neurofibrillary tangles
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Cells ◽  
2022 ◽  
Vol 11 (2) ◽  
pp. 286
Author(s):  
Hesham Essa ◽  
Lee Peyton ◽  
Whidul Hasan ◽  
Brandon Emanuel León ◽  
Doo-Sup Choi

Alzheimer’s disease is the most common neurodegenerative disease, affecting more than 6 million US citizens and representing the most prevalent cause for dementia. Neurogenesis has been repeatedly reported to be impaired in AD mouse models, but the reason for this impairment remains unclear. Several key factors play a crucial role in AD including Aβ accumulation, intracellular neurofibrillary tangles accumulation, and neuronal loss (specifically in the dentate gyrus of the hippocampus). Neurofibrillary tangles have been long associated with the neuronal loss in the dentate gyrus. Of note, Aβ accumulation plays an important role in the impairment of neurogenesis, but recent studies started to shed a light on the role of APP gene expression on the neurogenesis process. In this review, we will discuss the recent approaches to neurogenesis in Alzheimer disease and update the development of therapeutic methods.


2021 ◽  
Vol 10 (1) ◽  
pp. 56
Author(s):  
Sandhya T. Chakravarthi ◽  
Suresh G. Joshi

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.


Author(s):  
Stephan A. Kaeser ◽  
Lisa M. Häsler ◽  
Marius Lambert ◽  
Carina Bergmann ◽  
Astrid Bottelbergs ◽  
...  

2021 ◽  
pp. 1-20
Author(s):  
Wolfgang J. Streit ◽  
Jonas Rotter ◽  
Karsten Winter ◽  
Wolf Müller ◽  
Habibeh Khoshbouei ◽  
...  

Background: Neuritic plaques contain neural and microglial elements, and amyloid-β protein (Aβ), but their pathogenesis remains unknown. Objective: Elucidate neuritic plaque pathogenesis. Methods: Histochemical visualization of hyperphosphorylated-tau positive (p-tau+) structures, microglia, Aβ, and iron. Results: Disintegration of large projection neurons in human hippocampus and neocortex presents as droplet degeneration: pretangle neurons break up into spheres of numerous p-tau+ droplets of various sizes, which marks the beginning of neuritic plaques. These droplet spheres develop in the absence of colocalized Aβ deposits but once formed become encased in diffuse Aβ with great specificity. In contrast, neurofibrillary tangles often do not colocalize with Aβ. Double-labelling for p-tau and microglia showed a lack of microglial activation or phagocytosis of p-tau+ degeneration droplets but revealed massive upregulation of ferritin in microglia suggesting presence of high levels of free iron. Perl’s Prussian blue produced positive staining of microglia, droplet spheres, and Aβ plaque cores supporting the suggestion that droplet degeneration of pretangle neurons in the hippocampus and cortex represents ferroptosis, which is accompanied by the release of neuronal iron extracellularly. Conclusion: Age-related iron accumulation and ferroptosis in the CNS likely trigger at least two endogenous mechanisms of neuroprotective iron sequestration and chelation, microglial ferritin expression and Aβ deposition, respectively, both contributing to the formation of neuritic plaques. Since neurofibrillary tangles and Aβ deposits colocalize infrequently, tangle formation likely does not involve release of neuronal iron extracellularly. In human brain, targeted deposition of Aβ occurs specifically in response to ongoing ferroptotic droplet degeneration thereby producing neuritic plaques.


Author(s):  
Aayushi Singh ◽  
Asha Jha

Alzheimer’s disease (AD) is defined as a progressive neurodegenerative disorder that has lately become the top reason for dementia in the elderly population (usually above 60-65 years). As mentioned before, most AD cases are sporadic and have a late onset. This disease is characterized by impairment of higher cognitive functions like deficits in memory, language comprehension, coordination, etc. The primary pathophysiology behind Alzheimer’s disease is loss of cholinergic innervation due to the formation of neuritic (senile) amyloid-beta plaques and tau protein-containing neurofibrillary tangles (NFTs) in parts of the brain associated with memory functions. These neurofibrillary tangles (NFTs) and amyloid β plaques can cause the induction of other aetiologies of Alzhedisease-likes like neuroinflammation and central hyperexcitability. The brain's main regions affected by Alzheimer’s disease are the neocortex, the basal nucleus of Meynert, and the hippocampus. These areas are associated with higher cognitive functions like memory, arousal, attention, sensory processing, etc. Thus, cholinesterase inhibitors have been widely used as first-line drug therapy for symptomatic relief in Alzheimer’s disease. They function by inhibiting acetylcholinesterase or catabolizing it and henceforth enhancing synaptic availability of Acetylcholine. The commonly prescribed drugs of this class include donepezil, galantamine, physostigmine, metrifonate, and rivastigmine. This article will discuss the widely used cholinesterase inhibitors (old & new) for managing AD symptoms in detail.


