Beta-amyloid Deposition Research Articles

Circulating Chlamydia Trachomatis Antigens in Subjects With Alzheimer's Disease.

Chlamydia pneumoniae (C. pneumoniae) is implicated in the pathogenesis of Alzheimer's disease (AD). Chlamydial elementary and reticulate bodies have been identified in tissues from afflicted AD brain regions by electron and immunoelectron microscopy, whereas similar tests of non-AD brains were negative for the bacterium. Studies in mice have shown that C. pneumoniae can rapidly penetrate the central nervous system by entering glia and causing beta amyloid deposition via the nerves between the nasal cavity and the brain, which serve as invasion pathways. We used data from the UK Biobank (UKBB) to assess the relationship of chlamydia and AD. Circulating C. pneumoniae antigen measurements were not available, but UKBB data field 23037 held measurements of PorB antigen for Chlamydia trachomatis (C. trachomatis). We used C. trachomatis as a surrogate for C. pneumoniae since serum cross-reactivity to C. trachomatis and C. pneumoniae antigens occurs in patients with documented infection and in healthy children as revealed by microimmunofluorescence and immunoblotting techniques. Single nucleotide polymorphism (SNP) data for rs429358 and rs7412 were used to impute ApoE genotypes. PorB antigen levels for C. trachomatis were significantly higher in subjects with AD (p=0.007). PorB antigen levels were not related to ApoE genotype (e3e3, e3e4, e4e4) p=0.783. To control for the effects of age, sex, educational level, and apoE genotype, logistic regression analysis was performed. AD was the dependent variable. Independent variables were sqrt PorB antigen for C. trachomatis, age, sex, educational level, apoE genotype. AD odds ratio (OR) increased 1.156 for each unit increase of sqrt PorB antigen for C. trachomatis and the effect was significant (p=0.004). PorB antigens for C. trachomatis being significantly higher in subjects with AD, corroborates previous studies demonstrating that C. pneumoniae inflammation appears to play a role in AD development. AD may result from the reactivation of embryologic processes and pathways silenced at birth. A trigger for the reactivation may be bacterial or viral infections. Further studies are warranted.

Potential biomarkers of early diagnosis of Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disease of the brain, in which there are cognitive and behavioral disorders, but also visual impairment can occur. Deposits of beta-amyloid (Aβ) were also found in the retina of AD patients. At the same time, primary open-angle glaucoma (POAG) occupies the first place among geronto-ophthalmic pathologies in patients with AD. POAG, like AD, is a neurodegenerative disease. AD and POAG have common symptoms, and therefore several common principles for their early diagnosis can be developed. Therefore, a promising direction is the search for biomarkers for the early detection of AD and POAG. Currently, the diagnosis of early AD biomarkers in cerebrospinal fluid and biomarkers in the brain (imaging of amyloid plaques and tau positron emission tomography) are well studied, while data in literature on using these biomarkers in patients with POAG is scarce. However, the above diagnostic methods are not considered in routine clinical practice due to their invasiveness and high cost. There is a growing need for conventional, affordable biomarkers for AD and POAG, as it is necessary to start treatment of prodromal conditions from symptoms to onset of symptoms. In this connection, biomarkers such as Aβ and tau protein in blood serum and plasma are actively evaluated in patients with AD. In patients with POAG, there is no published data on studies of these biomarkers, which requires scientific research. Many authors discover the role of sirtuins (SIRT) in aging and age-related diseases, such as AD, glaucoma, age-related macular degeneration, and others. Possibly, SIRT could become potential biomarkers of neurodegenerative diseases.

High-fidelity imaging of amyloid-beta deposits with an ultrasensitive fluorescent probe facilitates the early diagnosis and treatment of Alzheimer's Disease.

