Beta-amyloid Plaque Deposition Research Articles

P2Y1 receptor in Alzheimer's disease.

Alzheimer's disease is the most frequent form of dementia characterized by the deposition of amyloid-beta plaques and neurofibrillary tangles consisting of hyperphosphorylated tau. Targeting amyloid-beta plaques has been a primary direction for developing Alzheimer's disease treatments in the last decades. However, existing drugs targeting amyloid-beta plaques have not fully yielded the expected results in the clinic, necessitating the exploration of alternative therapeutic strategies. Increasing evidence unravels that astrocyte morphology and function alter in the brain of Alzheimer's disease patients, with dysregulated astrocytic purinergic receptors, particularly the P2Y1 receptor, all of which constitute the pathophysiology of Alzheimer's disease. These receptors are not only crucial for maintaining normal astrocyte function but are also highly implicated in neuroinflammation in Alzheimer's disease. This review delves into recent insights into the association between P2Y1 receptor and Alzheimer's disease to underscore the potential neuroprotective role of P2Y1 receptor in Alzheimer's disease by mitigating neuroinflammation, thus offering promising avenues for developing drugs for Alzheimer's disease and potentially contributing to the development of more effective treatments.

Super-Resolution Ultrasound Reveals Cerebrovascular Impairment in a Mouse Model of Alzheimer's Disease.

Increasing evidence has suggested a link between cerebrovascular disease and the cognitive impairment associated with Alzheimer's disease. However, detailed descriptions of microvascular changes across brain regions and how they relate to other more traditional pathology have been lacking. Additionally, the efforts to elucidate the interplay between cerebral microvascular function and Alzheimer's disease progression are complicated by the necessity of probing deep-brain structures since early-stage Alzheimer's disease typically involves hippocampal pathology. The purpose of this study was to examine changes in microvascular dynamics in a mouse model of Alzheimer's disease using cohorts that were age-matched to wild-type controls. Data from both sexes were included in this study. Super-resolution ultrasound localization microscopy revealed microvascular functional and structural features throughout the whole brain depth to visualize and quantify. We found that functional decreases in hippocampal and entorhinal flow velocity preceded structural derangements in regional vascular density. Co-registered histological sectioning confirmed the regionalized perfusion deficits seen on ultrasound imaging, which were co-localized with amyloid beta plaque deposition. In addition to providing global vascular quantifications of deep brain structures with a high local resolution, this technology also permitted velocity-profile analysis of individual vessels and, in some cases, allowed for decoupling of arterial and venous flow contributions. These data suggest that microvascular pathology is an early and pervasive feature of Alzheimer's disease and may represent a novel therapeutic target for this disease.

Neuroprotective potentials of Lead phytochemicals against Alzheimer's disease with focus on oxidative stress-mediated signaling pathways: Pharmacokinetic challenges, target specificity, clinical trials and future perspectives

BackgroundAlzheimer's diseases (AD) and dementia are among the highly prevalent neurological disorders characterized by deposition of beta amyloid (Aβ) plaques, dense deposits of highly phosphorylated tau proteins, insufficiency of acetylcholine (ACh) and imbalance in glutamatergic system. Patients typically experience cognitive, behavioral alterations and are unable to perform their routine activities. Evidence also suggests that inflammatory processes including excessive microglia activation, high expression of inflammatory cytokines and release of free radicals. Thus, targeting inflammatory pathways beside other targets might be the key factors to control- disease symptoms and progression. PurposeThis review is aimed to highlight the mechanisms and pathways involved in the neuroprotective potentials of lead phytochemicals. Further to provide updates regarding challenges associated with their use and their progress into clinical trials as potential lead compounds. MethodsMost recent scientific literature on pre-clinical and clinical data published in quality journals especially on the lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin was collected using SciFinder, PubMed, Google Scholar, Web of Science, JSTOR, EBSCO, Scopus and other related web sources. ResultsLiterature review indicated that the drug discovery against AD is insufficient and only few drugs are clinically approved which have limited efficacy. Among the therapeutic options, natural products have got tremendous attraction owing to their molecular diversity, their safety and efficacy. Research suggest that natural products can delay the disease onset, reduce its progression and regenerate the damage via their anti-amyloid, anti-inflammatory and antioxidant potentials. These agents regulate the pathways involved in the release of neurotrophins which are implicated in neuronal survival and function. Highly potential lead phytochemicals including curcumin, catechins, quercetin, resveratrol, genistein and apigenin regulate neuroprotective signaling pathways implicated in neurotrophins-mediated activation of tropomyosin receptor kinase (Trk) and p75 neurotrophins receptor (p75NTR) family receptors. ConclusionsPhytochemicals especially phenolic compounds were identified as highly potential molecules which ameliorate oxidative stress induced neurodegeneration, reduce Aβ load and inhibit vital enzymes. Yet their clinical efficacy and bioavailability are the major challenges which need further interventions for more effective therapeutic outcomes.

