary tangles (NFT), intracellular filamentous inclusions of tau, a microtubule-associated protein. It is well-established that cerebrovascular dysfunction is an early feature of AD pathology, but the detrimental mechanisms leading to blood vessel impairment and the associated neurovascular deregulation are not fully understood. In 90% of AD cases, Aβ deposition around the brain vasculature, known as cerebral amyloid angiopathy (CAA), alters blood brain barrier (BBB) essential functions. While the effects of vascular Aβ accumulation are better documented, the scientific community has only recently started to consider the impact of tau on neurovascular pathology in AD. Emerging compelling evidence points to transmission of neuronal tau to different brain cells, including astrocytes, as well as to the release of tau into brain interstitial fluids, which may lead to perivascular neurofibrillar tau accumulation and toxicity, affecting vessel architecture, cerebral blood flow (CBF), and vascular permeability. BBB integrity and functionality may therefore be impacted by pathological tau, consequentially accelerating the progression of the disease. Tau aggregates have also been shown to induce mitochondrial damage: it is known that tau impairs mitochondrial localization, distribution and dynamics, alters ATP and reactive oxygen species production, and compromises oxidative phosphorylation systems. In light of this previous knowledge, we postulate that tau can initiate neurovascular pathology in AD through mitochondrial dysregulation. In this review, we will explore the literature investigating tau pathology contribution to the malfunction of the brain vasculature and neurovascular unit, and its association with mitochondrial alterations and caspase activation, in cellular, animal, and human studies of AD and tauopathies.

The Contribution of Vascular Pathology Toward Cognitive Impairment in Older Individuals with Intermediate Braak Stage Tau Pathology

The pathological features of Alzheimer's disease (AD) are well described but little is known as to how both neurodegeneration and vascular changes might interact in causing cognitive impairment. The present study aims to investigate relationships between vascular and AD pathology in cognitively healthy and cognitively impaired individuals with a particular emphasis on those at intermediate Braak tau stages. We investigated the interplay between Braak tau stage and measures of vascular pathology as described by the vascular cognitive impairment neuropathology guidelines (VCING) in 185 brains from the Brains for Dementia Research programme and The University of Manchester Longitudinal Study of Cognition in Healthy Old Age. VCING asserts that at least one large (>10 mm) infarct, moderate/severe occipital leptomeningeal cerebral amyloid angiopathy, and moderate/severe arteriosclerosis in occipital white matter accurately predicts the contribution of cerebrovascular pathology to cognitive impairment. We found that the extent of arteriosclerosis in the occipital white matter did not differ between cognitive groups at intermediate (III-IV) Braak stages whereas moderate/severe leptomeningeal occipital cerebral amyloid angiopathy was greater in cognitively impaired than normal individuals at Braak stage III-IV. This finding remained significant after controlling for effects of age, sex, CERAD score, Thal phase, presence/severity of primary age-related tauopathy, presence/severity of limbic-predominant age-related TDP43 encephalopathy and small vessel disease in basal ganglia. Interventions targeting cerebral amyloid angiopathy may contribute to delay the onset of cognitive impairment in individuals with intermediate Alzheimer's type pathology.

Restricted Effect of Cerebral Microbleeds on Regional Magnetic Susceptibility.

Cortical iron accumulation has been reported as a pathological feature of Alzheimer's disease (AD). The cause of cortical iron elevation in AD is unknown but may be contributed by hemosiderin deposits in cerebral microbleeds that frequently occur in this disease. To investigate the impact of cerebral microbleeds (which are more frequent in AD) on the magnetic susceptibility of the surrounding brain tissue. 32 MRI scans from the Australian Imaging, Biomarker and Lifestyle (AIBL) study were found to have cerebral microbleeds by manual assessment of susceptibility weighted images. Quantitative susceptibility mapping (QSM; an MRI technique that is sensitive to iron) was used to estimate iron content in the tissue surrounding the microbleed in four concentric radii. Furthermore, the mirror regions on the contralateral hemisphere were also demarcated. A simulation analysis was conducted to investigate the effect of QSM imaging on cerebral microbleeds with varying sizes. 77 microbleeds were identified from the available scans. The immediate proximal region to the cerebral microbleeds had enhanced tissue susceptibility (∼0.02 PPM), but importantly, this did not extend beyond one voxel radius. This finding with in vivo data was also replicated in a simulation study. However, the presence of microbleeds could lead to over-estimation of tissue QSM in unsupervised quantification, therefore processing methods to avoid this artefact without the need for their manual identification are proposed. The local changes in susceptibility due to microbleeds outside the focal lesion are restricted to 1 voxel and may be explained by partial voluming artefacts caused by limited imaging resolution. The susceptibly change induced by the microbleed is a relatively small proportion of tissue and could not account for regional iron changes observed in AD cortex.

Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common cause of dementia. Mutations of presenilin (PSEN) genes that encode presenilin proteins have been found as the vital causal factors for early-onset familial AD (FAD). AD pathological features such as memory loss, synaptic dysfunction, and formation of plaques have been successfully mimicked in the transgenic mouse models that coexpress FAD-related presenilin and amyloid precursor protein (APP) variants. γ-Secretase (GS) is an enzyme that plays roles in catalyzing intramembranous APP proteolysis to release pathogenic amyloid beta (Aβ). It has been found that presenilins can play a role as the GS's catalytic subunit. FAD-related mutations in presenilins can modify the site of GS cleavage in a way that can elevate the production of longer and highly fibrillogenic Aβ. Presenilins can interact with β-catenin to generate presenilin complexes. Aforesaid interactions have also been studied to observe the mutational and physiological activities in the catenin signal transduction pathway. Along with APP, GS can catalyze intramembrane proteolysis of various substrates that play a vital role in synaptic function. PSEN mutations can cause FAD with autosomal dominant inheritance and early onset of the disease. In this article, we have reviewed the current progress in the analysis of PSENs and the correlation of PSEN mutations and AD pathogenesis.

Dendrobium nobile Lindl alkaloid and metformin ameliorate cognitive dysfunction in senescence-accelerated mice via suppression of endoplasmic reticulum stress

The senescence-accelerated mouse prone 8 (SAMP8) mice have many pathological features of Alzheimer’s disease (AD) with aging. We previously reported that Dendrobium nobile Lindl alkaloid (DNLA) effectively improved cognitive deficits in multiple Alzheimer’s disease (AD) models. This study further used SAMP8 mice to study the anti-aging effects of DNLA, focusing on endoplasmic reticulum (ER) stress. DNLA and metformin were orally administered to SAMP8 mice starting at 4-month of age for 6 months. Behavioral tests were performed in 10-month-old SAMP8 mice and age-matched SAMR1 control mice. At the end of experiment, neuron damage was evaluated by histology and transmission electron microscopy. ER stress-related proteins were analyzed with Western-blot. DNLA improved learning and memory impairments, reduced the loss of neurons and Nissl bodies in the hippocampus and cortex. DNLA ameliorated ER dilation and swelling in the hippocampal neurons. DNLA down-regulated the protein kinase RNA-like endoplasmic reticulum kinase (PERK) signaling pathway, decreased calpain 1, GSK-3β and Cdk5 activities and the Tau hyper-phosphorylation. The effects of DNLA were comparable to metformin. In summary, DNLA was effective in improving cognitive deficits in aged SAMP8 mice, possibly via suppression of ER stress-related PERK signaling pathway, sequential inhibition of calpain 1, GSK-3β and Cdk5 activities, and eventually reducing the hyper-phosphorylation of Tau.

Correction to "Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer's Disease".

Correction to "Orobol: An Isoflavone Exhibiting Regulatory Multifunctionality against Four Pathological Features of Alzheimer's Disease".

Regulation of exosome for Alzheimer's disease derived from mesenchymal stem cells.

Alzheimer's disease (AD) is the most common type of dementia in the elderly, accounting for about 75% of all dementia patients. The pathological feature of AD is the deposition of β-amyloid (Aβ) with strong neurotoxicity in brain tissue, while the hyperphosphorylation of tau in many neuronal cells forms neurofibrillary tangles (NFT). The combination of the two conditions leads to a large number of neuronal necrosis, disordered function of the brain, and serious cognitive dysfunction. Mesenchymal stem cells (MSCs) are a kind of adult stem cells, which can produce a large number of polyvesicular body secreted to the extracellular to form exosomes. Exosomes vary in size, with a diameter of about 30-150 nm, and can cross the blood-brain barrier. Exosomes can carry a large number of small miRNA and protein molecules to the brain to play a role. Exosomes derived from MSCs play regulatory roles on AD.

Novel multifunctional iron chelators of the aroyl nicotinoyl hydrazone class that markedly enhance cellular NAD+ /NADH ratios.

Alzheimer's disease (AD) is a multifactorial condition leading to cognitive decline and represents a major global health challenge in ageing populations. The lack of effective AD therapeutics led us to develop multifunctional nicotinoyl hydrazones to target several pathological characteristics of AD. We synthesised 20 novel multifunctional agents based on the nicotinoyl hydrazone scaffold, which acts as a metal chelator and a lipophilic delivery vehicle, donating a NAD+ precursor to cells, to target metal dyshomeostasis, oxidative stress, β-amyloid (Aβ) aggregation, and a decrease in the NAD+ /NADH ratio. The most promising compound, 6-methoxysalicylaldehyde nicotinoyl hydrazone (SNH6), demonstrated low cytotoxicity, potent iron (Fe)-chelation efficacy, significant inhibition of copper-mediated Aβ aggregation, oxidative stress alleviation, effective donation of NAD+ to NAD-dependent metabolic processes (PARP and sirtuin activity) and enhanced cellular NAD+ /NADH ratios, as well as significantly increased median Caenorhabditis elegans lifespan (to 1.46-fold of the control); partly decreased BACE1 expression, resulting in significantly lower soluble amyloid precursor protein-β (sAPPβ) and Aβ1-40 levels; and favourable blood-brain barrier-permeation properties. Structure-activity relationships demonstrated that the ability of these nicotinoyl hydrazones to increase NAD+ was dependent on the electron-withdrawing or electron-donating substituents on the aldehyde- or ketone-derived moiety. Aldehyde-derived hydrazones containing the ONO donor set and electron-donating groups were required for NAD+ donation and low cytotoxicity. The nicotinoyl hydrazones, particularly SNH6, have the potential to act as multifunctional therapeutic agents and delivery vehicles for NAD+ precursors for AD treatment.