Background: Imaging amyloid-beta (Aβ) deposits with high fidelity in naturally aging brains is crucial for the early diagnosis of Alzheimer's disease (AD). However, this is impeded by the lack of highly sensitive probes.Methods: By conducting computational modelling to quantitatively fine-tune the twisted intramolecular charge transfer (TICT) tendency of Thioflavin T (ThT) analogues, we developed an ultrasensitive probe AH-2. AH-2 retained the binding affinity and binding mode of ThT towards Aβ deposits, and exhibited ca 10-fold less background fluorescence and 5-10 folds of improved signal-to-background contrast upon binding Aβ deposits. These desirable features endowed AH-2 the sensitivity to detect Aβ deposition in naturally aging wild-type mice.Results: AH-2 imaging revealed that Aβ puncta signals appeared near the nuclei in young mice and spread through the intracellular and extracellular compartments in older mice. Moreover, Aβ deposits were observed to emerge earlier in mice cerebral cortex than in the hippocampus region. Given this desirable sensitivity and good spatiotemporal resolution, AH-2 was successfully applied in the preclinical evaluation of Aβ-targeted treatment by melatonin.Conclusions: We expect that AH-2 is promising for early diagnosis of AD and will serve as a sensitive tool for studying Aβ-related AD pathology.

Brain endothelium-derived extracellular vesicles containing amyloid-beta induce mitochondrial alterations in neural progenitor cells.

Elevated brain deposits of amyloid beta (Aβ40) contribute to neuropathology and cognitive dysfunction in Alzheimer's disease (AD). However, the role of the blood-brain barrier (BBB) as an interface for the transfer of Aβ40 from the periphery into the brain is not well characterized. In addition, a substantial population of neural progenitor cells (NPCs) resides in close proximity to brain capillaries that form the BBB. The aim of this study is to understand the impact of brain endothelium-derived extracellular vesicles (EV) containing Aβ40 on metabolic functions and differentiation of NPCs. Endothelial EVs were derived from an in vitro model of the brain endothelium treated with 100 nM Aβ40 or PBS. We then analyzed the impact of these EVs on mitochondrial morphology and bioenergetic disruption of NPCs. In addition, NPCs were differentiated and neurite development upon exposure to EVs was assessed using the IncuCyte Zoom live cell imaging system. We demonstrate that physiological concentrations of Aβ40 can be transferred to accumulate in NPCs via endothelial EVs. This transfer results in mitochondrial dysfunction, disrupting crista morphology, metabolic rates, fusion and fission dynamics of NPCs, as well as their neurite development. Intercellular transfer of Aβ40 is carried out by brain endothelium-derived EVs, which can affect NPC differentiation and induce mitochondrial dysfunction, leading to aberrant neurogenesis. This has pathological implications because NPCs growing into neurons are incorporated into cerebral structures involved in learning and memory, two common phenotypes affected in AD and related dementias.

Diffuse brain deposition of beta-amyloid among italian ferroalloy workers

Diffuse brain deposition of beta-amyloid among italian ferroalloy workers

Application of QPLEXTM biomarkers in cognitively normal individuals across a broad age range and diverse regions with cerebral amyloid deposition

The deposition of beta-amyloid (Aβ) in the brain precedes the onset of symptoms such as cognitive impairment in Alzheimer’s disease (AD); therefore, the early detection of Aβ accumulation is crucial. We previously reported the applicability of the QPLEXTM Alz plus assay kit for the prescreening of Aβ accumulation. Here, we tested the specific application of the kit in a large cohort of cognitively normal (CN) individuals of varying ages for the early detection of Aβ accumulation. We included a total of 221 CN participants with or without brain Aβ. The QPLEXTM biomarkers were characterized based on age groups (1st–3rd tertile) and across various brain regions with cerebral amyloid deposition. The 3rd tertile group (>65 years) was found to be the most suitable age group for the application of our assay kit. Receiver operating characteristic curve analysis showed that the area under the curve (AUC, discrimination power) was 0.878 with 69.7% sensitivity and 98.4% specificity in the 3rd tertile group. Additionally, specific correlations between biomarkers and cerebral amyloid deposition in four different brain regions revealed an overall correlation with general amyloid deposition, consistent with previous findings. Furthermore, the combinational panel with plasma Aβ1–42 levels maximized the discrimination efficiency and achieved an AUC of 0.921 with 95.7% sensitivity and 67.3% specificity. Thus, we suggest that the QPLEXTM Alz plus assay is useful for prescreening brain Aβ levels in CN individuals, especially those aged >65 years, to prevent disease progression via the early detection of disease initiation.

