Not just amyloid: physiological functions of the amyloid precursor protein family

Key Points Amyloid precursor protein (APP) and the APP-like proteins APLP1 and APLP2 form the mammalian APP gene family. They have important physiological functions in the peripheral and central nervous systems, some of which are still emerging. APP family members share a similar structure and have partially overlapping functions. Their processing by canonical and non-canonical secretases results in numerous biologically active fragments, which mediate distinct and even opposing functions. Membrane-bound APP family members interact in cis or in trans , which enables them to function as cell-adhesion molecules. Large numbers of extracellular and intracellular binding partners have been identified, and this Review summarizes those that are involved in physiological pathways in vivo . Biological functions in which APP family members are involved include nervous system development, the formation and function of the neuromuscular junction, synaptogenesis, dendritic complexity and spine density, axonal growth and guidance, and synaptic functions, including synaptic plasticity, learning and memory. α-Secretase cleavage of APP releases the neuroprotective and neurotrophic fragment APPsα. It upregulates protective pathways, inhibits neuronal apoptosis, increases neuronal resistance to brain injuries and has a crucial role in synaptic plasticity, learning and memory. Increasing APPsα levels may be of therapeutic value. Pharmacotherapeutic and gene-therapeutic approaches could complement amyloid-targeting strategies. Amyloid precursor protein (APP) has been heavily implicated in Alzheimer disease, but the physiological roles of APP and the related APP-like proteins (APLPs) remain less well understood. This Review examines the functions of the APP family and its fragments in CNS development, synaptic function, brain injury and ageing. Amyloid precursor protein (APP) gives rise to the amyloid-β peptide and thus has a key role in the pathogenesis of Alzheimer disease. By contrast, the physiological functions of APP and the closely related APP-like proteins (APLPs) remain less well understood. Studying these physiological functions has been challenging and has required a careful long-term strategy, including the analysis of different App -knockout and Aplp -knockout mice. In this Review, we summarize these findings, focusing on the in vivo roles of APP family members and their processing products for CNS development, synapse formation and function, brain injury and neuro