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Distinct in vivo roles of secreted APP ectodomain variants APP sα and APP sβ in regulation of spine density, synaptic plasticity, and cognition
Author(s) -
Richter Max C,
Ludewig Susann,
Winschel Alex,
Abel Tobias,
Bold Charlotte,
Salzburger Leonie R,
Klein Susanne,
Han Kang,
Weyer Sascha W,
Fritz AnnKristina,
Laube Bodo,
Wolfer David P,
Buchholz Christian J,
Korte Martin,
Müller Ulrike C
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201798335
Subject(s) - ectodomain , biology , synaptic plasticity , microbiology and biotechnology , dendritic spine , neuroplasticity , neuroscience , genetics , receptor , hippocampal formation
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 ( APP s). The specific roles of APP sα and APP sβ fragments, generated by non‐amyloidogenic or amyloidogenic APP processing, respectively, remain however unclear. Here, we expressed APP sα or APP sβ in the adult brain of conditional double knockout mice ( cDKO ) lacking APP and the related APLP 2. APP sα efficiently rescued deficits in spine density, synaptic plasticity ( LTP and PPF ), and spatial reference memory of cDKO mice. In contrast, APP sβ failed to show any detectable effects on synaptic plasticity and spine density. The C‐terminal 16 amino acids of APP sα (lacking in APP sβ) proved sufficient to facilitate LTP in a mechanism that depends on functional nicotinic α7‐ nAChR s. Further, APP sα showed high‐affinity, allosteric potentiation of heterologously expressed α7‐ nAChR s in oocytes. Collectively, we identified α7‐ nAChR s as a crucial physiological receptor specific for APP sα and show distinct in vivo roles for APP sα versus APP sβ. This implies that reduced levels of APP sα that might occur during Alzheimer pathogenesis cannot be compensated by APPsβ.