IMPROVING MITOCHONDRIAL HEALTH LIMITS DENSE-CORE PLAQUE ACCUMULATION IN ALZHEIMER’S DISEASE MOUSE MODEL

Alzheimer’s disease (AD) is neuropathologically defined by the early accumulation of amyloid-β (Aβ) plaques and the subsequent emergence of tau neurofibrillary tangles, which are closely associated with progressive cognitive decline. In addition to these hallmark features, mitochondrial dysfunction is increasingly recognized as a key contributor to AD pathogenesis, impacting neuronal energy metabolism, oxidative stress, and cellular resilience. However, whether targeting mitochondrial repair can modify amyloid plaque burden and composition across disease stages remains incompletely understood.
To address this question, mice in a transgenic model of progressive amyloid pathology were treated with a mitochondrial-targeting compound. Mitochondrial functional was assessed by high resolution respirometry in permeabilized cortex and hippocampus (n=5 mice/group) and behavioral tests assessing locomotion, including open field, elevated plus maze, and challenged beam, were conducted (n=10 mice/group). Plaque burden and composition were evaluated using AmyloGlo staining, 6E10 and OC immunostaining (n=5 mice/group), along with measurements of Aβ40 and Aβ42 levels in brain lysates (n=5 mice).
Mitochondrial assays confirmed improvement of mitochondrial health and metabolic capacity in treated mice, with no adverse effects on locomotion following compound administration. Notably, sustained treatment initiated at the early disease stage significantly reduced dense-core plaque load compared to age-matched controls. These findings demonstrate that targeting mitochondrial function modulates amyloid pathology and improves cellular metabolic capacity in vivo.Together, this work supports mitochondrial restoration as a promising disease-modifying approach for AD.