Mild deficiency of mitochondrial Complex III in a mouse model of Alzheimer’s disease decreases amyloid beta plaque formation

Abstract Background: For decades, mitochondrial dysfunctions and the generation of reactive oxygen species have been proposed to promote the development and progression of the amyloid pathology in Alzheimer’s disease, but this association is still debated. In particular, it is still unclear if mitochondrial dysfunctions are a trigger or rather a consequence of the formation of amyloid aggregates, and in particular, the role of the different mitochondrial oxidative phosphorylation complexes in Alzheimer’s patients’ brain remains poorly understood. Methods: To study how mitochondrial Complex III defects affect amyloid beta pathology in vivo , we partially knocked out mitochondrial Complex III (CIII KO ) in mature forebrain neurons of an Alzheimer’s mouse model that develops plaque pathology (APP/PS1). Results: We found that Complex III dysfunction in adult neurons induced mild oxidative stress which did not correlate with increased amyloid beta accumulation. In fact, CIII KO -AD mice showed decreased plaque number, decreased Aβ42 toxic fragment and altered amyloid precursor protein cleavage pathway. Conclusions: Our results support a model in which mitochondrial dysfunction is not the cause of amyloid oligomer accumulation but rather a consequence of amyloid beta toxicity.