Influence of complement protein C1q or complement receptor C5aR1 on gut microbiota composition in wildtype and Alzheimer’s mouse models

The contribution of the gut microbiome to neuroinflammation, cognition, and Alzheimer’s disease progression has been highlighted over the past few years. Additionally, inhibition of various components of the complement system has repeatedly been demonstrated to reduce neuroinflammation and improve cognitive performance in AD mouse models. Whether the deletion of these complement components is associated with distinct microbiome composition, which could impact neuroinflammation and cognitive performance in mouse models has not yet been examined. Here, we provide a comprehensive analysis of conditional and constitutive knockouts, pharmacological inhibitors, and various housing paradigms for the animal models and wild-type controls at various ages. We aimed to determine the impact of C1q or C5aR1 inhibition on the microbiome in the Arctic and Tg2576 mouse models of AD, which develop amyloid plaques at different ages and locations. Analysis of fecal samples from WT and Arctic mice following global deletion of C1q demonstrated significant alterations to the microbiomes of Arctic but not WT mice, with substantial differences in abundances of Erysipelotrichales, Clostridiales and Alistipes. While no differences in microbiome diversity were detected between cohoused wildtype and Arctic mice with or without the constitutive deletion of the downstream complement receptor, C5aR1, a difference was detected between the C5aR1 sufficient (WT and Arctic) and deficient (C5ar1KO and ArcticC5aR1KO) mice, when the mice were housed segregated by C5aR1 genotype. However, cohousing of C5aR1 sufficient and deficient wildtype and Arctic mice resulted in a convergence of the microbiomes and equalized abundances of each identified order and genus across all genotypes. Similarly, pharmacologic treatment with the C5aR1 antagonist, PMX205, beginning at the onset of beta-amyloid plaque deposition in the Arctic and Tg2576 mice, demonstrated no impact of C5aR1 inhibition on the microbiome. This study demonstrates the importance of C1q in microbiota homeostasis in neurodegenerative disease. In addition, while demonstrating that constitutive deletion of C5aR1 can significantly alter the composition of the fecal microbiome, these differences are not present when C5aR1-deficient mice are cohoused with C5aR1-sufficient animals with or without the AD phenotype and suggests limited if any contribution of the microbiome to the previously observed prevention of cognitive and neuronal loss in the C5aR1-deficient AD models.

In silico Evaluation and Neuroprotective Effect of Jasmonic Acid on Sleep Deprivation Induced Alzheimer’s in Zebrafish

Background:Disturbances in the sleep cycle have been often associated with the depletion of oxidant enzymes and deposition of beta-amyloid plaques leading to neurodegeneration in Alzheimer's disease (AD). Healthy sleep time and sleep cycles were proven to clear the betaamyloid out of the brain and also promote the synthesis and functions of anti-oxidant enzymes.Objective:Jasmonic acid was evaluated to enhance the cognition and acetylcholine enzyme in the sleep deprivation-induced Alzheimer's by using the zebrafish model.Methods:The molecular properties, bioactivity score, and pharmacokinetic parameters of jasmonic acid were predicted using Molinspiration, SwissADME, and PreADMET tools. Jasmonic acid obeys Lipinski's rule and has significant bioavailability and blood-brain barrier penetration. The prediction of binding energy and interactions of jasmonic acid with six selected receptors was performed using AutoDock 4.2 software. It has significant binding affinity and interactions with different receptors which predict a multi-target potential using in-silico studies. In vivo neurobehavioral analysis of jasmonic acid was performed with zebrafish by using T-maze, Y-maze, and inhibitory avoidance apparatus and the results reveal Jasmonic acid produces more memory retention in zebrafish. In vitro assays of jasmonic acid on acetylcholinesterase enzyme level, glucose level, catalase activity, and lipid peroxidation activity were performed. Jasmonic acid shows cholinesterase inhibition, it acts as a good anti-oxidant and increases glucose metabolism on zebra fish brain homogenate using various assays. Jasmonic acid decreases neurodegeneration, and amyloid deposits in zebrafish brains using histopathological studies.Results:In silico molecular docking studies, in vitro assays, in vivo neurobehavioral analysis and histopathological studies reveal that jasmonic acid showed significant activity against sleep deprivation- induced AD in the zebrafish model.Conclusion:Hence, jasmonic acid will be carried out for further preclinical and clinical studies in order to prove the same for the management of Alzheimer's disease.

