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Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.

ABSTRACT: INTRODUCTION:Alzheimer apolipoprotein E (APOE) ?4/?4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs. METHODS:Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE genotype and in a glioblastoma cell line expressing either apoE3 or apoE4. Computational modeling assessed interactions between apoE and mutated apoE with CLEAR or modified DNA. RESULTS:Three TFEB-regulated mRNA transcripts-SQSTM, MAP1LC3B, and LAMP2-were lower in AD ?4/?4 than in AD ?3/?3 brains. Computational modeling predicted avid specific binding of apoE4 to CLEAR motifs. ApoE was found in cellular nuclei, and in vitro binding assays suggest competition between apoE4 and TFEB at CLEAR sites. CONCLUSION:ApoE4-CLEAR interactions may account for suppressed autophagy in APOE ?4/?4 carriers and, in this way, contribute to earlier AD onset.

SUBMITTER: Parcon PA

PROVIDER: S-EPMC6613789 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.

Parcon Paul A PA Balasubramaniam Meenakshisundaram M Ayyadevara Srinivas S Jones Richard A RA Liu Ling L Shmookler Reis Robert J RJ Barger Steven W SW Mrak Robert E RE Griffin W Sue T WST

Alzheimer's & dementia : the journal of the Alzheimer's Association 20170922 2

<h4>Introduction</h4>Alzheimer apolipoprotein E (APOE) ɛ4/ɛ4 carriers have earlier disease onset and more protein aggregates than patients with other APOE genotypes. Autophagy opposes aggregation, and important autophagy genes are coordinately regulated by transcription factor EB (TFEB) binding to "coordinated lysosomal expression and regulation" (CLEAR) DNA motifs.<h4>Methods</h4>Autophagic gene expression was assessed in brains of controls and Alzheimer's disease (AD) patients parsed by APOE g ...[more]

PMID: 28945989

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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.

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Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.

Publications

Apolipoprotein E4 inhibits autophagy gene products through direct, specific binding to CLEAR motifs.

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