scholarly journals Exposure to Environmental Arsenic and Emerging Risk of Alzheimer’s Disease: Perspective Mechanisms, Management Strategy, and Future Directions

Toxics ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 188
Author(s):  
Md. Ataur Rahman ◽  
Md. Abdul Hannan ◽  
Md Jamal Uddin ◽  
Md Saidur Rahman ◽  
Md Mamunur Rashid ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Arsenic Exposure ◽  
Amyloid Β ◽  
Brain Regions ◽  
Convincing Evidence ◽  
Neurological Deficits ◽  
Mitochondrial Dysfunctions ◽  
Emerging Risk ◽  
Exact Etiology

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregates in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth’s crust, and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition, although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not yet clear. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.

scholarly journals Exposure to Environmental Factor Arsenic and Emerging Risk of Alzheimer’s Disease: Perspective Mechanisms, Management Strategy, And Future Directions

2021 ◽  
Author(s):  
Md. Ataur Rahman ◽  
Md. Abdul Hannan ◽  
Md Jamal Uddin ◽  
Md Saidur Rahman ◽  
Md Mamunur Rashid ◽  
...  
Keyword(s):  
Arsenic Exposure ◽  
Brain Regions ◽  
Convincing Evidence ◽  
Neurological Deficits ◽  
Protein Homeostasis ◽  
Future Directions ◽  
Mitochondrial Dysfunctions ◽  
Naturally Occurring ◽  
Emerging Risk ◽  
Exact Etiology

Alzheimer’s disease (AD) is one of the most prevailing neurodegenerative diseases, characterized by memory dysfunction and the presence of hyperphosphorylated tau and amyloid β (Aβ) aggregate in multiple brain regions, including the hippocampus and cortex. The exact etiology of AD has not yet been confirmed. However, epidemiological reports suggest that populations who were exposed to environmental hazards are more likely to develop AD than those who were not. Arsenic (As) is a naturally occurring environmental risk factor abundant in the Earth’s crust and human exposure to As predominantly occurs through drinking water. Convincing evidence suggests that As causes neurotoxicity and impairs memory and cognition although the hypothesis and molecular mechanism of As-associated pathobiology in AD are not clear yet. However, exposure to As and its metabolites leads to various pathogenic events such as oxidative stress, inflammation, mitochondrial dysfunctions, ER stress, apoptosis, impaired protein homeostasis, and abnormal calcium signaling. Evidence has indicated that As exposure induces alterations that coincide with most of the biochemical, pathological, and clinical developments of AD. Here, we overview existing literature to gain insights into the plausible mechanisms that underlie As-induced neurotoxicity and the subsequent neurological deficits in AD. Prospective strategies for the prevention and management of arsenic exposure and neurotoxicity have also been discussed.

Pathways linking Aβ and tau pathologies

2010 ◽  
Vol 38 (4) ◽  
pp. 993-995 ◽  
Author(s):  
Frank M. LaFerla
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurological Disorders ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Convincing Evidence ◽  
Amyloid Β Peptide ◽  
Tau Pathology ◽  
Aβ Amyloid ◽  
Cellular Compartments

Aβ (amyloid β-peptide) and tau are the main proteins that misfold and accumulate in amyloid plaques and NFTs (neurofibrillary tangles) of Alzheimer's disease and other neurological disorders. Historically, because plaques and NFTs accumulate in diverse cellular compartments, i.e. mainly extracellularly for plaques and intracellularly for NFTs, it was long presumed that the constituent proteins formed these lesions via unrelated pathways. Animal and cell studies over the last decade, however, have provided convincing evidence to show that Aβ can facilitate the development of tau pathology by altering several cell-dependent and -independent mechanisms. In the present article, results are reviewed from several laboratories that show that modulating Aβ pathology can directly affect the development of tau pathology, which has significant implications for the treatment of Alzheimer's disease.

scholarly journals Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer’s Disease mouse model brain

