The brains of Alzheimer’s disease (AD) patients are riddled with plaques of amyloid-beta (Aß) protein — but what causes the accumulation of the plaques?

One candidate is mitochondrial dysfunction, which can result in high levels of reactive oxygen species (ROS) and also rob the cell of energy it needs for maintenance of homeostasis. Hauptmann et al. report that in an AD mouse model, mitochondrial dysfunction can be observed very early in the progression of the disease: Indeed, mitochondria begin to exhibit respiratory-chain defects well before extracellular plaques can be observed:

Mitochondrial dysfunction: An early event in Alzheimer pathology accumulates with age in AD transgenic mice Recent evidence suggests mitochondrial dysfunction as a common early pathomechanism in Alzheimer’s disease integrating genetic factors related to enhanced amyloid-beta (Aß) production and tau-hyperphosphorylation with aging, as the most relevant sporadic risk factor. To further clarify the synergistic effects of aging and Aß pathology, we used isolated mitochondria of double Swedish and London mutant APP transgenic mice and of non-tg littermates. Pronounced mitochondrial dysfunction in adult Thy-1 APP mice, such as a drop of mitochondrial membrane potential and reduced ATP-levels already appeared at 3 months when elevated intracellular but not extracellular Aß deposits are present. Mitochondrial dysfunction was associated with higher levels of reactive oxygen species, an altered Bcl-xL/Bax ratio and reduction of COX IV activity. We observed significant decreases in state 3 respiration and FCCP-uncoupled respiration in non-tg mice after treatment with extracellular Aß. Similar deficits were seen only in aged Thy-1 APP mice, probably due to compensation within the respiratory chain in young animals. We conclude that Aß dependent mitochondrial dysfunction starts already at 3 months in this AD model before extracellular deposition of Aß and progression accelerates substantially with aging.

To the extent that mitochondrial dysfunction contributes to pathology, it could partially explain why AD is a disease of old age, since mitochondria deteriorate over the course of aging.

Granted, these mice are APP mutants and already primed to develop AD. In a wildtype animal, could mitochondrial dysfunction somehow interfere with protein folding, secretion or clearance machinery and thereby jump-start the process of Aß aggregation?