Association between beta amyloid plaque deposition and neuronal activity measured by Resting‐state fMRI in Alzheimer’s Disease and mild cognitive impairment

AbstractBackgroundDespite the important role of amyloid‐beta protein (Aβ) in the initiation and progression of Alzheimer’s Disease (AD), the precise mechanism by which Aβ disrupts neuronal activity (NA) and structure during disease development, and whether this protein is an appropriate therapeutic target is still controversial. Recently, we introduced several novel NA metrics (Kazemeifar, PLoS One 2017; Haddad, ISMRM 2019) based on specific spatiotemporal features of the resting‐state fMRI (rs‐fMRI) signal. These NA metrics are significantly lower in AD and mild cognitive impairment (MCI) compared to normal elderly controls. Here, we examine whether there is an association between resting‐state fMRI NA levels and Aβ deposition in grey matter (GM) measured by PET in AD and MCI.Method[18F]florbetapir Aβ PET images and rs‐fMRI data (TR = 3s, 197 volumes) in 9 participants from the Alzheimer’s Disease Neuroimaging Initiative (ADNI, 3 early MCI (EMCI), 3 MCI, and 3 AD, aged 77 ± 7 years, 3 females) were included. The rs‐fMRI data was pre‐processed and decomposed into independent components (ICs) using IC analysis. The ICs associated with neuronal activity were identified using a support vector machine classifier (Demertzi, Cortex 2014). NA was quantified in each voxel using the magnitude of the neuronal ICs in the rs‐fMRI signal. This magnitude was calculated based on similarity (cross‐covariance) between each neuronal IC and rs‐fMRI signal (Haddad, ISMRM 2019). In each subject, the pre‐processed PET images (Jagust, Alzheimers. Dement. 2015) were registered to the T1‐weighted image to which the NA maps were already registered. GM voxelwise correlation was then conducted between the NA and [18F]florbetapir uptake maps in each subject.ResultThe NA and [18F]florbetapir uptake maps in one EMCI subject (Figure 1) and related scatter plot (Figure 2) show the correlation between NA and [18F]florbetapir uptake in GM. In all subjects studied, NA and [18F]florbetapir uptake were significantly negatively correlated (r = ‐0.25 ± 0.14) (Table 1).ConclusionThe negative correlation between NA and [18F]florbetapir uptake in this preliminary study indicates that Aβ deposition contributes to decreased neuronal activity in AD and MCI measured by rs‐fMRI. Future studies should determine the susceptibility of various brain regions to Aβ accumulation.

0089 Chronic sleep disruption increases amyloid beta deposition and gliosis in the 5xFAD mouse model

Abstract Introduction Recent studies have found that mid-life sleep disruption is associated with the development of Alzheimer’s disease-related neuropathology, including the deposition of amyloid beta. Yet, the mechanism connecting sleep disruption, particularly over chronic timescales, and downstream Alzheimer’s pathology remains unclear. Methods In this study, we evaluated the impact chronic sleep disruption has on the development of neuroinflammation and amyloid beta plaques in the 5xFAD amyloidosis mouse model. Chronic sleep disruption in male and female C57BL/6 and 5xFAD+ mice was performed in Lafayette sleep fragmentation cages from 10-18 weeks of age. Glymphatic function was assessed by measuring the influx of fluorescent cerebrospinal fluid tracers into brain tissue. Aquaporin-4 localization, amyloid-beta plaque deposition, and markers of astroglial and microglial activation were assessed by immunofluorescence. Results We observed that chronic sleep disruption increased neuropathological outcomes in 5xFAD+ and littermate controls. This was evident in significantly increased amyloid-beta plaque deposition and significantly increased gliosis, indicated by increases in both astrocyte (GFAP) and microglial (Iba1) expression. The impact on glymphatic function, evaluated through both cerebrospinal fluid tracer distribution and assessment of aquaporin-4 mislocalization, was assessed in parallel and correlated with neuropathological outcomes. Conclusion These findings highlight the critical association between dysfunctional sleep and the development of Alzheimer’s-related amyloid beta pathology. They indicate that there is an interaction between chronic sleep disruption, neuroinflammation, and amyloid □ deposition. Support (if any)

