The Drosophila beta-amyloid precursor protein homolog promotes synapse differentiation at the neuromuscular junction

Although abnormal processing of beta-amyloid precursor protein (APP) has be en implicated in the pathogenic cascade leading to Alzheimer's disease, the normal function of this protein is poorly understood. To gain insight into APP function, we used a molecular-genetic approach to manipulate the struc ture and levels of the Drosophila APP homolog APPL. Wild-type and mutant fo rms of APPL were expressed in motoneurons to determine the effect of APPL a t the neuromuscular junction (NMJ). We show that APPL was transported to mo tor axons and that its overexpression caused a dramatic increase in synapti c bouton number and changes in synapse structure. In an Appl null mutant, a decrease in the number of boutons was found. Examination of NMJs in larvae overexpressing APPL revealed that the extra boutons had normal synaptic co mponents and thus were likely to form functional synaptic contacts. Deletio n analysis demonstrated that APPL sequences responsible for synaptic altera tion reside in the cytoplasmic domain, at the internalization sequence GYEN PTY and a putative G(o)-protein binding site. To determine the likely mecha nisms underlying APPL-dependent synapse formation, hyperexcitable mutants, which also alter synaptic growth at the NMJ, were examined. These mutants w ith elevated neuronal activity changed the distribution of APPL at synapses and partially suppressed APPL-dependent synapse formation. We propose a mo del by which APPL, in conjunction with activity-dependent mechanisms, regul ates synaptic structure and number.