Mitochondrial function and Aβ in Alzheimer's disease postmortem brain

Introduction: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). However, the relationship between functional mitochondrial deficits and AD pathologies is not well established in human subjects. Methods: Post-mortem human brain tissue from 11 non-demented (ND) and 12 AD subjects was used to examine mitochondrial electron transport chain (ETC) function. Data were analyzed by neuropathology diagnosis and Apolipoprotein E (APOE) genotype. Relationships between AD pathology and mitochondrial function were determined. Results: AD subjects had reductions in brain cytochrome oxidase (COX) function and complex II Vmax. APOE ε4 carriers had COX, complex II and III deficits. AD subjects had reduced expression of Complex I-III ETC proteins, no changes were observed in APOE ε4 carriers. No correlation between p-Tau Thr 181 and mitochondrial outcomes was observed, although brains from non-demented subjects demonstrated positive correlations between Aβ concentration and COX Vmax. Discussion: These data support a dysregulated relationship between brain mitochondrial function and Aβ pathology in AD

Intrinsic aerobic capacity, sex, and brain aging: Determinants of Alzheimer- s disease risk

BackgroundLow aerobic capacity (or cardiorespiratory fitness) is strongly associated with all- cause mortality and risk for Alzheimer- s disease (AD). Individuals with early dementia and AD have lower aerobic capacity compared to age- matched controls. The mechanism by which low aerobic capacity influences AD are unknown but are suggestive of an impairment in mitochondrial energetics.MethodHere we used rats selectively bred over several generations to have intrinsic low or high exercise capacity. Rats were bred based on low or high capacity to complete an aerobic treadmill running test resulting in rats with robustly different intrinsic aerobic capacity despite being maintained sedentary. We examined mitochondrial function, RNA sequencing, and markers of AD in brain tissue from 18- month- old male and female Low Capacity Runners (LCR) and High Capacity Runners (HCR) from generation 43 of selection.ResultWe found lower mitochondrial respiration in brains of female LCR rats for complex I- , ADP- , uncoupled- , and complex II- driven flux when compared to LCR males. Brain Complex I driven respiratory flux was reduced in LCR females when compared to HCR females. No differences were observed in complex I or citrate synthase (CS) Vmax but complex IV Vmax was lower in LCR males versus HCR males. Female LCR rats had higher Aβ42 while both male and female LCR rats had higher phosphorylated tau at threonine 181 in whole brain homogenates. RNAseq revealed a greater effect of sex on gene expression than strain (HCR vs. LCR). However, FOXO signaling, axonal guidance, ubiquitination, and protein phosphorylation pathways were greater in male LCR versus male HCR rats. Glutamate NMDA receptor subunit 3A (Grin3a) and Transcription factor 7- like 2 (TCF7L2) were identified as coordinating numerous downstream targets with IPA analysis in male LCR rats. RNA sequencing outcomes suggest downregulation of AMPK signaling in female LCR rats.ConclusionThese data support a strong relationship between intrinsic aerobic capacity, sex, and markers of brain mitochondrial function and AD in late- middle aged HCR and LCR rats.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171533/1/alz054940.pd