Xiuli Dan, PhD; Paul D Robbins, PhD | University of Minnesota; Vilhelm A. Bohr, PhD | University of Copenhagen; Deborah L. Croteau, PhD | National Institute on Aging, NIH
Competition Sponsor: US National Academy of Medicine
Awardee Year: 2023
Alzheimer’s disease (AD) is a prevalent neurodegenerative condition associated with aging. Despite extensive research focusing on tau proteins and amyloid plaques, therapeutic efforts targeting these aspects have not succeeded in clinical trials, rendering AD incurable. Thus, a clearer understanding of AD pathology is needed.
Using our newly established APP/PSEN1/mtKeima mouse model, we unveiled mitochondria-enriched structures with notable mitophagy signals in AD brains. As these mitochondria-enriched structures accumulated in a plaque-like format, we term them mitochondrial plaques. These MPs largely co-localize with lysosomal-associated membrane protein 1, which confirms their presence within acidic lysosomes. While MPs and amyloid-beta (Aβ) plaques are spatially proximate, they represent distinct entities with variable overlapping volume. Crucially, MPs are detected positive of amyloid-beta precursor protein, thus potentially contributing to the formation of Aβ plaques formed around MPs. Our study demonstrated that Aβ plaques are not the only type of plaques in AD. Other types of plaques, like the novel MPs identified in our preliminary studies, can also form. Based on our novel and exciting findings, we now propose to provide an in-depth understanding of the molecular mechanism of AD and propose new treatment strategies by targeting MPs or both MPs and Aβ plagues.