The neuronal retromer can regulate both neuronal and microglial phenotypes of Alzheimer's disease.

SUMMARYDisruption of retromer-dependent endosomal trafficking is considered pathogenic in late-onset Alzheimer’s disease (AD). Here, to investigate this disruption in the intact brain, we turn to a genetic mouse model where the retromer core protein VPS35 is depleted in hippocampal neurons, and then we replete VPS35 using an optimized viral vector protocol. The VPS35 depletion-repletion studies strengthen the causal link between the neuronal retromer and AD-associated neuronal phenotypes, including the acceleration of amyloid precursor protein cleavage and the loss of synaptic glutamate receptors. Moreover, the studies show that the neuronal retromer can regulate a distinct, dystrophic, microglia morphology, phenotypic of hippocampal microglia in AD. Finally, the neuronal and, in part, the microglia responses to VPS35 depletion were found to occur independent of tau. Showing that the neuronal retromer can regulate AD-associated pathologies in two of AD’s principal cell types strengthens the link, and clarifies the mechanism, between endosomal trafficking and late-onset sporadic AD.

How mind-body therapies might reduce pathological features of Alzheimer's disease.

How mind-body therapies might reduce pathological features of Alzheimer's disease.

(D-Ser2) oxyntomodulin recovers hippocampal synaptic structure and theta rhythm in Alzheimer's disease transgenic mice.

In our previous studies, we have shown that (D-Ser2) oxyntomodulin (Oxm), a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide, protects hippocampal neurons against Aβ1-42-induced cytotoxicity, and stabilizes the calcium homeostasis and mitochondrial membrane potential of hippocampal neurons. Additionally, we have demonstrated that (D-Ser2) Oxm improves cognitive decline and reduces the deposition of amyloid-beta in Alzheimer's disease model mice. However, the protective mechanism remains unclear. In this study, we showed that 2 weeks of intraperitoneal administration of (D-Ser2) Oxm ameliorated the working memory and fear memory impairments of 9-month-old 3×Tg Alzheimer's disease model mice. In addition, electrophysiological data recorded by a wireless multichannel neural recording system implanted in the hippocampal CA1 region showed that (D-Ser2) Oxm increased the power of the theta rhythm. In addition, (D-Ser2) Oxm treatment greatly increased the expression level of synaptic-associated proteins SYP and PSD-95 and increased the number of dendritic spines in 3×Tg Alzheimer's disease model mice. These findings suggest that (D-Ser2) Oxm improves the cognitive function of Alzheimer's disease transgenic mice by recovering hippocampal synaptic function and theta rhythm.

Neurobiological effects of gastrodin and its possible use in neurology and psychiatry

Gastrodin is the main biologically active component of the rhizomes of the Gastrodia elata Blume. In recent years, this compound has attracted attention through a wide range of neurobiological effects. The neuroprotective effect of gastrodin on the brain after ischemic damage and exposure to toxic compounds has been determined. Gastrodin reduces amyloid beta deposition and excess glutamate, inhibits ferroptosis and restores electrophysiological parameters of synaptic plasticity. Moreover, this substance increases the level of brain-derived neurotrophic factor and stimulates neurogenesis. Studies have revealed the ability of gastrodin to reduce microglial activity and modulate dopamine concentration. Clinical studies have shown the effectiveness of this drug in the treatment of post-stroke depression. This compound also improves cognitive functions, including memory and learning. The anticonvulsant effect of gastrodin has been established. Theoretical justifications of application of gastrodin in certain neurodegenerative and convulsive diseases, as well as some mental disorders are given.

