Impact of APOE Locus on Aging-Related Mitochondrial Function in Alzheimer’s Disease and Longevity

The APOE locus is critically important in the study of Alzheimer’s disease (AD) due to its strong genetic association with the condition. The APOE locus includes several functionally distinct genes: APOE, APOC1, NECTIN2, and TOMM40. These genes are in strong linkage disequilibrium, complicating the identification of specific effectors of AD risk. Both AD, characterized as aging-related neurodegeneration, and morbidity in old age, viewed as unsuccessful longevity, share aging-related mitochondrial dysfunction as a common biological feature. This shared trait suggests mitochondrial function as a key area for understanding the biological impact of the APOE locus on AD and longevity. Within the APOE locus, TOMM40 gene generates a mitochondria structural protein called Tom40, which directly influences mitochondria function. To this end, a new study was published in the International Journal of Molecular Sciences. It was conducted by Dr. Eun-Gyung Lee, Mr. Lesley Leong, Dr. Sunny Chen, Dr. Jessica Tulloch, and Dr. Chang-En Yu from the VA Puget Sound Health Care System, Seattle, WA, USA. The study investigated the changes in mitochondrial structure and function in response to oxidative stress in human cellular models and postmortem brains of individuals with AD and normal controls. Specifically, the study investigated a range of expressional alterations in the mitochondrial structure/function-related genes and the APOE locus genes. Additionally, the study investigated how mitochondrial DNA copy number (mtDNA CN) and mitochondrial dysfunction vary with APOE genotype in response to oxidative stress, using both cellular models and postmortem brain samples.

Initially, the team exposed human brain cell lines of astrocyte, microglia, and neurons to hydrogen peroxide (H₂O₂) to induce oxidative stress mimicking conditions that might contribute to aging and AD. The exposure duration was set for 24 hours, followed by a recovery phase where cells were given fresh media and allowed to recover for additional 24 or 48 hours. Afterward, the authors evaluated post-oxidative stress induction by measuring mitochondrial markers, including mitochondrial membrane potential (MMP) and mtDNA CN using quantitative PCR, which gave insight into mitochondrial integrity and biogenesis. They found all three cell lines have a reduction in mitochondrial membrane potential and mitochondrial DNA copy number immediately following oxidative stress. The extent of reduction varied by cell type, with astrocyte-like and microglia-like cells exhibiting more significant changes compared to neuron-like cells. During the recovery phase, mitochondrial membrane potential and DNA copy number generally returned towards baseline levels, indicating some recovery of mitochondrial function. However, the degree of recovery varied, with some cell lines showing partial restoration even after 48 hours. Moreover, they analyzed gene expression in response to oxidative stress through quantitative PCR (RT-qPCR) to assess how stress impacts the expression of genes within the APOE locus (APOE, APOC1, NECTIN2, TOMM40) and other genes related to mitochondrial function and oxidative stress response. The team found consistent upregulation of genes within the APOE locus across all cell models post-H₂O₂ treatment. This upregulation persisted into the recovery phase, suggesting a stress-related activation of these genes. Other mitochondrial and oxidative stress-related genes showed varied expression patterns, with some genes upregulated and others downregulated, indicating celltype-specific responses to oxidative stress. Researchers also included postmortem brain tissues from individuals diagnosed with AD and normal controls. These samples were used to validate findings from the cellular models, measuring expression of marker genes of mitochondrial function and the APOE locus genes to explore differences potentially attributable to AD pathology versus normal aging processes. Postmortem brain tissues from AD patients showed an overall upregulation in the expression of APOE locus genes compared to controls, aligning with the cellular model findings in response to oxidative stress. This suggests a potential role of these genes in the pathology of AD. The study also found AD status impacts on mitochondrial DNA copy numbers in AD brains, varied depending on APOE genotype, indicating a genetic contribution to mitochondrial dysfunction due to prolonged oxidative stress in AD.

Overall, the experiments performed by Dr.  Eun-Gyung Lee and colleagues suggest that the APOE locus plays a significant role in modulating mitochondrial function, potentially through a coordinated regulation of multiple genes in this locus. This co-regulation may occur within the same topologically associated domain (TAD), a fundamental unit of three-dimensional genome organization, yielding combined biological effects that contribute to outcomes of AD and aging. Moreover, the interaction between APOE genotype and mitochondrial dysfunction could help explain the varied manifestations of AD and aging, highlighting the importance of considering genetics in planning therapeutic strategies. The potential coordinated regulation of the APOE locus genes and their collective impact on mitochondrial function demonstrate the need for further research into co-regulation mechanisms of these genes within the APOE locus, particularly in aging and age-related diseases. The study as well offers deeper insights into why certain individuals might be more susceptible to AD by linking the APOE locus, particularly variations in APOE genotype, with changes in mitochondrial dynamics and cellular stress responses. The association of the APOE locus with longevity, beyond its established connections to AD provides valuable genetic clues about the mechanisms of aging. Understanding how the APOE locus genes influence mitochondrial function, can reveal why some individuals experience healthier aging processes than others. This could lead to targeted therapies or interventions designed to mimic these beneficial effects in broader populations. The identification of specific gene expression changes linked to oxidative stress and mitochondrial dysfunction in AD, opens the door for developing targeted therapeutic interventions. Drugs or genetic therapies designed to modulate the expression of genes within the APOE locus could potentially improve mitochondrial health, thereby slowing or altering the progression of neurodegenerative diseases and possibly extending healthy lifespan. The differential expression of genes within the APOE locus between AD and healthy control and its impact on mitochondrial parameters could serve as biomarkers for early detection of AD or markers of aging. Early detection is crucial for the effective management of AD, and having reliable biomarkers could significantly improve diagnostic and prognostic capabilities.