2020 ◽  
Author(s):  
Bhargy Sharma ◽  
Joanes Grandjean ◽  
Margaret Phillips ◽  
Ambrish Kumar ◽  
Francesca Mandino ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Mouse Brain ◽  
Amyloid Fibrils ◽  
Amyloid Β ◽  
Brain Regions ◽  
Mri Contrast ◽  
Neuroprotective Function

AbstractEndogenous brain proteins can recognize the toxic oligomers of amyloid-β (Aβ) peptides implicated in Alzheimer’s disease (AD) and interact with them to prevent their aggregation. Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major Aβ-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain. These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

scholarly journals Plasma neurofilament light is associated with white matter damage in Alzheimer's disease

2020 ◽  
Author(s):  
Fardin Nabizadeh ◽  
Mohammad Balabandian ◽  
Mohammad Reza Rostami ◽  
Samuel Berchi Kankam ◽  
Fetemeh Ranjbaran ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
White Matter ◽  
Diffusion Tensor ◽  
Amyloid Β ◽  
Brain Regions ◽  
Csf Biomarkers ◽  
Cross Sectional ◽  
Neurofilament Light ◽  
Microstructural Changes

Abstract The most replicated blood biomarker for monitoring Alzheimer’s disease is neurofilament light (NFL). Recent evidence revealed that the plasma level of the NFL has a strong predictive value in cognitive decline and is elevated in AD patients. The Diffusion Tensor Imaging (DTI) is understood to reflect white matter disruption, neurodegeneration, and synaptic damage in AD. However, few investigations have been carried out on the association between plasma NFL and white matter microstructure integrity. We have investigated the cross-sectional associations of plasma NFL, CSF total tau, phosphorylated tau, and Amyloid β with white matter microstructural changes as measured by DTI in 92 mild cognitive impairment (MCI) participants. We investigated potential correlations of the DTI values of each region of the MNI atlas, with plasma NFL, separately using a partial correlation model controlled for the effect of age, sex, and APOE ε4 genotype. Our findings revealed a significant correlation between plasma and CSF biomarkers with altered white matter microstructural changes in widespread brain regions. Plasma NFL negatively correlates with FA and the positive correlation with RD, DA, and MD values in different regions. Our findings showed that plasma NFL is associated with white matter changes and AD-related features, including atrophy and hypometabolism. Plasma NFL promises to be an early biomarker of microstructural changes in MCI and MCI progression to AD.

scholarly journals Characterization of mitochondrial DNA quantity and quality in the human aged and Alzheimer's disease brain

2021 ◽  
Author(s):  
Hans-Ulrich Klein ◽  
Caroline Trumpff ◽  
Hyun-Sik Yang ◽  
Annie J Lee ◽  
Martin Picard ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dna ◽  
Human Brain ◽  
Neurodegenerative Diseases ◽  
Late Onset ◽  
Multivariable Analysis ◽  
Amyloid Β ◽  
Brain Regions ◽  
Mtdna Copy Number

Mitochondrial dysfunction is a feature of neurodegenerative diseases, including Alzheimer's disease (AD). Using whole-genome sequencing, we assessed mitochondrial DNA (mtDNA) heteroplasmy levels and mtDNA copy number (mtDNAcn) in 1,361 human brain samples of five brain regions from three studies. Multivariable analysis of ten common brain pathologies identified tau pathology in the dorsolateral prefrontal cortex and TDP-43 pathology in the posterior cingulate cortex as primary drivers of reduced mtDNAcn in the aged human brain. Amyloid-β pathology, age, and sex were not associated with mtDNAcn. Further, there is evidence for a direct effect of mitochondrial health on cognition. In contrast, while mtDNA heteroplasmy levels increase by about 1.5% per year of life in the cortical regions, we found little evidence for an association with brain pathologies or cognitive functioning. Thus, our data indicates that mtDNA heteroplasmy burden is unlikely to be involved in the pathogenesis of late-onset neurodegenerative diseases.

scholarly journals Molecular subtyping of Alzheimer’s disease using RNA sequencing data reveals novel mechanisms and targets