YKL-40 as a Potential Biomarker for the Differential Diagnosis of Alzheimer's Disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, associated with extensive neuronal loss, dendritic and synaptic changes resulting in significant cognitive impairment. An increased number of studies have given rise to the neuroinflammatory hypothesis in AD. It is widely accepted that AD brains show chronic inflammation, probably triggered by the presence of insoluble amyloid beta deposits and neurofibrillary tangles (NFT) and is also related to the activation of neuronal death cascade. In the present study we aimed to investigate the role of YKL-40 levels in the cerebrospinal fluid (CSF) in the diagnosis of AD, and to discuss whether there are further potential roles of this protein in the management and treatment of AD. We conducted an online search on PubMed, Web of Science, and the Cochrane library databases from 1990 to 2021. The quantitative analysis showed that the levels of YKL-40 were significantly higher in Alzheimer’s disease compared to controls, to mild cognitive impairment (MCI) AD (MCI-AD) and to stable MCI. They were also increased in MCI-AD compared to stable MCI. The present study shows that the CSF levels of YKL-40 could be potentially used as a biomarker for the prognosis of mild cognitive impairment and the likelihood of progression to AD, as well as for the differential diagnosis between AD and MCI.

An Association of Pathogens and Biofilms with Alzheimer's Disease.

As one of the leading causes of dementia, Alzheimer’s disease (AD) is a condition in which individuals experience progressive cognitive decline. Although it is known that beta-amyloid (Aβ) deposits and neurofibrillary tangles (NFT) of tau fibrils are hallmark characteristics of AD, the exact causes of these pathologies are still mostly unknown. Evidence that infectious diseases may cause AD pathology has been accumulating for decades. The association between microbial pathogens and AD is widely studied, and there are noticeable correlations between some bacterial species and AD pathologies, especially spirochetes and some of the oral microbes. Borrelia burgdorferi has been seen to correlate with Aβ plaques and NFTs in infected cells. Because of the evidence of spirochetes in AD patients, Treponema pallidum and other oral treponemes are speculated to be a potential cause of AD. T. pallidum has been seen to form aggregates in the brain when the disease disseminates to the brain that closely resemble the Aβ plaques of AD patients. This review examines the evidence as to whether pathogens could be the cause of AD and its pathology. It offers novel speculations that treponemes may be able to induce or correlate with Alzheimer’s disease.

Sensory Impairment and Beta-Amyloid Deposition in the Baltimore Longitudinal Study of Aging

Studies have demonstrated a link between sensory impairment and dementia risk, but little is known about the presence of beta-amyloid plaques in individuals with single and multisensory impairments. Sensory function (combinations of vision, hearing, vestibular function, and proprioception) and amyloid PET imaging were measured in 170 BLSA participants (age=78± 9 years; 53% women; 77% white; 28% amyloid positive) from 2012 to 2019. Log-binomial regression models were used to examine the prevalence ratios (PR) of amyloid positivity for individual sensory impairments and across categories of impairments. While crude associations indicate associations of vision impairment (PR=1.72, p=0.04) and impairments in all four senses (PR=2.38, p=0.03) with amyloid positivity, these associations were insignificant after adjusting for age, sex, race, and education. There were no other crude and adjusted associations. These results suggest sensory impairments may be related to dementia independent of AD pathology. Future studies with larger sample sizes are warranted.

Discovery of screened potential inhibitors for Alzheimer disease responsible enzymes: Insights from atomistic simulations

AbstractBackgroundOne of the cruelest neurogenerative disorder is Alzheimer disease (AD) which majorly affects old aged humans. It initially affects a person’s ability to carry out daily functions and leads to death. Basically, many diverse factors are leading to neuronal cell death such as low level of acetylcholine, deposition of amyloid beta, aggregation of tau proteins, oxidative stress, neuro‐inflammation, excitotoxicity, genetic and heredity factors. Some of the recent reports also outline about AD and it was characterized by different hypothesis and are named as cholinergic hypothesis, amyloid hypothesis, tau hypothesis and others (oxidative stress and genetic). Therefore, the present study focused to identify a potential inhibitor to control the level of Alzheimer disease.MethodWe have selected two different databases (ZINC15 and DUNDEE) and four different enzymes (Acetylcholinesterase, Butyrylcholinesterase, β‐Secretase and Glycogen synthase kinase 3 beta) for the study and carried out the high throughput virtual screening (HTVS), molecular docking, molecular dynamics simulation and binding free energy calculation to understand the active site effects and its stability.ResultIn the AChE and BChE, the screened molecules are showing good binding with strong interactions; notably, π‐cationic interactions were observed between amine group of ligand and tyrosine, tryptophan residues of AChE. Whereas in the BChE, active site residue Glu197 is highly stable. The catalytic dyad residue Asp93 of BACE1 maintains their hydrogen bond and Asp133 of GSK3β also sustain the strong interactions during the MD simulation. Apart from this, the statistical parameters (RMSD, RMSF and Rg) of these complexes are acceptable.ConclusionIn‐silico based analyses demonstrate that all the selected molecules are forming strong hydrogen bonding with catalytic residues and these interactions are highly stable during the atomistic simulation with high affinity. This comparative study allows to understand binding affinity, stability of intermolecular interactions and molecular flexibility of the molecules in the active site of AChE/BChE enzymes. Computational understanding of unproven molecules may lead towards the developing against AD.

