| First Author | Richter MC | Year | 2018 |
| Journal | EMBO J | Volume | 37 |
| Issue | 11 | PubMed ID | 29661886 |
| Mgi Jnum | J:265667 | Mgi Id | MGI:6192977 |
| Doi | 10.15252/embj.201798335 | Citation | Richter MC, et al. (2018) Distinct in vivo roles of secreted APP ectodomain variants APPsalpha and APPsbeta in regulation of spine density, synaptic plasticity, and cognition. EMBO J 37(11) |
| abstractText | 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 APPsalpha and APPsbeta fragments, generated by non-amyloidogenic or amyloidogenic APP processing, respectively, remain however unclear. Here, we expressed APPsalpha or APPsbeta in the adult brain of conditional double knockout mice (cDKO) lacking APP and the related APLP2. APPsalpha efficiently rescued deficits in spine density, synaptic plasticity (LTP and PPF), and spatial reference memory of cDKO mice. In contrast, APPsbeta failed to show any detectable effects on synaptic plasticity and spine density. The C-terminal 16 amino acids of APPsalpha (lacking in APPsbeta) proved sufficient to facilitate LTP in a mechanism that depends on functional nicotinic alpha7-nAChRs. Further, APPsalpha showed high-affinity, allosteric potentiation of heterologously expressed alpha7-nAChRs in oocytes. Collectively, we identified alpha7-nAChRs as a crucial physiological receptor specific for APPsalpha and show distinct in vivo roles for APPsalpha versus APPsbeta. This implies that reduced levels of APPsalpha that might occur during Alzheimer pathogenesis cannot be compensated by APPsbeta. |
