The role of β-amyloid in cognition in normal and APP knock-in mice (360G-Wellcome-105217_A_14_A)

Working hypothesis: modulation of beta-amyloid (Abeta) production (in the absence of APP overexpression) in mice will lead to changes in brain network activity and cognitive function. Our understanding of dementia pathogenesis has been heavily influenced by the amyloid cascade hypothesis. However, progress is hampered by the fact that (1) little is known about the normal function of Abeta and (2) current mouse models of amyloid pathology rely on over-expression of human APP mutations. APP over-expression alone causes synaptic and cognitive changes that are independent of Abeta production. We propose to examine the role of normal Abeta production in synaptic plasticity and cognition and to characterize a novel knock-in mouse model of amyloid pathology (Saito et al., 2014; the NL-F mouse). We will examine cognitive changes in NL-F mice during aging to establish a profile of brain network changes. We will test the effects of steric hindrance of Abeta production on memory by using an antibody (2B3) that binds across the beta-secretase cleavage site in both NL-F and WT mice. Analysis of memory function will be accompanied by assessment of network activity (c-fos expression), brain metabolite profile (MR-Spectroscopy) and APP cleavage products (using standard biochemical assays) in NL-F and WT mice.