Natural Products with BACE1 and GSK3β Inhibitory Activity.

Alzheimer's disease (AD) is a neurodegenerative, progressive, and fatal disorder characterized by marked atrophy of the cerebral cortex and loss of basal forebrain cholinergic neurons. The main pathological features of AD are related to neuronal degeneration and include extracellular deposition of amyloid beta plaques (Aβ plaques), intracellular formation of neurofibrillary tangles (NFTs), and neuroinflammation. So far, drugs used to treat AD have symptomatic and palliative pharmacological effects, disappearing with continued use due to neuron degeneration and death. Therefore, there are still problems with an effective drug for treating AD. Few approaches evaluate the action of natural products other than alkaloids on the molecular targets of β-amyloid protein (Aβ protein) and/or tau protein, which are important targets for developing neuroprotective drugs that will effectively contribute to finding a prophylactic drug for AD. This review gathers and categorizes classes of natural products, excluding alkaloids, which in silico analysis (molecular docking) and in vitro and/or in vivo assays can inhibit the BACE1 and GSK-3β enzymes involved in AD.

Sensory impairment and beta-amyloid deposition in the Baltimore longitudinal study of aging.

Beta-amyloid (Aβ) plaque deposition is a biomarker of preclinical Alzheimer's disease (AD). Impairments in sensory function are associated with cognitive decline. We sought to investigate the relationship between PET-indicated Aβ deposition and sensory impairment. Using data from 174 participants ≥55 years in the Baltimore Longitudinal Study of Aging, we analyzed associations between sensory impairments and Aβ deposition measured by PET and Pittsburgh Compound B (PiB) mean cortical distribution volume ratio (cDVR). The combinations of hearing and proprioceptive impairment and hearing, vision, and proprioceptive impairment, were positively correlated with cDVR (β=0.087 and p=0.036, β=0.110 and p=0.018, respectively). In stratified analyses of PiB+ participants, combinations of two, three, and four sensory impairments (all involving proprioception) were associated with higher cDVR. Our findings suggest a relationship between multi-sensory impairment (notably proprioceptive impairment) and Aβ deposition, which could reflect sensory impairment as an indicator or potentially a risk factor for Aβ deposition.

Probing changes in brain esterified oxylipin concentrations during the early stages of pathogenesis in Alzheimer’s Disease transgenic rats

Despite known pathological hallmarks of Alzheimer’s Disease (AD) including neuronal loss, gliosis (inflammation), beta-amyloid plaque deposition and neurofibrillary tangle accumulation in the brain, little is known about inflammation resolution in early AD pathogenesis. In the brain, inflammation and resolution pathways are mediated by free oxylipins which are mostly bound (i.e. esterified), and therefore must be released (i.e. become free) to exert bioactivity. Recently, we showed reductions in brain esterified pro-resolving oxylipins in a transgenic rat model of AD (TgF344-AD rat) at 15 months of age, suggesting deficits in the source and availability of free pro-resolving oxylipins. In the present study, we tested whether these changes are discernable earlier in the disease process, i.e., at age of 10 months. We observed significant reductions in esterified pro-resolving 8(9)-epoxyeicosatrienoic acid (8(9)-EpETrE), 13-hydroxyoctadecatrienoic acid (13-HOTrE) and 15-hydroxyeicosapentaenoic acid (15-HEPE) oxylipins, and in pro-inflammatory 13-hydroxy-octadecadienoic acid (13-HODE), 20-hydroxy-eicosatetraenoic acid (20-HETE), 15-deoxy-prostaglandin J2 (15-deoxy-PGJ2) and prostaglandin E2 (PGE2) oxylipins in male and/or female transgenic AD rats compared to wildtype controls. These findings point to a deficit in esterified pro-resolving lipid mediators in the early stages of AD, concident with. changes in esterified lipid mediators involved in promoting inflammation.