In vitro pathological model of Alzheimer's disease based on neuronal network chip and its real-time dynamic analysis

Alzheimer's disease (AD) is a chronic central neurodegenerative disease. The pathological features of AD are the extracellular deposition of senile plaques formed by amyloid-β oligomers (AβOs) and the intracellular accumulation of neurofibrillary tangles formed by hyperphosphorylated tau protein. In this paper, an in vitro pathological model of AD based on neuronal network chip and its real-time dynamic analysis were presented. The hippocampal neuronal network was cultured on the microelectrode array (MEA) chip and induced by AβOs as an AD model in vitro to simultaneously record two firing patterns from the interneurons and pyramidal neurons. The spatial firing patterns mapping and cross-correlation between channels were performed to validate the degeneration of neuronal network connectivity. This biosensor enabled the detection of the AβOs toxicity responses, and the identification of connectivity and interactions between neuronal networks, which can be a novel technique in the research of AD pathological model in vitro.

Quantitative Trait Module-Based Genetic Analysis of Alzheimer's Disease.

The pathological features of Alzheimer’s Disease (AD) first appear in the medial temporal lobe and then in other brain structures with the development of the disease. In this work, we investigated the association between genetic loci and subcortical structure volumes of AD on 393 samples in the Alzheimer’s Disease Neuroimaging Initiative (ADNI) cohort. Brain subcortical structures were clustered into modules using Pearson’s correlation coefficient of volumes across all samples. Module volumes were used as quantitative traits to identify not only the main effect loci but also the interactive effect loci for each module. Thirty-five subcortical structures were clustered into five modules, each corresponding to a particular brain structure/area, including the limbic system (module I), the corpus callosum (module II), thalamus–cerebellum–brainstem–pallidum (module III), the basal ganglia neostriatum (module IV), and the ventricular system (module V). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment results indicate that the gene annotations of the five modules were distinct, with few overlaps between different modules. We identified several main effect loci and interactive effect loci for each module. All these loci are related to the function of module structures and basic biological processes such as material transport and signal transduction.

TAU-INDUCED ASTROCYTE SENESCENCE: A NOVEL MECHANISM FOR NEURONAL DYSFUNCTION IN ALZHEIMER’S DISEASE

Chronic sterile inflammation is a pathological feature of Alzheimer’s disease (AD) and other neurodegenerative diseases. The mechanisms that drive neuroinflammation and its impact on AD progression are still incompletely understood. The accumulation of molecular damage in somatic cells can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the “senescence-associated secretory phenotype” (SASP). Misfolded tau forms pathogenic soluble aggregates that are released extracellularly and are transmitted trans-neuronally, promoting native tau phosphorylation and aggregation in target cells. We recently showed that, in addition to neurons, pathogenic soluble extracellular tau aggregates propagate to brain microvascular endothelial cells, where microtubule destabilization triggers senescence/SASP. Because astrocytes have a critical role in the regulation of both synaptic function and cerebral blood flow and are directly exposed to tau at its site of release at the tripartite synapse, we conducted studies to define whether soluble aggregated tau propagates to astrocytes, inducing astrocyte senescence/SASP and neuronal dysfunction/damage. Our studies indicate that tau can be propagated transcellularly to astrocytes, triggering cellular senescence/SASP. Our studies suggest that astrocyte senescence is detrimental to dendritic and synaptic structure and density, suggesting that pathogenic soluble tau-induced astrocyte senescence may contribute to synaptic dysfunction and loss in AD. Drugs that eliminate senescent cells are FDA-approved and antibody-based approaches to remove tau from brain are already in clinical trials. Our studies suggest that these interventions could be effective in the treatment of AD and other tauopathies.

Curcumin effect on non-amyloidogenic pathway for preventing Alzheimer’s disease

Amyloid beta (Aβ) plaque deposition is a pathological feature of Alzheimer’s disease (AD) that is characterized by dementia. Therapies approaches affecting Aβ synthesis and accumulation are necessary for improving AD. The present review, as the future prospective study, focuses on the possible effect of curcumin on the non-amyloidogenic pathways for inhibiting the Aβ plaque in AD. Activators of non-amyloidogenic pathways emerge as a novel strategy in attenuating Aβ. Drugs and natural compounds can affect neurotrophic signaling pathways including protein kinase C (PKC), tyrosine kinase (TK), mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling, and Ca2+ signaling as wells serotonergic and acetylcholine systems, resulting to stimulate nonamyloidogenic pathways. Curcumin, active constituent of Curcuma longa L. (turmeric), has a potent effect against AD through prevention Aβ generation and deposition. With attention to the effect of curcumin on the molecular mechanism behind the nonamyloidogenic pathways, we suggest designing more studies to identify curcumin as a therapeutic restricting AD agent via its impact on the non-amyloidogenic pathway.