APOE genotype dependent molecular abnormalities in the cerebrovasculature of Alzheimer’s disease and age-matched non-demented brains

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.

Transcranial magnetic stimulation treatment in Alzheimer’s disease: a meta-analysis of its efficacy as a function of protocol characteristics and degree of personalization

“…The following inclusion criteria were used to identify eligible studies: ( (21)(22)(23)(24)(25)(26) or moderate (10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) AD and/or a Clinical Dementia Rating scale (CDR) score of 1 or 2 [48]. If present, diagnosis severity based on laboratory results, such as computed tomography, magnetic resonance imaging, positron emission tomography or lumbar puncture, was also considered.…”

“…Yet, little is known about the causes of Alzheimer's disease and no curative treatments are available [9]. In this complex framework, some unmodifiable risk factors are acknowledged, such as age, family history, cardiovascular pathologies and genetic factors, such as the presence of the Apolipoprotein E4 (APOE4) allele [10][11][12][13]. On the other hand, modifiable risk factors are represented by poor diet choices [14,15], lack of physical exercise [16,17] and cognitive stimulation [18], as well as hearing loss Arianna Menardi and Lisa Dotti contributed equally to this work.…”

Age and APOE affect L-carnitine system metabolites in the brain in the APOE-TR model

“…The direct influence of the E4 allele on FA-related bioenergetics (i.e., the transport and use of metabolites, in this case FAs, for energy) within the cerebrovasculature requires further attention, specifically in E4 carriers because of their increased cerebrovascular vulnerability observed with age which could impair nutrient transport to the brain and affect proper neuronal and glial functioning (Ojo et al, 2021). A recent proteomic study suggested altered mitochondrial function in the cerebrovasculature isolated from deceased cognitively healthy E4 carriers compared to non-E4 carriers, indicating that cerebrovascular bioenergetics may indeed be altered in cognitively healthy E4 carriers (Ojo et al, 2021).…”

“…The direct influence of the E4 allele on FA-related bioenergetics (i.e., the transport and use of metabolites, in this case FAs, for energy) within the cerebrovasculature requires further attention, specifically in E4 carriers because of their increased cerebrovascular vulnerability observed with age which could impair nutrient transport to the brain and affect proper neuronal and glial functioning (Ojo et al, 2021). A recent proteomic study suggested altered mitochondrial function in the cerebrovasculature isolated from deceased cognitively healthy E4 carriers compared to non-E4 carriers, indicating that cerebrovascular bioenergetics may indeed be altered in cognitively healthy E4 carriers (Ojo et al, 2021). While the role of the cerebrovascular system in regulating nutrient transport to the brain and the impairments in glucose transport in E4s has been shown in both clinical populations and animal models (Reiman et al, 2005;Alata et al, 2015;Zhao et al, 2017;Johnson et al, 2019), limited information is available regarding bioenergetics within the cerebrovasculature, particularly in relation to both FA uptake and fatty acid oxidation (FAO) capabilities within the context of aging and different APOE genotypes, despite the fact that cerebrovascular FAO has been suggested to be an essential process in maintaining its transport functions (Goldstein, 1979).…”

“…Given that the E4 allele is associated with both an increased reliance on alternative fuels, such as FAs, and more severe cerebrovascular dysfunction with age (Yassine and Finch, 2020;Ojo et al, 2021), it is possible that, aging E4 carriers may display alterations in L-carnitine, L-carnitine gut metabolites, and acylcarnitine profiles in the brain and the periphery reflecting such alterations. We therefore hypothesized that with age different APOE genotypes would be associated with changes in L-carnitine, L-carnitine metabolites and acylcarnitines in the brain and the periphery.…”