Roles of ZnT86D in Neurodevelopment and Pathogenesis of Alzheimer Disease in a Drosophila melanogaster Model.

Zinc is a fundamental trace element essential for numerous biological processes, and zinc homeostasis is regulated by the Zrt-/Irt-like protein (ZIP) and zinc transporter (ZnT) families. ZnT7 is mainly localized in the Golgi apparatus and endoplasmic reticulum (ER) and transports zinc into these organelles. Although previous studies have reported the role of zinc in animal physiology, little is known about the importance of zinc in the Golgi apparatus and ER in animal development and neurodegenerative diseases. In this study, we demonstrated that ZnT86D, a Drosophila ortholog of ZnT7, plays a pivotal role in the neurodevelopment and pathogenesis of Alzheimer disease (AD). When ZnT86D was silenced in neurons, the embryo-to-adult survival rate, locomotor activity, and lifespan were dramatically reduced. The toxic phenotypes were accompanied by abnormal neurogenesis and neuronal cell death. Furthermore, knockdown of ZnT86D in the neurons of a Drosophila AD model increased apoptosis and exacerbated neurodegeneration without significant changes in the deposition of amyloid beta plaques and susceptibility to oxidative stress. Taken together, our results suggest that an appropriate distribution of zinc in the Golgi apparatus and ER is important for neuronal development and neuroprotection and that ZnT7 is a potential protective factor against AD.

AdipoRon induces AMPK activation and ameliorates Alzheimer's like pathologies and associated cognitive impairment in APP/PS1 mice

Alzheimer's disease (AD) is a progressive devastating neurodegenerative disorder characterized by extracellular amyloid beta (Aβ42) plaque formation, hyperphosphorylation of tau protein leading to intracellular neurofibrillary tangle formation. Recently discovered hallmark features responsible for AD pathogenesis are neuronal insulin resistance, dysregulation in adiponectin and AMPK signaling. The presence of adiponectin and its receptor in the brain with its unique anti-diabetic effects and association with neurodegenerative diseases has raised our interest in exploring orally active small molecule adiponectin receptor agonist, AdipoRon. To date, all the available drugs for the treatment of AD provides symptomatic relief and do not stall the progression of the disease. Indeed, it is becoming increasingly apparent to find appropriate targets. Here, we attempt to shed lights on adiponectin receptor agonist, AdipoRon and its downstream molecular targets in reducing disease pathogenesis and insulin resistance. In brain, AdipoRon induced AMPK activation, increased insulin sensitivity, reduced amyloid beta plaque deposition and improved cognitive impairment. Levels of BACE were also downregulated while LDLR, APOE and neprilysin were upregulated promoting amyloid beta clearance from brain. AdipoRon further reduced the chronic inflammatory marker, GFAP and improved synaptic markers PSD-95 and synaptophysin in APP/PS1 mice. Our in-vitro studies further confirmed the potential role of AdipoRon in improving insulin sensitivity by increasing GLUT 4 translocation, glucose uptake and insulin signaling under hyperinsulinemic condition. Our findings suggest that AdipoRon could be a promising lead in the future treatment strategies in the development of effective AD treatment.

Cognitive Performance on the Montreal Cognitive Assessment Test and Retinal Structural and Functional Measures in Glaucoma.

