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A Study on PHF-Tau Network Effected by Apolipoprotein E4.

ABSTRACT: Apolipoprotein E 4 Allele (APOE 4) is an important factors in Mild cognitive impairment (MCI) and Alzheimer's disease(AD). It plays a primary role in abnormal modification of aggregated Tau protein-paired helical filaments Tau (PHF-Tau). In this study, 143 subjects with PHF-Tau PET were divided into 2 groups (APOE 4 carriers and noncarriers). The measurements of the PHF-Tau network properties and resilient were calculated for 2 group networks respectively. APOE 4 carriers group showed significant differences in all the network properties in the results. We also found significant differences of betweenness centrality in some brain regions for APOE 4 carriers. Moreover, the APOE 4 carriers showed less resilient to targeted or random node failure. Our results indicated that the effects of APOE 4 may lead to abnormalities of PHF-Tau protein network. These findings may be particularly helpful in uncovering the pathophysiology underlying the cognitive dysfunction in MCI patients.

SUBMITTER: Li Y

PROVIDER: S-EPMC10623995 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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A Study on PHF-Tau Network Effected by Apolipoprotein E4.

Li Yuan Y Yao Zhijun Z Yang Yongqing Y Zhao Feng F Fu Yu Y Zou Ying Y Hu Bin B

American journal of Alzheimer's disease and other dementias 20200101

Apolipoprotein E 4 Allele (APOE 4) is an important factors in Mild cognitive impairment (MCI) and Alzheimer's disease(AD). It plays a primary role in abnormal modification of aggregated Tau protein-paired helical filaments Tau (PHF-Tau). In this study, 143 subjects with PHF-Tau PET were divided into 2 groups (APOE 4 carriers and noncarriers). The measurements of the PHF-Tau network properties and resilient were calculated for 2 group networks respectively. APOE 4 carriers group showed significan ...[more]

PMID: 33258666

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Project description:Although the increased risk of developing sporadic Alzheimer's disease (AD) associated with the inheritance of the apolipoprotein E4 (APOE4) allele is well characterized, the molecular underpinnings of how ApoE4 imparts risk remains unknown. Enhanced proteolysis of the ApoE4 protein with a toxic-gain of function has been suggested and a 17 kDa amino-terminal ApoE4 fragment (nApoE41-151) has been identified in post-mortem human AD frontal cortex sections. Recently, we demonstrated in vitro, exogenous treatment of nApoE41-151 in BV2 microglial cells leads to uptake, trafficking to the nucleus and increased expression of genes associated with cell toxicity and inflammation. In the present study, we extend these findings to zebrafish (Danio rerio), an in vivo model system to assess the toxicity of nApoE41-151. Exogenous treatment of nApoE41-151 to 24-hour post-fertilization for 24 hours resulted in significant mortality. In addition, developmental abnormalities were observed following treatment with nApoE41-151 including improper folding of the hindbrain, delay in ear development, deformed yolk sac, enlarged cardiac cavity, and significantly lower heart rates. A similar nApoE31-151 fragment that differs by a single amino acid change (C>R) at position 112 had no effects on these parameters under identical treatment conditions. Decreased presence of pigmentation was noted for both nApoE31-151- and nApoE41-151-treated larvae compared with controls. Behaviorally, touch-evoked responses to stimulus were negatively impacted by treatment with nApoE41-151 but did not reach statistical significance. Additionally, triple-labeling confocal microscopy not only confirmed the nuclear localization of the nApoE41-151 fragment within neuronal populations following exogenous treatment, but also identified the presence of tau pathology, one of the hallmark features of AD. Collectively, these in vivo data demonstrating toxicity as well as sublethal effects on organ and tissue development support a novel pathophysiological function of this AD associated-risk factor.

Project description:In addition to being the greatest genetic risk factor for Alzheimer's disease, expression of the ɛ4 allele of apolipoprotein E can lead to cognitive decline during ageing that is independent of Alzheimer's amyloid-β and tau pathology. In human post-mortem tissue and mouse models humanized for apolipoprotein E, we examined the impact of apolipoprotein E4 expression on brain exosomes, vesicles that are produced within and secreted from late-endocytic multivesicular bodies. Compared to humans or mice homozygous for the risk-neutral ɛ3 allele we show that the ɛ4 allele, whether homozygous or heterozygous with an ɛ3 allele, drives lower exosome levels in the brain extracellular space. In mice, we show that the apolipoprotein E4-driven change in brain exosome levels is age-dependent: while not present at age 6 months, it is detectable at 12 months of age. Expression levels of the exosome pathway regulators tumor susceptibility gene 101 (TSG101) and Ras-related protein Rab35 (RAB35) were found to be reduced in the brain at the protein and mRNA levels, arguing that apolipoprotein E4 genotype leads to a downregulation of exosome biosynthesis and release. Compromised exosome production is likely to have adverse effects, including diminishing a cell's ability to eliminate materials from the endosomal-lysosomal system. This reduction in brain exosome levels in 12-month-old apolipoprotein E4 mice occurs earlier than our previously reported brain endosomal pathway changes, arguing that an apolipoprotein E4-driven failure in exosome production plays a primary role in endosomal and lysosomal deficits that occur in apolipoprotein E4 mouse and human brains. Disruption of these interdependent endosomal-exosomal-lysosomal systems in apolipoprotein E4-expressing individuals may contribute to amyloidogenic amyloid-β precursor protein processing, compromise trophic signalling and synaptic function, and interfere with a neuron's ability to degrade material, all of which are events that lead to neuronal vulnerability and higher risk of Alzheimer's disease development. Together, these data suggest that exosome pathway dysfunction is a previously unappreciated component of the brain pathologies that occur as a result of apolipoprotein E4 expression.

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Dataset Information

A Study on PHF-Tau Network Effected by Apolipoprotein E4.

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A Study on PHF-Tau Network Effected by Apolipoprotein E4.

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