Non-cell autonomous choroid plexus-derived sAPPα regulates adult hippocampus proliferation and plasticity
Résumé
While Aβ peptides derived from amyloid precursor protein (APP) play a key role in Alzheimer disease pathogenesis, the extracellular sAPPα soluble ectodomain has been shown to stimulate adult neurogenesis and synaptic plasticity. Elevated expression of App in the choroid plexus has been recently reported, suggesting an important role for APP in cerebrospinal fluid. We conditionally knocked down App expression specifically in the adult mouse choroid plexus either by genetic deletion or shRNA expression, which led to reduced proliferation in both subventricular zone and hippocampus dentate gyrus neurogenic niches. Conversely, proliferation in both niches was increased either by viral expression of App in choroid plexus or by infusion of sAPPα but not sAPPβ in cerebrospinal fluid. To test the hypothesis that favoring the production of Aβ specifically in choroid plexus could negatively affect niche functions, we used AAV5 mediated expression of human mutated APP specifically in the choroid plexus of adult wild type mice. These mice showed reduced niche proliferation and, after one year, exhibited behavioral defects in reversal learning. Consistent with impaired memory, electrophysiological analysis revealed impaired synaptic plasticity as evidenced by deficits in hippocampal LTP. 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.
Domaines
Neurobiologie
Origine : Fichiers produits par l'(les) auteur(s)
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