Background: Glaucoma, the leading cause of irreversible blindness, is classified as a neurodegenerative disease, and its incidence increases with age. Pathophysiological changes, such as the deposition of amyloid-beta plaques in the retinal ganglion cell layer, as well as neuropsychological changes, including cognitive decline, have been reported in glaucoma. However, the association between cognitive ability and retinal functional and structural measures in glaucoma, particularly glaucoma subtypes, has not been studied. We studied the association between cognitive ability and the visual field reliability indices as well as the retinal ganglion cell (RGC) count estimates in a cohort of glaucoma patients. Methods: A total of 95 eyes from 61 glaucoma patients were included. From these, 20 were normal-tension glaucoma (NTG), 25 were primary open-angle glaucoma (POAG), and 16 were glaucoma suspects. All the participants had a computerised Humphrey visual field (HVF) assessment and optical coherence tomography (OCT) scan and were administered the written Montreal Cognitive Assessment (MoCA) test. RGC count estimates were derived based on established formulas using the HVF and OCT results. A MoCA cut-off score of 25 and less was designated as cognitive impairment. Student’s t-test was used to assess differences between the groups. The Pearson correlation coefficient was used to assess the association between MoCA scores and retinal structural and functional measures. Results: Significant associations were found between MoCA scores and the false-negative and pattern standard deviation indices recorded on the HVF (r = −0.19, r = −0.22, p < 0.05). The mean IOP was significantly lower in the cognitively impaired group (i.e., MOCA ≤ 25) (13.7 ± 3.6 vs. 15.7 ± 4.5, p < 0.05). No significant association was found between RGC count estimates and MoCA scores. Analysis of these parameters in individual glaucoma subtypes did not reveal any group-specific significant associations either.

Phosphorus metabolism in the brain of cognitively normal midlife individuals at risk for Alzheimer's disease

BackgroundNeurometabolic abnormalities and amyloid-beta plaque deposition are important early pathophysiologic changes in Alzheimer's disease (AD). This study investigated the relationship between high-energy phosphorus-containing metabolites, glucose uptake, and amyloid plaque using phosphorus magnetic resonance spectroscopy (31P-MRS) and positron emission tomography (PET). MethodsWe measured 31P-MRS, fluorodeoxyglucose (FDG)-PET, and Pittsburgh Compound B (PiB)-PET in a cohort of 20 cognitively normal middle-aged adults at risk for AD. We assessed 31P-MRS reliability by scanning a separate cohort of 13 healthy volunteers twice each. We calculated the coefficient-of-variation (CV) of metabolite ratios phosphocreatine-to-adenosine triphosphate (PCr/α-ATP), inorganic phosphate (Pi)-to-α-ATP, and phosphomonoesters-to-phosphodiesters (PME/PDE), and pH in pre-defined brain regions. We performed linear regression analysis to determine the relationship between 31P measurements and tracer uptake, and Dunn's multiple comparison tests to investigate regional differences in phosphorus metabolism. Finally, we performed linear regression analysis on 31P-MRS measurements in both cohorts to investigate the relationship of phosphorus metabolism with age. ResultsMost regional 31P metabolite ratio and pH inter- and intra-day CVs were well below 10%. There was an inverse relationship between FDG-SUV levels and metabolite ratios PCr/α-ATP, Pi/α-ATP, and PME/PDE in several brain regions in the AD risk group. There were also several regional differences among 31P metabolites and pH in the AD risk group including elevated PCr/α-ATP, depressed PME/PDE, and elevated pH in the temporal cortices. Increased PCr/α-ATP throughout the brain was associated with aging. ConclusionsPhosphorus spectroscopy in the brain can be performed with high repeatability. Phosphorus metabolism varies with region and age, and is related to glucose uptake in adults at risk for AD. Phosphorus spectroscopy may be a valuable approach to study early changes in brain energetics in high-risk populations.

Modulation of Inflammatory Mediators and Microglial Activation Through Physical Exercise in Alzheimer's and Parkinson's Diseases.

Neuroinflammation is an inflammatory process in the central nervous system (CNS), in addition to being one of the main features of Alzheimer's disease (AD) and Parkinson's disease (PD). Microglia are known for their immune functions and have multiple reactive phenotypes related to the types of stages involving neurodegenerative diseases. Depending on the state of activation of microglia in the CNS, it can be neuroprotective or neurotoxic. In this context, AD is a neurodegenerative and neuroinflammatory disease characterized by the deposition of beta-amyloid plaques, formation of fibrillar tangles of tau protein, and loss of neurons due to neurotoxic activation of microglia. However, PD is characterized by the loss of dopaminergic neurons in the substantia nigra and accumulation of alpha-synuclein in the cortical regions, spinal cord, and brain stem, which occurs by microglial activation, contributing to the neuroinflammatory process. In this aspect, the activation of microglia in both pathologies triggers high levels of inflammatory markers, such as interleukins, and causes the neuroinflammatory process of the diseases. Thus, physical exercise is pointed out as neuroprotective, as it can act to strengthen neurogenesis and reduce the inflammatory process. Therefore, the present review addresses the neuroprotective effect of microglia after different types of physical exercise protocols and evaluates the activity and effects of inflammatory and anti-inflammatory parameters and mechanisms of AD and PD. This review will discuss the anti-inflammatory effects of physical exercise through microglia activation with neuroprotective activity and the role of pro-and anti-inflammatory cytokines in AD and PD.

