Distinct in vivo roles of secreted APP ectodomain variants APPs? and APPs? in regulation of spine density, synaptic plasticity, and cognition.

ABSTRACT: Increasing evidence suggests that synaptic functions of the amyloid precursor protein (APP), which is key to Alzheimer pathogenesis, may be carried out by its secreted ectodomain (APPs). The specific roles of APPs? and APPs? fragments, generated by non-amyloidogenic or amyloidogenic APP processing, respectively, remain however unclear. Here, we expressed APPs? or APPs? in the adult brain of conditional double knockout mice (cDKO) lacking APP and the related APLP2. APPs? efficiently rescued deficits in spine density, synaptic plasticity (LTP and PPF), and spatial reference memory of cDKO mice. In contrast, APPs? failed to show any detectable effects on synaptic plasticity and spine density. The C-terminal 16 amino acids of APPs? (lacking in APPs?) proved sufficient to facilitate LTP in a mechanism that depends on functional nicotinic ?7-nAChRs. Further, APPs? showed high-affinity, allosteric potentiation of heterologously expressed ?7-nAChRs in oocytes. Collectively, we identified ?7-nAChRs as a crucial physiological receptor specific for APPs? and show distinct in vivo roles for APPs? versus APPs?. This implies that reduced levels of APPs? that might occur during Alzheimer pathogenesis cannot be compensated by APPs?.

SUBMITTER: Richter MC 

PROVIDER: S-EPMC5983155 | biostudies-literature | 2018 Jun

REPOSITORIES: biostudies-literature