Abstract
Cerebrovascular dysfunction is a hallmark feature of Alzheimer's disease (AD). One of the greatest risk factors for AD is the apolipoprotein E4 (E4) allele. The APOE4 genotype has been shown to negatively impact vascular amyloid clearance, however, its direct influence on the molecular integrity of the cerebrovasculature compared to other APOE variants (APOE2 and APOE3) has been largely unexplored. To address this, we employed a 10-plex tandem isobaric mass tag approach in combination with an ultra-high pressure liquid chromatography MS/MS (Q-Exactive) method, to interrogate unbiased proteomic changes in cerebrovessels from AD and healthy control brains with different APOE genotypes. We first interrogated changes between healthy control cases to identify underlying genotype specific effects in cerebrovessels. EIF2 signaling, regulation of eIF4 and 70S6K signaling and mTOR signaling were the top significantly altered pathways in E4/E4 compared to E3/E3 cases. Oxidative phosphorylation, EIF2 signaling and mitochondrial dysfunction were the top significant pathways in E2E2 vs E3/E3cases. We also identified AD-dependent changes and their interactions with APOE genotype and found the highest number of significant proteins from this interaction was observed in the E3/E4 (192) and E4/E4 (189) cases. As above, EIF2, mTOR signaling and eIF4 and 70S6K signaling were the top three significantly altered pathways in E4 allele carriers (i.e. E3/E4 and E4/E4 genotypes). Of all the cerebrovascular cell-type specific markers identified in our proteomic analyses, endothelial cell, astrocyte, and smooth muscle cell specific protein markers were significantly altered in E3/E4 cases, while endothelial cells and astrocyte specific protein markers were altered in E4/E4 cases. These proteomic changes provide novel insights into the longstanding link between APOE4 and cerebrovascular dysfunction, implicating a role for impaired autophagy, ER stress, and mitochondrial bioenergetics. These APOE4 dependent changes we identified could provide novel cerebrovascular targets for developing disease modifying strategies to mitigate the effects of APOE4 genotype on AD pathogenesis.
Highlights
Alzheimer’s disease (AD) is the most predominant type of dementia, which to date remains untreatable
APOE2/2 cases were low in sample size for the AD group, and as such were removed from our analyses
From our proteomic analyses we revealed unique changes in proteins and molecular pathways driven by APOE genotype that could explain the vulnerability of the cerebrovasculature in the pathological sequelae of AD
Summary
Alzheimer’s disease (AD) is the most predominant type of dementia, which to date remains untreatable. Vascular lesions are routinely reported in early prodromal and later stages of AD This is typified by cerebral amyloid angiopathy (CAA) [6], lesions of cerebral small vessel disease (CSVD) such as lacunar infarcts and microhemorrhages [7,8,9], cerebral atherosclerosis [10,11,12], degenerating small blood vessels, capillaries and mural cells [13,14,15,16,17], weakened blood–brain barrier (BBB) [18], and buildup of phagolysosomes-lipofuscin deposits and dysmorphic mitochondria in cerebrovascular cells [3, 16, 19]. The specific molecular triggers and factors driving these degenerative cerebrovascular phenotypes and the timing of these events in the sequelae of AD remain elusive
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