Distribution and inter-regional relationship of amyloid-beta plaque deposition in a 5xFAD mouse model of Alzheimer's disease.

Alzheimer’s disease (AD) is the most common form of dementia. Although previous studies have selectively investigated the localization of amyloid-beta (Aβ) deposition in certain brain regions, a comprehensive characterization of the rostro-caudal distribution of Aβ plaques in the brain and their inter-regional correlation remain unexplored. Our results demonstrated remarkable working and spatial memory deficits in 9-month-old 5xFAD mice compared to wildtype mice. High Aβ plaque load was detected in the somatosensory cortex, piriform cortex, thalamus, and dorsal/ventral hippocampus; moderate levels of Aβ plaques were observed in the motor cortex, orbital cortex, visual cortex, and retrosplenial dysgranular cortex; and low levels of Aβ plaques were located in the amygdala, and the cerebellum; but no Aβ plaques were found in the hypothalamus, raphe nuclei, vestibular nucleus, and cuneate nucleus. Interestingly, the deposition of Aβ plaques was positively associated with brain inter-regions including the prefrontal cortex, somatosensory cortex, medial amygdala, thalamus, and the hippocampus. In conclusion, this study provides a comprehensive morphological profile of Aβ deposition in the brain and its inter-regional correlation. This suggests an association between Aβ plaque deposition and specific brain regions in AD pathogenesis.

Adipose tissue-derived stem cells as a potential candidate in treatment of Alzheimer's disease: A systematic review on preclinical studies.

In recent years, numerous investigations have evaluated the efficacy of adipose tissue‐derived stem cells (ADSCs) and their exosome transplantation in managing Alzheimer's disease (AD) in different animal models. However, there are still many contradictions among the studies that hinder reaching a reliable conclusion. Therefore, we aimed to systematically review the existing evidence regarding the efficacy of ADSCs administration in treatment of AD. The systematic search was conducted in the databases of Medline (via PubMed), Embase, Scopus, and Web of Science, in addition to the manual search in Google and Google scholar, to find articles published until March 13, 2021. Preclinical studies were included and two independent reviewers summarized the eligible papers. Ten articles were included in our review. The treatment strategies varied between isolated ADSC, ADSCs exosomes, ADSCs conditioned medium, and combination therapy (ADSCs plus conditioned medium in one study, and ADSCs plus melatonin in another study). Overview of the included articles showed promising results of ADSCs and its conditioned medium/exosome administration in animal models of AD. These studies showed significant learning and memory improvements through ADSCs and their conditioned medium/exosome administration in animal models of AD. In addition, the application of ADSCs reduced the amyloid‐beta plaque deposits in the hippocampus and neocortex of these animals. Based on the aforementioned evidence, studies have suggested potential beneficial effects of ADSCs in the treatment of AD, particularly through decreasing the size of Aβ plaques and improvement of cognitive deficits. Further investigations regarding the subject are encouraged to achieve more accurate conclusions.

Amelioration of cognitive and biochemical impairment in Aβ-based rodent model of Alzheimer's disease following fractionated X-irradiation.