2021 ◽  
Vol 7 (2) ◽  
pp. eabb5398
Author(s):  
Ryan A. Neff ◽  
Minghui Wang ◽  
Sezen Vatansever ◽  
Lei Guo ◽  
Chen Ming ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Models ◽  
Molecular Subtypes ◽  
Amyloid Β ◽  
Brain Regions ◽  
Molecular Heterogeneity ◽  
Sequencing Data ◽  
Integrative Network ◽  
Pathophysiologic Mechanisms

Alzheimer’s disease (AD), the most common form of dementia, is recognized as a heterogeneous disease with diverse pathophysiologic mechanisms. In this study, we interrogate the molecular heterogeneity of AD by analyzing 1543 transcriptomes across five brain regions in two AD cohorts using an integrative network approach. We identify three major molecular subtypes of AD corresponding to different combinations of multiple dysregulated pathways, such as susceptibility to tau-mediated neurodegeneration, amyloid-β neuroinflammation, synaptic signaling, immune activity, mitochondria organization, and myelination. Multiscale network analysis reveals subtype-specific drivers such as GABRB2, LRP10, MSN, PLP1, and ATP6V1A. We further demonstrate that variations between existing AD mouse models recapitulate a certain degree of subtype heterogeneity, which may partially explain why a vast majority of drugs that succeeded in specific mouse models do not align with generalized human trials across all AD subtypes. Therefore, subtyping patients with AD is a critical step toward precision medicine for this devastating disease.

scholarly journals Protein contributions to brain atrophy acceleration in Alzheimer’s disease and primary age-related tauopathy

Brain ◽  
2020 ◽  
Vol 143 (11) ◽  
pp. 3463-3476
Author(s):  
Keith A Josephs ◽  
Peter R Martin ◽  
Stephen D Weigand ◽  
Nirubol Tosakulwong ◽  
Marina Buciuc ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Atrophy ◽  
Neurofibrillary Tangle ◽  
Amyloid Β ◽  
Brain Regions ◽  
Hippocampal Atrophy ◽  
Brain Volumes ◽  
Age Related ◽  
Over Time

Abstract Alzheimer’s disease is characterized by the presence of amyloid-β and tau deposition in the brain, hippocampal atrophy and increased rates of hippocampal atrophy over time. Another protein, TAR DNA binding protein 43 (TDP-43) has been identified in up to 75% of cases of Alzheimer’s disease. TDP-43, tau and amyloid-β have all been linked to hippocampal atrophy. TDP-43 and tau have also been linked to hippocampal atrophy in cases of primary age-related tauopathy, a pathological entity with features that strongly overlap with those of Alzheimer’s disease. At present, it is unclear whether and how TDP-43 and tau are associated with early or late hippocampal atrophy in Alzheimer’s disease and primary age-related tauopathy, whether either protein is also associated with faster rates of atrophy of other brain regions and whether there is evidence for protein-associated acceleration/deceleration of atrophy rates. We therefore aimed to model how these proteins, particularly TDP-43, influence non-linear trajectories of hippocampal and neocortical atrophy in Alzheimer’s disease and primary age-related tauopathy. In this longitudinal retrospective study, 557 autopsied cases with Alzheimer’s disease neuropathological changes with 1638 ante-mortem volumetric head MRI scans spanning 1.0–16.8 years of disease duration prior to death were analysed. TDP-43 and Braak neurofibrillary tangle pathological staging schemes were constructed, and hippocampal and neocortical (inferior temporal and middle frontal) brain volumes determined using longitudinal FreeSurfer. Bayesian bivariate-outcome hierarchical models were utilized to estimate associations between proteins and volume, early rate of atrophy and acceleration in atrophy rates across brain regions. High TDP-43 stage was associated with smaller cross-sectional brain volumes, faster rates of brain atrophy and acceleration of atrophy rates, more than a decade prior to death, with deceleration occurring closer to death. Stronger associations were observed with hippocampus compared to temporal and frontal neocortex. Conversely, low TDP-43 stage was associated with slower early rates but later acceleration. This later acceleration was associated with high Braak neurofibrillary tangle stage. Somewhat similar, but less striking, findings were observed between TDP-43 and neocortical rates. Braak stage appeared to have stronger associations with neocortex compared to TDP-43. The association between TDP-43 and brain atrophy occurred slightly later in time (∼3 years) in cases of primary age-related tauopathy compared to Alzheimer’s disease. The results suggest that TDP-43 and tau have different contributions to acceleration and deceleration of brain atrophy rates over time in both Alzheimer’s disease and primary age-related tauopathy.

