Project Summary/Abstract Many patients with Down Syndrome (DS) develop early onset Alzheimer’s disease (AD), and an obvious mechanistic link between the two conditions is provided by the β-amyloid (Aβ) precursor protein (APP): Aβ is a major pathological agent in AD, and patients with DS have an extra copy of the APP gene (as it is localized on the chromosome 21 that is triplicated in DS) as well as elevated Aβ levels in plasma and cerebrospinal fluid. Aβ is well known to inhibit hippocampal long-term potentiation (LTP), a form of synaptic plasticity thought to underly higher brain functions such as learning, memory, and cognition (which are impaired in both AD and DS, albeit in different ways). Indeed, LTP is impaired in mouse models of both AD and DS. LTP is critically mediated by the Ca2+/calmodulin-dependent protein kinase II (CaMKII), and we have recently shown that Aβ interferes with LTP by affecting CaMKII signaling: Normal LTP requires CaMKII movement to excitatory synapses via regulated binding to the NMDA-receptor, and Aβ suppresses this CaMKII movement. Notably, in the AD-related impairment of LTP, APP acts not only as an upstream precursor but also as a downstream effector of Aβ. While the role of APP as Aβ precursor is well established, its role as Aβ effector is just emerging (and has not been examined at all in context of DS). Additionally, while the APP triplication in DS has been suggested as cause for the DS-associated early onset AD, a role in the DS-associated impairment of LTP prior to AD onset remains to be investigated. Here, we will determine the function of APP as Aβ precursor versus effector in a DS mouse model. As APP knockout prevents the Aβ-induced impairments of CaMKII movement and LTP, we hypothesize that the APP gene triplication in Down Syndrome sensitizes to the effects of Aβ on CaMKII movement and LTP (even before the manifestation of early onset AD). We will here determine if hippocampal neurons from a mouse model of DS are more sensitive to the Aβ-induced impairments of CaMKII movement, as reflected by a lower threshold for either dose or duration of Aβ exposure. Follow-up studies will investigate (i) a similar sensitization for Aβ-induced LTP impairments, and (ii) dependence of these effects on the additional copy of APP (by eliminating one of the APP copies in the DS mouse line).