The Role of nicotinic acetylcholine receptors nAChRs to mediate the synaptic functions of APPsα

• Applicants: Professor Dr. Martin Korte; Professorin Dr. Ulrike Müller
• Subject Area: Molecular Biology and Physiology of Neurons and Glial Cells
• Term: since 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 442783412

The amyloid precursor protein (APP) is central to the pathogenesis of Alzheimers disease (AD as it gives rise to Aβ peptides, that accumulate in the brain of AD patients. APP undergoes complex proteolytic processing that results on one hand in Aβ production, but also in the secretion of the large extracellular ectodomain APPs. Increasing evidence suggests that the physiological synaptic functions of APP are mediated by the secreted APPsα fragment. However, the APPsα receptor(s) and the precise molecular mechanisms of its action are still poorly understood. Previously, we have shown that APPsα is pivotal for neuronal viability and function, as it has neurotrophic, neuroprotective and synaptogenic properties. In this regard, we could demonstrate that APPsα largely rescues or ameliorates the synaptic impairments of transgenic AD model mice with established plaque pathology (APP/PS1ΔE9 mice). More recently, we expressed APPsα in the adult brain of conditional double knockout mice (cDKO) lacking APP and the related APLP2. AAV mediated APPsα expression efficiently rescued deficits in spine density, synaptic plasticity and spatial reference memory of cDKO mice. In vitro, we found that nanomolar concentrations of APPsα can facilitate LTP in slices of cDKO mice in a mechanism that required functional α7-nAChRs. These studies identified α7-nAChRs as the first potential endogenous receptor for APPsα. Despite this, these in vitro studies lack confirmation in vivo to firmly establish in as much this receptor pathway mediates the various synaptic functions of APPsα, beyond its role for LTP. Preliminary studies identified the last 16 C-terminal amino acids of APPsα (CTα16 region) as the crucial functional domain required for synaptic plasticity in vitro. The aims of this proposal are thus to (i) further characterize the interaction of APPsα/CTα16 with the α7-nAChR and possibly also with non-α7 heteromeric AChR subtypes and (ii) secondly, to determine the in vivo relevance of this pathway for structural and functional spine plasticity, LTP and cognition. To this end we will follow a pharmacological and complementary genetic gain and loss of function approach employing cDKO mice as well as constitutive and conditional α7-nAChR-KO mice. Finally, we aim to determine whether APPsα functions as an endogenous positive allosteric modulator (PAM) of the cholinergic system. These studies will lead to important mechanistic insights into the functions of APP that may also lead to novel therapeutic approaches for AD.

• DFG Programme: Research Grants