APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease

Lin, Ai-Ling; Parikh, Ishita; Yanckello, Lucille M.; White, Renee S; Hartz, Anika M.S.; Taylor, Chase E.; McCulloch, Scott; Thalman, Scott; Xia, Mengfan; McCarty, Katie; Ubele, Margo F.; Head, Elizabeth; Hyder, Fahmeed; Sanganahalli, Basavaraju G.

doi:10.1016/j.nbd.2020.104834

Cited by 31 publications

(25 citation statements)

References 59 publications

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“…Metabolites that play a role in tyrosine metabolism including phenol sulfate, phenol glucuronide, and p-cresol glucuronide were found to be lower in the inulin-fed mice, suggesting that inulin decreases inflammation in the E3FAD mice [28]. The higher abundance of Bifidobacterium found in the E3FAD mice compared to E4FAD mice suggests a reduced level of anxiety [29], which is consistent with our previous findings that E3FAD mice had lower anxiety compared to the E4FAD mice [30]. In contrast, E4FAD mice had enhanced TCA, PPP and bile acid metabolism compared to E3FAD mice.…”

Section: Discussionsupporting

confidence: 91%

Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

Yanckello

Hoffman

Chang

et al. 2021

Nutritional Neuroscience

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Objective: The goal of the study was to identify the potential nutrigenetic effects to inulin, a prebiotic fiber, in mice with different human apolipoprotein E (APOE) genetic variants. Specifically, we compared responses to inulin for the potential modulation of the systemic metabolism and neuroprotection via gut-brain axis in mice with human APOE ε3 and ε4 alleles. Method: We performed experiments with young mice expressing the human APOE3 (E3FAD mice and APOE4 gene (E4FAD mice). We fed mice with either inulin or control diet for 16 weeks starting from 3 months of age. We determined gut microbiome diversity and composition using16s rRNA sequencing, systemic metabolism using in vivo MRI and metabolomics, and blood-brain barrier (BBB) tight junction expression using Western blot. Results: In both E3FAD and E4FAD mice, inulin altered the alpha and beta diversity of the gut microbiome, increased beneficial taxa of bacteria and elevated cecal short chain fatty acid and hippocampal scyllo-inositol. E3FAD mice had altered metabolism related to tryptophan and tyrosine, while E4FAD mice had changes in the tricarboxylic acid cycle, pentose phosphate pathway, and bile acids. Differences were found in levels of brain metabolites related to oxidative stress, and levels of Claudin-1 and Claudin-5 BBB tight junction expression. Discussion: We found that inulin had many similar beneficial effects in the gut and brain for both E3FAD and E4FAD mice, which may be protective for brain functions and reduce risk for neurodegeneration. . E3FAD and E4FAD mice also had distinct responses in several metabolic pathways, suggesting an APOE-dependent nutrigenetic effects in modulating systemic metabolism and neuroprotection.

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Section: Discussionsupporting

confidence: 91%

Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

Yanckello

Hoffman

Chang

et al. 2021

Nutritional Neuroscience

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“…Because we observed similar biological functions altered between the E4/E4 vs E3/E3 controls, it is likely E4 genotype drives early cerebrovascular abnormalities in the aging process, which increases the vulnerability of the cerebrovasculature to further damage in AD pathogenesis. To corroborate our findings, previous studies have suggested that EIF2 α and mTOR pathways are major players in the APOE4 mediated cellular effects, and have been explored as therapeutic targets in mouse models of AD [72][73][74][75][76].…”

Section: Apoe Specific Effects On Cerebrovascular Proteome In Adsupporting

confidence: 86%

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

et al. 2021

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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.

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“…106,107 The APOE4 allele is the largest risk factor for AD, and targeted replacement knock-in mouse models carrying the human APOE allele are associated with CBF reductions in the cortex, hippocampus, thalamus, and the white matter. [108][109][110] The CBF reductions associated with APOE manipulation were found to correlate with pericyte loss, 111 decreased capillary density, 112 and BBB breakdown via the CypA-MMP9 pathway, 109,113 suggesting the possibility of mechanistic ties between different microvascular dysfunctions. In patients who carry the APOE4 allele, increased pericyte loss and BBB breakdown was also observed, as well as more severe cognitive decline.…”

Section: Cerebral Blood Flow Reductions In Mouse Models Of Admentioning

confidence: 96%

Causes and consequences of baseline cerebral blood flow reductions in Alzheimer’s disease

Bracko

Hernández

Park

et al. 2021

J Cereb Blood Flow Metab

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Reductions of baseline cerebral blood flow (CBF) of ∼10–20% are a common symptom of Alzheimer’s disease (AD) that appear early in disease progression and correlate with the severity of cognitive impairment. These CBF deficits are replicated in mouse models of AD and recent work shows that increasing baseline CBF can rapidly improve the performance of AD mice on short term memory tasks. Despite the potential role these data suggest for CBF reductions in causing cognitive symptoms and contributing to brain pathology in AD, there remains a poor understanding of the molecular and cellular mechanisms causing them. This review compiles data on CBF reductions and on the correlation of AD-related CBF deficits with disease comorbidities (e.g. cardiovascular and genetic risk factors) and outcomes (e.g. cognitive performance and brain pathology) from studies in both patients and mouse models, and discusses several potential mechanisms proposed to contribute to CBF reductions, based primarily on work in AD mouse models. Future research aimed at improving our understanding of the importance of and interplay between different mechanisms for CBF reduction, as well as at determining the role these mechanisms play in AD patients could guide the development of future therapies that target CBF reductions in AD.

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APOE genotype-dependent pharmacogenetic responses to rapamycin for preventing Alzheimer's disease

Cited by 31 publications

References 59 publications

Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

Apolipoprotein E genotype-dependent nutrigenetic effects to prebiotic inulin for modulating systemic metabolism and neuroprotection in mice via gut-brain axis

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

Causes and consequences of baseline cerebral blood flow reductions in Alzheimer’s disease

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