Choroid plexus APP regulates adult brain proliferation and animal behavior

Abstract Elevated amyloid precursor protein (APP) expression in the choroid plexus suggests an important role for extracellular APP metabolites in cerebrospinal fluid. Despite widespread App brain expression, we hypothesized that specifically targeting choroid plexus expression could alter animal physiology. Through various genetic and viral approaches in the adult mouse, we show that choroid plexus APP levels significantly impacted proliferation in both subventricular zone and hippocampus dentate gyrus neurogenic niches. Given the role of Aβ peptides in Alzheimer disease pathogenesis, we also tested whether favoring the production of Aβ in choroid plexus could negatively affect niche functions. After AAV5-mediated long-term expression of human mutated APP specifically in the choroid plexus of adult wild type mice, we observe reduced niche proliferation, behavioral defects in reversal learning, and deficits in hippocampal long-term potentiation. Our findings highlight the unique role played by the choroid plexus in regulating brain function, and suggest that targeting APP in choroid plexus may provide a means to improve hippocampus function and alleviate disease-related burdens.