The role of the amyloid precursor protein gene family in the adult mouse CNS

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Despite recent progress the physiological fimction(s) of APP family proteins in the CNS has remained largely elusive. We previously generated APP-KO mice that proved viable whereas APP/APLP2 double knockouts (DKO) and triple mutants died shortly after birth due to defects in neuromuscular synaptic transmission. This suggests a central role for APP/APLPs in synapse formation and function. To gain further insights into APP/APLP functions in the adult CNS and to circumvent perinatal lethality we therefore propose to generate condifional double knockout mice (cDKO). Recenfiy generated mice with floxed APP (and APLP2) alleles will be crossed with CamKII-iCreER mice to generate a forebrain-specific and time point controllable APP-KO on an APLP2-deficient background (Cre+APPflox/flox APLP2-/-). These mice will be analyzed with regard to brain morphology, neuronal survival, synapse formation and funclion, and finally functional consequences for cognition, learning and memory. We expect a rapid progress due to the collaborative phenotyping effort within the consortium. In addition, we intend lo study the role of APP family proleins for adult neurogenesis either via lentivims-mediated Cre delivery into neurogenic brain areas of APPflox/floxAPLP2-/- mice or by ablafing APP/APLP expression selectively in neuronal stem/progenitor cells using NestinCreERT2 cDKO mice. From these studies we expect major insights into the physiology of APP family functions that is also crucial to know for strategies of intervention in AD.