Early Mitochondrial Defects in the 5xFAD Mouse Model of Alzheimer's Disease

Background: Mitochondrial (MT) dysfunction is a hallmark of Alzheimer's disease (AD). Amyloid-beta protein precursor and amyloid-beta peptides localize to MT and lead to MT dysfunction in familial forms of AD. This dysfunction may trigger subsequent types of pathology. Objective: To identify the MT phenotypes that occur early in order to help understand the cascade of AD pathophysiology. Methods: The 5xFAD mouse model was used to explore the time course of MT pathologies in both sexes. Protein biomarkers for MT dynamics were measured biochemically and MT function was measured using oxygen consumption and ATP assays. Results: We discovered progressive alterations in mitochondrial dynamics (biogenesis, fission, fusion, and mitophagy) and function (O-2 consumption, ATP generation, and Ca2+ import) in the hippocampus of 5xFAD mice in both sexes as early as 2 months of age. Thus, mitochondrial dynamics and function become altered at young ages, consistent with an early role for mitochondria in the AD pathological cascade. Conclusion: Our study offers the baseline information required to understand the hierarchical relationship between the multiple pathologies that develop in this mouse model and provides early biomarkers for MT dysfunction. This will aid in dissecting the temporal cascade of pathologies, understanding sex-specific differences, and in testing the efficacy of putative mitochondrial therapeutics.

Automated summary

This study found that mitochondrial function and dynamics are altered at early stages of Alzheimer's disease, which may be related to the development of other pathologies. These findings provide early biomarkers for diagnosis, aid in understanding the temporal cascade of pathologies and sex-specific differences, and enable testing of mitochondrial therapeutics.