Alzheimer's disease is characterized by deposition of amyloid-beta plaques in the brain. Available pharmaceuticals provide temporary symptomatic relief without affecting disease progression. Use of radiation was found effective in treating extra-cranial amyloidosis, therefore, the present study was designed to investigate the neuroprotective role of fractionated X-irradiation in Aβ1-42-based rodent model of Alzheimer's disease. S.D. female rats were randomly divided into four groups: sham control (Group 1), Aβ1-42 injected (Group 2), cranial X-irradiated (Group 3) and Aβ1-42 injected followed by cranial X-irradiation (Group 4). A single dose of 5µL Aβ1-42 peptide was administered through intracerebroventricular (icv) injection in Group 2 and 4 animals, while Group 1 animals were administered 5µL of bi-distilled water (icv). The group 4 animals were further subjected to 10Gy X-irradiation (fractionated dose, 2Gy × 5days) after 4weeks of Aβ1-42 infusion of peptide. The animals in Group 3 were subjected to same dose of cranial fractionated X-irradiation (2Gy × 5days) only. Significant decrease in amyloid deposits were observed in the Aβ1-42 + radiation-treated animals confirmed by histopathological analysis. These finding were in concordance with neurobehavioral tests that showed a significant improvement in Aβ1-42-induced memory impairment in the animals subjected to fractionated cranial X-irradiation. Restoration of alterations in neurochemical and antioxidant defense indices further supported our results. The present study highlights the underexplored role of fractionated X-irradiation in curtailing the Aβ1-42-induced neurotoxicity, suggesting a novel treatment option for Alzheimer's disease-associated pathologies.

Does duration of HIV infection substitute for age as a risk factor for amyloid deposition?

Increasing access to more tolerable ARV treatments has vastly extended the expected lifespan of People with HIV (PWH), with some models predicting that in developed nations approximately two-thirds of PWH will be older than 50 years by 2030. Longer lifespans increase the risk of age-related neuropathologies, such as the deposition of amyloid beta plaques (Aβ42), regarded as an important prognostic marker of Alzheimer’s Disease (AD). Frequently first detected during mid-life, Aβ42 may predate the manifestation of neurocognitive symptoms associated with AD by 1-2 decades. The etiological significance of Aβ42 deposition in PWH is an active area of investigation. There is little clarity thus far in the clinical and research literature on whether the presence of Aβ42 in PWH leads to elevated risk of developing AD in those with and without HIV Associated Neurocognitive Disorders (HAND). Biological measures of neuropathology, such as CSF serum assays and brain tissue staining, have great potential in determining the extent to which Aβ42 deposition patterns in PWH are HAND-specific, and in linking these deposits to clinical outcomes. In this way, they might provide insight into otherwise seemingly paradoxical findings, such as the observation that neither age nor HIV clinical variables (including ARV status and duration of HIV infection) were able to explain the roughly 5 times greater incidence of mild cognitive impairment (MCI) over a period of 14 months in neurocognitively asymptomatic PWH compared to seronegative controls. In the study by Morgello and colleagues in this issue of AIDS, the authors examined hippocampal and frontal cortical tissue samples from a large cohort of 197 PWH and 63 HIV seronegative controls who donated brain tissue to the Manhattan HIV Brain Bank. Using this approach, they were able to quantify the association of HIV status and the presence of amyloid deposits in brain regions that are typically affected in AD. Despite the study being relatively well-powered, they were unable to identify between- 3 group differences in the occurrence of Aβ42 deposits. Rather, within the PWH cohort, duration of HIV infection, and, somewhat paradoxically, undetectable HIV viral load, emerged as significant predictors of the likelihood of detecting Aβ42.

Rheb-mTOR activation rescues Aβ-induced cognitive impairment and memory function by restoring miR-146 activity in glial cells

Deposition of amyloid beta plaques in adult rat or human brain is associated with increased production of proinflammatory cytokines by associated glial cells that are responsible for degeneration of the diseased tissue. The expression of these cytokines is usually under check and is controlled at the post-transcriptional level via several microRNAs. Computational analysis of gene expression profiles of cortical regions of Alzheimer’s disease patients’ brain suggests ineffective target cytokine mRNA suppression by existing micro-ribonucleoproteins (miRNPs) in diseased brain. Exploring the mechanism of amyloid beta-induced cytokine expression, we have identified how the inactivation of the repressive miR-146 miRNPs causes increased production of cytokines in amyloid beta-exposed glial cells. In exploration of the cause of miRNP inactivation, we have noted amyloid beta oligomer-induced sequestration of the mTORC1 complex to early endosomes that results in decreased Ago2 phosphorylation, limited Ago2-miRNA uncoupling, and retarded Ago2-cytokine mRNA interaction in rat astrocytes. Interestingly, constitutive activation of mTORC1 by Rheb activator restricts proinflammatory cytokine production by reactivating miR-146 miRNPs in amyloid beta-exposed glial cells to rescue the disease phenotype in the in vivo rat model of Alzheimer’s disease.