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

Abstract

Amyloid beta (A{beta}) accumulation is associated with inflammation, neurodegeneration, and cognitive decline in the context of neurodegenerative diseases. However, the effect of A{beta} during normal - i.e., non-pathological - brain aging remains poorly understood. In this study, we investigated the natural impact of A{beta} 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 A{beta} variant-- accumulates intra-neuronally in an age-dependent manner, co-localizing with the apoptosis marker TUNEL. The presence of intraneuronal pE11 was recapitulated in old (non-pathological) human brains, indicating that this phenotype is shared among vertebrates. To determine whether A{beta} 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 A{beta} precursor protein broadly affects vertebrate brain aging, making it a promising target for anti-aging interventions.