Amyloid Beta Precursor Protein contributes to brain aging and learning decline in short-lived turquoise killifish ( Nothobranchius furzeri )

Amyloid beta (Aβ) accumulation is associated with inflammation, neurodegeneration, and cognitive decline in the context of neurodegenerative diseases. However, its role during normal aging remains largely unexplored. In this study, we investigated the natural impact of Aβ precursor protein ( app ) on the aging brain using a short-lived vertebrate model, the turquoise killifish ( Nothobranchius furzeri ). We identified amyloid precursor protein derivatives in the killifish brain across different age groups and found that pyroglutamated amyloid beta —a neurotoxic Aβ variant—accumulates intra-neuronally in an age-dependent manner, co-localizing with the apoptosis marker TUNEL. To determine whether Aβ contributes to spontaneous brain aging, we used CRISPR/Cas9 to generate an “amyloid precursor protein a” ( appa ) knock-out killifish strain. Notably, appa −/− mutants exhibited reduced cell death and inflammation, an overall younger proteome, as well as improved learning capacity in old age. Taken together, we found that Aβ precursor protein broadly affects vertebrate brain aging, making it a promising target for anti-aging interventions.