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-β protein precursor and amyloid-β 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 (O2 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.