Porphyromonas gingivalis outer membrane vesicles as the major drivers of and source for the toxic insult and iron accumulation/deposition in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disease of the brain, defined by the accumulation and deposition of beta-amyloid, which has recently been identified as an antimicrobial peptide suggesting an infectious etiology. The NIH's Institute on Aging recently announced new initiative to look for alternate etiologies for AD that included a call for the better understanding of the role of peripheral verses local infections, as well as sources of both local and systemic inflammation. Proving if in the case of an oral bacteria that it is migrating from the oral cavity to the brain verses whether the peripheral oral source of the bacteria are instead mostly secreting toxic gingipains/LPS/complexes in soluble or as OMVs is central to understanding the pathogenesis for this disease including their role in iron toxicity in neurovascular disease and AD. A hypothetical model of Porphyromonas gingivalis (Pg) is put forth to address if: 1. either translocation to the brain from the oral cavity via blood lymphatics, intracellularly or via neuronal axoplasmic flow and establishing a productive infection of the brain leading to the local production and the accumulation of Pg exo-/endo-toxins (e.g. gingipains/LPS etc.) verses; 2. the oral peripheral infection/colonization in the oral cavity shedding exo-/endo toxins and other virulence factors as either soluble forms or associated with complex actively secreted outer membrane vesicles (OMVs) into the blood and/or lymphatics and trans-migrating the neuro-vascular endothelium with entry into the neural parenchyma and its association with iron are important and notable differences in both pathogenesis of disease and the focus of treatment. As follows. Overviewing all published papers on natural cases of human AD or murine experimental models of Pg suggest strongly that despite in the experimental case of very large and prolonged oral admisntrastion, little direct evidence is presented to support that metabolically active bacteria reside in the brain and are responsible for the production of the toxic by-products therein. A review of this literature showing the incomplete study designs along with convincing foundational new data and publications supporting Pg OMVs as the major delivery mechanism will be provided.

A study on the distribution of Porphyromonas gingivalis repeated epitope in hemagglutinin/adhesion and hagA gingipains domain antigen and DNA in Alzheimer brains

Alzheimer's disease (AD) is a progressive neuroinflammatory and neurodegenerative disease of the brain, defined by the accumulation and deposition of beta-amyloid, which has recently been identified as an antimicrobial peptide suggesting an infectious etiology. Specific bacterial infections and factors especially caused by the oral Keystone Pathogen-Porphyromonas gingivalis (Pg) in both humans and animal models have shown to initiate and chronically stimulate the systemic innate host defense systems and inflammasome. Overtime these compromise the integrity of the blood brain barrier, localize in the brain parenchyma neurons and supporting cells and through multiple inflammatory pathways and lead to activation of microglia and astrocytes.A novel anti-pg bacterial monoclonal antibody currently in pre- and clinical development was used for all described work. Forty-six brain tissue samples (frontal and temporal biopsies) from 23 brain specimens (7 AD and 16 AMC) were subjected to PCR-based liquid hybridization assay to detect P. gingivalis DNA. All were negative for P. gingivalis DNA. Alzheimer brain sections from multiple functionally distinct anatomic regions and 15 different patient choroid plexus were tested by Porphyromonas gingivalis antigen-specific immuno-histochemistry.A unique Pg clinically relevant antigen was detected by IHC in multiple functionally distinct brain sections from all AD brains tested. This antigen was found with greatest intensity and frequency in the Fronto-temporal, Hippocampal lobes, Choroid plexus, Occipital and Cerebellar lobes. No P.g. DNA was found by PCR in 7 different AD brains with 46 different tissue samples from the frontal and temporal lobes. Three AD brains tested for both DNA and the novel Pg antigen and found negative for DNA but strongly positive by IHC. This Pg antigen was found in neurons, astrocytes, microglial and choroid ependyma lining cells in the brain. Pull down experiments demonstrated the same protein fragments. Some aged match controls wee also positive by IHC and not Pg DNA.This is the first time for this clinically relevant, unique Pg antigen to be found in many AD brain tissues. Its role in systemic inflammatory diseases for Pg is well understood and now demonstrates that its most likely source is from OMVs of oral origin.

