TheDrosophilaβ-Amyloid Precursor Protein Homolog Promotes Synapse Differentiation at the Neuromuscular Junction

Abstract

Although abnormal processing of beta-amyloid precursor protein (APP) has been 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 structure and levels of the Drosophila APP homolog APPL. Wild-type and mutant forms of APPL were expressed in motoneurons to determine the effect of APPL at the neuromuscular junction (NMJ). We show that APPL was transported to motor axons and that its overexpression caused a dramatic increase in synaptic 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 components and thus were likely to form functional synaptic contacts. Deletion analysis demonstrated that APPL sequences responsible for synaptic alteration reside in the cytoplasmic domain, at the internalization sequence GYENPTY and a putative G(o)-protein binding site. To determine the likely mechanisms underlying APPL-dependent synapse formation, hyperexcitable mutants, which also alter synaptic growth at the NMJ, were examined. These mutants with elevated neuronal activity changed the distribution of APPL at synapses and partially suppressed APPL-dependent synapse formation. We propose a model by which APPL, in conjunction with activity-dependent mechanisms, regulates synaptic structure and number.

Drosophila homolog of APP-BP1 (dAPP-BP1) interacts antagonistically with APPL during Drosophila development

“…For APPL, increased cell death is observed only when two copies of APPL are overexpressed and flies are reared at 291C (data not shown, Figure 6e-j). Because expression levels of these UAS lines are not significantly different, 23 these results demonstrate that cleavage of APPL is important for its regulation. Overexpression of APPL consistently failed to produce abnormal phenotypes (Figure 7c).…”

“…Torroja et al 23 reported that overexpression of wild-type and mutant forms of APPL in Drosophila motor neurons caused a dramatic increase in synaptic bouton number. Interestingly, recent studies show that synaptic bouton number in motor neuron endings was greatly increased in a Drosophila Cul-5 mutant.…”

“…20 However, loss-and gain-of-function studies have revealed a role for APPL in synapse differentiation and axonal transport. [22][23][24] The mutant loechrig presents with a neurodegenerative phenotype that is strongly enhanced by Appl d mutants. 25 Overexpression of wild-type and mutant APPL proteins has also been shown to cause abnormal neurite outgrowth.…”

Dissecting the pathological effects of human Aβ40 and Aβ42 in Drosophila : A potential model for Alzheimer's disease

“…A null mutation of APPL exhibits behavioral deficits, which are rescued by a human APP transgene (19). Drosophila has been used to study the physiological functions of APP and APPL in synaptogenesis (20), axonal transport (21,22), and apoptosis (22). To determine whether Drosophila can be used as a model to study the molecular basis of AD pathogenesis, we examined the effects of A␤40 and A␤42 in the Drosophila brain using the GAL4-UAS system (23).…”

Synapse development in health and disease

“…APP was found to promote synaptogenesis in culture and is required both pre-and post-synaptically to regulate mammalian NMJ structure and function, presumably by forming a transsynaptic adhesion complex [25]. Similarly, regulation of the Drosophila APP homolog critically controls synaptic growth at the NMJ [26]. The involvement of various synaptic cell adhesion proteins in neuropsychiatric diseases indicates that abnormal synapse formation or specification may be a common risk factor for mental disorders.…”