The Uppsala APP Mutation Promotes Wild-Type Amyloid-β Aggregation and Deposition In Vivo.

Amyloid-β (Aβ) is widely regarded as a key initiator of theneurodegenerative cascade in Alzheimer's disease (AD).Studies of pathogenic mutations in the amyloid precursor protein (APP) genehave greatly advanced understanding of Aβ biochemistry, aggregation, anddeposition. One such mutation, Uppsala APP (APPUpp), produces AβUpp42Δ19-24, whichis highly aggregation-prone due to a six-amino-acid deletion in its central region.In both human APPUpp carriers and the recently developed tg-UppSwe mouse model, Aβ depositspredominantly consist of the human AβUpp mutant.However, whereas human carriers produce both wild-type Aβ (Aβwt) and AβUpp, tg-UppSwe mice express only AβUpp. To better mimic the human condition, weinvestigated the pathological interplay between Aβwt and AβUpp using in vitroco-aggregation assays and in vivo analyses in abitransgenic mouse model generated by crossing tg-UppSwe with tg-Swe mice. ELISA, immunohistochemistry, and MALDI mass spectrometry imaging revealed that earlydeposition of AβUpp42Δ19-24accelerates aggregation and deposition of Aβwt species (Aβwt38, Aβwt40, Aβwt42), likely through a seeding or catalytic mechanism. Notably, bitransgenic mice developed pronounced plaque-associated gliosisan alteration absent in tg-UppSwe animals. These findings suggest a synergistic interaction betweenAβUpp and Aβwt that may influence onset, progression, and structural featuresof Aβ plaques in APPUpp mutation carriers.