2021 ◽  
Author(s):  
Tian Tang ◽  
Junli Jia ◽  
Emanuela Garbarino ◽  
Luyao Chen ◽  
Jingjing Ma ◽  
...  

Human herpesvirus 6 (HHV-6) belongs to the betaherpesvirus subfamily and is divided into two distinct species, HHV-6A and HHV-6B. HHV-6 can infect nerve cells and is associated with a variety of nervous system diseases. Recently, the association of HHV-6A infection with Alzheimer's disease (AD) has been suggested. The main pathological phenomena of AD are the accumulation of β-amyloid (Aβ), neurofibrillary tangles, and neuroinflammation, however, the specific molecular mechanism of pathogenesis of AD is not fully clear. In this study, we focused on the effect of HHV-6A U4 gene function on Aβ expression. Co-expression of HHV-6A U4 with APP resulted in inhibition of ubiquitin-mediated proteasomal degradation of amyloid precursor protein (APP). Consequently, accumulation of β-amyloid peptide (Aβ), insoluble neurofibrillary tangles, and loss of neural cells may occur. Immunoprecipitation coupled to mass spectrometry (IP-MS) showed that HHV-6A U4 protein interacts with E3 ubiquitin ligase composed of DDB1 and Cullin 4B which is also responsible for APP degradation. We hypothesize that HHV-6A U4 protein competes with APP for binding to E3 ubiquitin ligase, resulting in inhibition of APP ubiquitin modification and clearance. Finally, this is leading to the increase of APP expression and Aβ deposition, which is the hallmark of AD. These findings provide novel evidence for the etiological hypothesis of AD that can contribute to the further analysis of HHV-6A role in AD. IMPORTANCE The association of HHV-6A infection with Alzheimer’s disease has attracted increasing attention, although its role and molecular mechanism remain to be established. Our results here indicate that HHV-6A U4 inhibits APP (amyloid precursor protein) degradation. U4 protein interacts with CRLs (Cullin-RING E3 ubiquitin-protein ligases) which is also responsible for APP degradation. We propose a model that U4 competitively binds to CRLs with APP, resulting in APP accumulation and Aβ generation. Our findings provide new insights into the etiological hypothesis of HHV-6A in AD that can help further analyses.


2021 ◽  
Author(s):  
Alessandro Soloperto ◽  
Deborah Quaglio ◽  
Paola Baiocco ◽  
Isabella Romeo ◽  
Mattia Mori ◽  
...  

Abstract Numerous studies have shown a strong correlation between the number of neurofibrillary tangles of the tau protein and Alzheimer's disease progression, making the quantitative detection of tau very promising from a clinical point of view. However, the lack of highly reliable fluorescent probes for selective imaging of tau neurofibrillary tangles is a major challenge due to sharing similar β−sheet motifs with homologous Amyloid-β fibrils. In the current work, we describe the rational design and the in silico evaluation of a small-size focused library of fluorescent probes, consisting of a BODIPY core (electron acceptor) featuring highly conjugated systems (electron donor) with a length in the range 13-19 Å at C3. Among the most promising probes in terms of binding mode, theoretical affinity and polarity, BT1 has been synthesized and tested in vitro onto human induced pluripotent stem cells derived neuronal cell cultures. The probe showed excellent photophysical properties and high selectivity allowing in vitro imaging of hyperphosphorylated tau protein filaments with minimal background noise. Our findings offer new insight into the structure-activity relationship of this class of tau selective fluorophores, paving the way for boosting tau tangle detection in patients possibly through retinal spectral scans.


2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Maria José Ferreira ◽  
Tânia Soares Martins ◽  
Odete da Cruz e Silva ◽  
Rui Vitorino ◽  
Ana Gabriela Henriques

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 5-5
Author(s):  
Hind Bouzid ◽  
Julia Belk ◽  
Max Jan ◽  
Yanyan Qi ◽  
Chloé Sarnowski ◽  
...  

