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Astrocytic expression of the Alzheimer's disease risk allele, ApoE?4, potentiates neuronal tau pathology in multiple preclinical models.

ABSTRACT: ApoE?4 is a major genetic risk factor for Alzheimer's disease (AD), a disease hallmarked by extracellular amyloid-beta (A?) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoE?4 allele is associated with increased A? deposition and a role for ApoE?4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocytes. The isoform-specific effects of human ApoE were evaluated within in vitro models of tau pathology within neuron/astrocyte co-cultures, as well as in a transgenic tau mouse model. Tau aggregation, accumulation, and phosphorylation were measured to determine if the three isoforms of human ApoE had differential effects on tau. Astrocytic overexpression of the human ApoE?4 allele increased phosphorylation and misfolding of overexpressed neuronal tau in multiple models, including the aggregation and accumulation of added tau oligomers, in an isoform-specific manner. The ability of ApoE?4 to increase tau aggregation could be inhibited by an ApoE?4-specific antibody. This study indicates that astrocytic expression of ApoE?4 can potentiate tau aggregation and phosphorylation within neurons and supports a gain of toxic function hypothesis for the effect of hApoE?4 on tau.

SUBMITTER: Jablonski AM

PROVIDER: S-EPMC7873246 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Astrocytic expression of the Alzheimer's disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models.

Jablonski Angela Marie AM Warren Lee L Usenovic Marija M Zhou Heather H Sugam Jonathan J Parmentier-Batteur Sophie S Voleti Bhavya B

Scientific reports 20210209 1

ApoEε4 is a major genetic risk factor for Alzheimer's disease (AD), a disease hallmarked by extracellular amyloid-beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). The presence of the ApoEε4 allele is associated with increased Aβ deposition and a role for ApoEε4 in the potentiation of tau pathology has recently emerged. This study focused on comparing the effects of adeno-associated virus (AAV)-mediated overexpression of the three predominant human ApoE isoforms within astrocyt ...[more]

PMID: 33564035

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Project description:BackgroundTwo of the main causes for dementia are Alzheimer's disease (AD) and vascular pathology, with most patients showing mixed pathology. Plasma biomarkers for Alzheimer's disease-related pathology have recently emerged, including Aβ (amyloid-beta), p-tau (phosphorylated tau), NfL (neurofilament light), and GFAP (glial fibrillary acidic protein). There is a current gap in the literature regarding whether there is an association between these plasma biomarkers with vascular pathology and neurodegeneration.Methods and resultsCross-sectional data from 594 individuals (mean [SD] age: 64 [8] years; 17% female) were included from the SMART-MR (Second Manifestations of Arterial Disease-Magnetic Resonance) study, a prospective cohort study of individuals with a history of arterial disease. Plasma markers were assessed using single molecular array assays (Quanterix). Magnetic resonance imaging markers included white matter hyperintensity volume, presence of infarcts (yes/no), total brain volume, and hippocampal volume assessed on 1.5T magnetic resonance imaging. Linear regressions were performed for each standardized plasma marker with white matter hyperintensity volume, total brain volume, and hippocampal volume as separate outcomes, correcting for age, sex, education, and intracranial volume. Logistic regressions were performed for the presence of lacunar and cortical infarcts. Higher p-tau181 was associated with larger white matter hyperintensity volume (b per SD increase=0.16 [95% CI, 0.06-0.26], P=0.015). Higher NfL (b=-5.63, [95% CI, -8.95 to -2.31], P=0.015) was associated with lower total brain volume and the presence of infarcts (odds ratio [OR], 1.42 [95% CI, 1.13-1.78], P=0.039). Higher GFAP levels were associated with cortical infarcts (OR, 1.45 [95% CI, 1.09-1.92], P=0.010).ConclusionsPlasma biomarkers that have been associated with tau pathology, axonal injury, and astrocytic activation are related to magnetic resonance imagingmarkers of vascular pathology and neurodegeneration in patients with manifest arterial disease.

Dataset Information

Astrocytic expression of the Alzheimer's disease risk allele, ApoE?4, potentiates neuronal tau pathology in multiple preclinical models.

Publications

Astrocytic expression of the Alzheimer's disease risk allele, ApoEε4, potentiates neuronal tau pathology in multiple preclinical models.

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