APP overexpression delays synaptic development and alters neuronal network properties

The amyloid precursor protein (APP) regulates neuronal excitability by altering the structure of the axon initial segment. Using high density multielectrode arrays we compared the electrophysiological consequences of APP overexpression with exposure to β-amyloid (Aβ) and found that the two manipulations affected neural activity in largely non-overlapping ways. In mature cultures (>18 days in vitro, DIV18), APP reduced the firing probability of individual neurons, while β-amyloid stripped synapses impacting whole-network connectivity. In immature cultures (DIV10), increasing APP – either acutely with lentiviral vectors or genetically by culturing APP transgenic neurons – revealed a separate developmental function. Synaptogenesis and axonal branch formation were blocked. Aβ, by contrast, interfered primarily with network behavior. Our findings suggest that Alzheimer’s disease is likely an amalgamation of APP mis-regulation plus the effects of Aβ accumulation. They also urge consideration of the idea that familial and sporadic forms of Alzheimer’s may represent distinct disease processes.