Year: 2019
Type: dissertation
Abstract: APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease.ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms.However, whether APOE independently influences tau pathology or tau-mediated neurodegeneration, is not clear.Previous works using tau transgenic mice (P301S) on either a human ApoE knock-in (KI) or ApoE knockout (KO) background have shown that P301S/ApoE4 mice have significantly higher tau levels in the brain and microglia immune reactivity in vivo.The goal of this study was to characterize ApoE4 mediated neurodegeneration in vitro and screen Liver X receptor (LXR) agonist GW3965 as possible inducer of neuroprotection.Here we show ApoE4-expressing microglia in vitro exhibit altered expression of immune and lysosomal modulators at baseline.Co-culturing P301S tau-expressing neurons with ApoE4-expressing mixed glia results in markedly reduced neuronal viability compared with neuron/WT and neuron/ApoE3 co-cultures.Neurons cultured alone or with WT mixed glia showed the greatest viability.Neuron/ApoE4 viability was restored to WT levels after treatment with LXR agonist GW3965.This was accompanied by a significantly lower level of tumor-necrosis factor-α (TNF-α) secretion in addition to lower Cystatin F (CST7) and triggering receptor that is expressed on myeloid cells (TREM2) expression.In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe neurodegeneration.In individuals who are positive for amyloid-β and tau pathology, ε4-carriers demonstrate greater rates of disease progression.Our results demonstrate that ApoE affects tau mediated neurodegeneration, neuroinflammation, and may potentially be exacerbated by lipid transport pathways in microglia.
Author: Pardeep Singh
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
Funder: National Institutes of Health
OpenAlex ID: W2980760274