scholarly journals Imaging stable isotope labelling kinetics (iSILK) for following spatial Aβ plaque aggregation dynamics in evolving Alzheimer’s disease pathology

2020 ◽  
Author(s):  
Wojciech Michno ◽  
Katie Stringer ◽  
Thomas Enzlein ◽  
Melissa K. Passarelli ◽  
Stephane Escrig ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Stable Isotope ◽  
Clinical Symptoms ◽  
Imaging Mass Spectrometry ◽  
Amyloid Β ◽  
Brain Regions ◽  
Plaque Formation ◽  
Stable Isotope Labelling ◽  
Isotope Labelling

AbstractFor our understanding of Alzheimer’s disease (AD) pathophysiology, it is of critical importance to determine how key pathological factors, specifically amyloid β (Aβ) plaque formation, are interconnected and implicated in neurodegeneration, disease progression and the development of clinical symptoms. Exactly how Aβ plaque formation is initiated and how the ongoing plaque deposition proceeds is not well understood. This is partly because we can only examine details of the molecular pathology after death in humans, and in mice, we can only examine a particular point in time without any longitudinal information on the fate of individually formed deposits. Herein, we used metabolic labelling of proteins with stable isotopes, together with multimodal imaging mass spectrometry (IMS) for imaging stable isotope labelling kinetics (iSILK) in the APPNL-G-F knock-in mouse model of AD. The aim was to monitor the earliest seeds of Aβ deposition through ongoing plaque development and track the deposition of Aβ that is produced later in relation to already deposited plaques. This allowed us to visualize Aβ peptide aggregation dynamics within individual deposits across different brain regions. We identified the cortex as a primary site of deposition in precipitating plaque pathology. Further, our data show that structural plaque heterogeneity is associated with differential peptide deposition. Specifically, Aβ1-42 is forming an initial core seed followed by radial outgrowth and late secretion and deposition of Aβ1-38.Together these data prove the potential of iSILK for probing amyloid protein secretion, processing and aggregation dynamics in AD pathology.

scholarly journals Brain geometry matters in Alzheimer’s disease progression: a simulation study

2020 ◽  
Author(s):  
Masoud Hoore ◽  
Jeffrey Kelling ◽  
Mahsa Sayadmanesh ◽  
Tanmay Mitra ◽  
Marta Schips ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Activity ◽  
Amyloid Β ◽  
Amyloid Plaque ◽  
Brain Regions ◽  
Plaque Formation ◽  
Secretion Rate ◽  
Heterogeneous Distribution ◽  
The Brain

AbstractThe Amyloid cascade hypothesis (ACH) for Alzheimer’s disease (AD) is modeled over the whole brain tissue with a set of partial differential equations. Our results show that the amyloid plaque formation is critically dependent on the secretion rate of amyloid β (Aβ), which is proportional to the product of neural density and neural activity. Neural atrophy is similarly related to the secretion rate of Aβ. Due to a heterogeneous distribution of neural density and brain activity throughout the brain, amyloid plaque formation and neural death occurs heterogeneously in the brain. The geometry of the brain and microglia migration in the parenchyma bring more complexity into the system and result in a diverse amyloidosis and dementia pattern of different brain regions. Although the pattern of amyloidosis in the brain cortex from in-silico results is similar to experimental autopsy findings, they mismatch at the central regions of the brain, suggesting that ACH is not able to explain the whole course of AD without considering other factors, such as tau-protein aggregation or neuroinflammation.

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