Abstract Clonal hematopoiesis of indeterminate potential (CHIP) occurs when hematopoietic stem cells (HSCs) acquire a mutation, most commonly a null variant in TET2 or DNMT3A, that confers a selective advantage. Blood cancers may result if additional cooperating mutations are acquired. However, CHIP may also cause atherosclerosis and other inflammatory diseases because these mutations alter the function or development of effector immune cells derived from the HSCs. Genome-wide association studies have implicated microglia, the resident myeloid cells in the brain, as key players in the biology of Alzheimer's disease (AD). Here, we asked whether CHIP associated with AD dementia or neuropathologic change, and whether mutant marrow-derived cells could be found in the brains of CHIP carriers. To test for an association, we used data from the Trans-omics for Precision Medicine project (TOPMed) and the Alzheimer's Disease Sequencing Project (ADSP), where whole genome or exome sequencing data as well as AD phenotype data was available on 5,730 persons. TOPMed contained population-based cohorts unselected for AD, while ADSP was a case-control study for AD. We surprisingly discovered that the presence of CHIP was associated with a reduced risk of AD dementia in both projects (fixed-effects meta-analysis odds ratio 0.64, p = 3.0 x 10-5, adjusted for age, sex and APOE genotype) (Figure 1). The protective effect of CHIP was strongest in those with APOE e3 or e4 alleles, but not seen in those with APOE e2 allele. No substantial differences in AD risk were seen based on mutated driver gene. In addition, the presence of CHIP was associated with a reduced burden of amyloid plaques and neurofibrillary tangles in the brains of those without dementia. In sum, our human genetic analyses indicated that CHIP was robustly associated with protection from AD dementia and AD-related neuropathologic changes. A causal link between CHIP and AD would be strengthened by finding the mutated cells infiltrating the brain. However, it is presumed that bone marrow progenitors have minimal contribution to the adult microglial pool. To determine if the mutations seen in the blood of CHIP carriers could also be found in the brain, we obtained 8 occipital cortex samples from autopsy of donors with CHIP, 6 of whom were cognitively normal at the time of death. The 8 CHIP carriers had mutations in DNMT3A, TET2, ASXL1, SF3B1, and GNB1 with the highest frequency in DNMT3A and TET2, which is representative of the relative proportion of these mutations in the general population. We detected the CHIP somatic variants in the microglia enriched (NeuN- c-Maf+) fraction of brain in 7 out of 8 CHIP carriers, with a VAF ranging from 0.02 to 0.28 (representing 4% to 56% of nuclei) (Figure 2), but at low levels or absent in the other fractions of brain. We then performed single-cell ATAC-sequencing on brain samples from 2 CHIP carriers and 1 control to specify the cellular population harboring CHIP mutations. This revealed that hematopoietic cells in the 3 samples formed a single myeloid cluster that had accessible chromatin at the microglia marker genes TMEM119, P2RY12, and SALL1, but not in genes specific to monocytes or dendritic cells. We further determined that the proportion of cells in this cluster bearing the CHIP mutations ranged from ~40-80% in these two samples, indicating widespread replacement of the endogenous microglial pool by mutant cells. We show here that, unexpectedly, the presence of CHIP is associated with protection from AD dementia. CHIP is also associated with lower levels of neuritic plaques and neurofibrillary tangles in those without dementia, indicating a possible modulating effect of CHIP on the underlying pathophysiology of AD. Consistent with this hypothesis, we also detect substantial infiltration of brain by marrow-derived mutant cells which adopt a microglial-like phenotype. We speculate that the mutations associated with CHIP confer circulating precursor cells with an enhanced ability to engraft in the brain, to differentiate into microglia once engrafted, and/or to clonally expand relative to unmutated cells in the brain microenvironment. These non-mutually exclusive possibilities could provide protection from AD by supplementing the phagocytic capacity of the endogenous microglial system during aging. Figure 1 Figure 1. Disclosures Jaiswal: Novartis: Consultancy, Honoraria; Foresite Labs: Consultancy; Genentech: Consultancy, Honoraria; AVRO Bio: Consultancy, Honoraria; Caylo: Current holder of stock options in a privately-held company.


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