Mitochondrial function and Aß 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 Aß concentration and COX Vmax. DISCUSSION: These data support a dysregulated relationship between brain mitochondrial function and Aß pathology in AD.

Intrinsic aerobic capacity modulates Alzheimer's disease pathological hallmarks, brain mitochondrial function and proteome during aging.

Low aerobic capacity 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 aerobic capacity influences AD risk is unknown but is likely mediated by sexual dimorphism and tissue-level differences in mitochondrial energetics. Here, we used rats selectively bred for large differences in intrinsic aerobic exercise capacity. Brain tissue from 18-month and 24-month-old female and male low-capacity runner (LCR) and high-capacity runner (HCR) rats were analyzed for markers of mitochondrial function and AD-associated pathologies. LCR rats, irrespective of sex, exhibited a greater increase in brain amyloid beta (Aß42) and tau hyperphosphorylation (pTauthr181/total tau) with aging. In female LCR rats, brain mitochondrial respiration at states 3, 4, and FCCP-induced uncoupling, when stimulated with pyruvate/malate, was reduced at 18 and 24 months, leading to lower ATP-linked mitochondrial respiration compared to mitochondria from HCR rats. Male LCR rats also showed reduced complex II-stimulated mitochondrial respiration (succinate + rotenone) at 24 months compared to HCR rats. Differences in mitochondrial respiration were associated with tau hyperphosphorylation and Aß42 alterations in both HCR and LCR strains. Proteomic analysis unveiled a distinct difference in the mitochondrial proteome, wherein female LCR rats displayed diminished mitochondrial translation and oxidative phosphorylation (OXPHOS) proteins at 18 months compared to female HCR rats. Conversely, male LCR rats exhibited increased OXPHOS protein abundance but reduced tricarboxylic acid (TCA) cycle proteins compared to male HCR rats. These findings underscore a robust association between intrinsic aerobic exercise capacity, brain mitochondrial function, and AD pathologies during aging.

Cell type and sex specific mitochondrial phenotypes in iPSC derived models of Alzheimer's disease.

Introduction: Mitochondrial dysfunction is observed in Alzheimer's disease (AD). Altered mitochondrial respiration, cytochrome oxidase (COX) Vmax, and mitophagy are observed in human subjects and animal models of AD. Models derived from induced pluripotent stem cells (iPSCs) may not recapitulate these phenotypes after reprogramming from differentiated adult cells. Methods: We examined mitochondrial function across iPSC derived models including cerebral organoids, forebrain neurons, and astrocytes. iPSCs were reprogrammed from fibroblasts either from the University of Kansas Alzheimer's Disease Research Center (KU ADRC) cohort or purchased from WiCell. A total of four non-demented and four sporadic AD iPSC lines were examined. Models were subjected to mitochondrial respiration analysis using Seahorse XF technology, spectrophotometric cytochrome oxidase (COX) Vmax assays, fluorescent assays to determine mitochondrial mass, mitochondrial membrane potential, calcium, mitochondrial dynamics, and mitophagy levels. AD pathological hallmarks were also measured. Results: iPSC derived neurons and cerebral organoids showed reduced COX Vmax in AD subjects with more profound defects in the female cohort. These results were not observed in astrocytes. iPSC derived neurons and astrocytes from AD subjects had reduced mitochondrial respiration parameters with increased glycolytic flux. iPSC derived neurons and astrocytes from AD subjects showed sex dependent effects on mitochondrial membrane potential, mitochondrial superoxide production, and mitochondrial calcium. iPSC derived neurons from AD subjects had reduced mitochondrial localization in lysosomes with sex dependent effects on mitochondrial mass, while iPSC derived astrocytes from female AD subjects had increased mitochondrial localization to lysosomes. Both iPSC derived neurons and astrocytes from AD subjects showed altered mitochondrial dynamics. iPSC derived neurons had increased secreted Aß, and sex dependent effects on total APP protein expression. iPSC derived astrocytes showed sex dependent changes in GFAP expression in AD derived cells. Conclusion: Overall, iPSC derived models from AD subjects show mitochondrial phenotypes and AD pathological hallmarks in a cell type and sex dependent manner. These results highlight the importance of sex as a biological variable in cell culture studies.