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Apolipoprotein E4 Suppresses Neuronal-Specific Gene Expression in Maturing Neuronal Progenitor Cells Exposed to HIV.

ABSTRACT: The apolipoprotein ?4 gene allele and the apolipoprotein E4 protein (ApoE4) are important host susceptibility factors linked to neurocognitive disorders associated with HIV infection or Alzheimer's disease. Our previous studies showed differential effects of the two most common human ApoE genotypes, APOE3/3 and APOE3/4, on gene expression by differentiating human neuroepithelial progenitor cells continuously exposed to HIV. To investigate the effects of ApoE3 versus ApoE4 isoforms specifically on maturing neurons, we adapted a human neuronal progenitor cell line, hNP1, with ApoE genotype APOE3/3. Differentiating hNP1 cells were exposed for 16 days to HIV- or mock-infected supernatants and to added recombinant ApoE isoforms rApoE3 or rApoE4 to modulate the ApoE phenotype of the cells. Gene expression was investigated using microarray and functional genomics analyses. Added rApoE3 differentially affected 36 genes. Added rApoE4 differentially affected 85 genes; 41 of which were differentially expressed only in HIV or mock-supernatant treated cells, and 80% of which were downregulated. Genes differentially downregulated only by rApoE4 represented multiple neuronal functions related to neurogenesis. Approximately five times more genes were differentially enriched by rApoE4 versus rApoE3 in the Gene Ontology (GO) cellular process analysis, with 4 orders of magnitude greater significance. Half of the top 10 GO processes affected by rApoE4 treatment were neurogenesis-related. The largest differences in gene expression between the two isoforms were observed within the HIV-exposed cultures, suggesting that HIV exposure magnifies ApoE4's suppressive effect on neuronal gene expression. This study provides evidence for neuronal-specific responses to ApoE4 that could affect neurogenesis and neuronal survival.

SUBMITTER: Geffin R

PROVIDER: S-EPMC5527073 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Apolipoprotein E4 Suppresses Neuronal-Specific Gene Expression in Maturing Neuronal Progenitor Cells Exposed to HIV.

Geffin Rebeca R Martinez Ricardo R de Las Pozas Alicia A Issac Biju B McCarthy Micheline M

Journal of neuroimmune pharmacology : the official journal of the Society on NeuroImmune Pharmacology 20170320 3

The apolipoprotein ε4 gene allele and the apolipoprotein E4 protein (ApoE4) are important host susceptibility factors linked to neurocognitive disorders associated with HIV infection or Alzheimer's disease. Our previous studies showed differential effects of the two most common human ApoE genotypes, APOE3/3 and APOE3/4, on gene expression by differentiating human neuroepithelial progenitor cells continuously exposed to HIV. To investigate the effects of ApoE3 versus ApoE4 isoforms specifically o ...[more]

PMID: 28321820

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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.

Dataset Information

Apolipoprotein E4 Suppresses Neuronal-Specific Gene Expression in Maturing Neuronal Progenitor Cells Exposed to HIV.

Publications

Apolipoprotein E4 Suppresses Neuronal-Specific Gene Expression in Maturing Neuronal Progenitor Cells Exposed to HIV.

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