Brain structural changes in subjective cognitive decline: A whole brain surface‐based analysis in the FACEHBI cohort

AbstractBackgroundSubjective cognitive decline (SCD) has been associated with increased risk of subsequent mild cognitive impairment (MCI) and dementia. Evidence from magnetic resonance imaging studies shows that neurodegenerative changes are already present years before dementia and thus, examining brain changes in SCD may contribute to identify potential biomarkers at an early stage of Alzheimer’s disease.Method198 individuals with SCD from the FACEHBI cohort were included (124 females; mean age 65.76 years). All subjects underwent magnetic resonance imaging and 18F‐Florbetaben positron emission tomography scan at baseline and were clinically follow‐up. Whole‐brain cortical surface‐based morphometry analysis were conducted using Freesurfer. Changes in cortical morphology (cortical thickness and surface area) were examined in relation to age, gender, brain amyloid beta deposition, ApoE‐e4 status (52 carrier/ 146 non carrier) and progression to MCI or dementia at the 4‐year follow‐up. Age, sex and years of education were included as covariates in all analyses.ResultAt p=0.05 corrected, higher age was associated with widespread cortical thickness reduction and reduced surface area in bilateral parahippocampal, left cuneus and middle frontal and in the right superior frontal cortex. Males had reduced cortical thickness in the right lingual and reduced surface area in the right superior temporal cortex. Higher amyloid beta deposition was related to higher surface area in the left inferior parietal cortex and no significant results were found in relation to ApoE‐e4 status. At the 4‐year follow‐up, 33 subjects had progressed to MCI and 118 remained cognitively unimpaired, but there were no significant differences in baseline cortical thickness or surface area between them. With a liberal threshold of p<0.0001 uncorrected, we found a cluster of reduced cortical thickness in the right isthmus cingulate in those who converted to MCI four years later.ConclusionBrain morphological changes in SCD are mainly characterized by cortical thickness reduction in relation to age and increased left inferior parietal surface area in relation to higher brain amyloid burden. Baseline reduced cortical thickness in the right isthmus cingulate is the only region associated with subsequent clinical progression to MCI and thus, it might be a useful predictive biomarker of cognitive decline in SCD individuals.

CSF sTREM2 predicts markers of blood brain barrier integrity and amyloid beta metabolism independent of APOE‐ε4 status

AbstractBackgroundTriggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor commonly studied for its roles in microglial regulation and amyloid beta deposition in Alzheimer’s disease (AD). Its soluble form, sTREM2, measurable in cerebrospinal fluid (CSF) is a novel biomarker of microglial activity. CSF sTREM2 has been associated with AD progression and biomarkers of neurodegeneration (for which tau is one), while associations with amyloid‐β biomarkers have been inconclusive. Furthermore, cerebrovascular injury commonly co‐occurs with AD, contributes to clinical progression, and drives microglial activation through independent signaling cascades. However, sTREM2 associations with cerebrovascular pathology have been largely unexplored.MethodLeveraging 155 Vanderbilt Memory and Aging Project (VMAP) participants (mean±standard deviation age=72±6.33 , male=67%, mild cognitive impairment=47%), associations between baseline CSF sTREM2 concentrations (measured using an in‐house immunoassay) and CSF AD biomarkers (Aβx‐42, Aβ1‐42, Aβx‐40, total tau, and phosphorylated tau) and cerebrovascular injury (CSF/plasma albumin ratio) were assessed using linear regression. Models adjusted for age, sex, education, cognitive status, and APOE‐ε4 status.ResultHigher baseline CSF sTREM2 concentrations predicted an increased CSF/plasma albumin ratio, indicative of compartmental blood brain barrier (BBB) permeability (p=1.36e‐07). Additionally, higher levels of sTREM2 predicted increased CSF protein levels of Aβx‐40 (p=1.53e‐09), and Aβx‐42 (p=7.73e‐03), but not Aβ1‐42 (p=0.26) levels, indicating a possible role for the TREM2 axis in regulating or responding to amyloid beta species composition. We also replicated previous associations between higher CSF sTREM2 and higher CSF tau (p=6.14e‐07) and p‐tau (p=1.82e‐08).ConclusionWe report a novel association between sTREM2 and a marker of BBB integrity, highlighting opportunities for further investigation of the TREM2 axis with cerebrovascular injury. We also report a novel association between sTREM2 and amyloid‐β abundance that does not seem to reflect amyloid burden in the brain, and we replicate an sTREM2 association with markers of neurodegeneration. Future work will seek to better characterize the timing of sTREM2 changes relative to markers of BBB dysfunction and AD pathogenesis.

Chitosan-coated Selenium nanoparticles enhance the efficiency of stem cells in the neuroprotection of streptozotocin-induced neurotoxicity in male rats.

Alzheimer's disease (AD) is one of the common neurodegenerative diseases characterized by memory impairment. The protective effects of stem cell-based therapy have been reported in AD. In this study, it was assumed that Chitosan-coated Selenium nanoparticles (ChSeNPs) increase the efficiency of stem cells in the attenuation of neurotoxicity in the rat AD model. The AD model was induced using Streptozotocin (STZ) and treated by the adipose-derived mesenchymal stem cells (AMSCs) and SeNPs/ChSeNPs (0.4mg/kg). Passive avoidance learning and recognition memory were assessed using shuttle box and novel object recognition tasks. The amyloid-beta deposition, the injected cells' homing and survival, antioxidant capacity, and BDNF concentration were evaluated using the histological, biochemical, and ELISA methods. The results showed that the combined administration of ChSeNPs and AMSCs is more effective in increasing the step-through latency and discrimination index than administering SeNPs and stem cells. Combined therapy caused a significant increase in antioxidant capacity that ChSeNPs was more effective than SeNPs, while AMSCs beside SeNPs had a greater effect on BDNF levels compared to conventional treatment of nanoparticles or AMSCs alone. Ultimately, the homing and survival of the transplanted AMSCs were greater in the group that received both stem cells and ChSeNPs. Taken together, it seems that the administration of ChSeNPs enhances the efficiency of transplanted stem cells in decreasing the neurotoxicity induced by STZ through an increase in the antioxidant capacity.

Default mode network dissociation linking cerebral beta amyloid retention and depression in cognitively normal older adults

AbstractBackgroundTo date, cerebral beta amyloid (Aß) deposition and late‐life depression (LLD) are known to be associated with trajectory of Alzheimer’s disease (AD). However, their neurobiological link is not clear. Although previous studies showed aberrant functional connectivity (FC) change of default mode network (DMN) in early Aß deposition and LLD respectively, its mediating role is not elucidated. The aim of this study is to investigate distinctive association pattern of DMN FC linking LLD and Aß retention in the cognitively normal older adults.MethodTwo hundred thirty‐five cognitively normal older adults with (N=118) and without depression (N=117) underwent resting state functional magnetic resonance image and 18F‐Flutemetamol positron emission tomography. We investigated associations among Aß burden, depression, and DMN FC.ResultIndependent component analysis showed increased anterior DMN FC and decreased posterior DMN FC in depression group compared with no depression group. Global cerebral Aß retention correlated positively with anterior and negatively with posterior DMN FC. Anterior DMN FCs were positively correlated with depression severity whereas posterior DMN FCs were negatively correlated with cognitive function. In addition, effect of global cerebral Aß retention on depression severity was mediated by subgenual anterior cingulate FC.ConclusionOur results of anterior and posterior DMN FC dissociation pattern might play pivotal role in linking cerebral Aß pathology and LLD in the course of AD progression. Further longitudinal studies would be needed to confirm causal relationships between cerebral Aß retention and LLD.