Despite the intense scrutiny of the proteolytic processing and products of the amyloid precursor protein (APP) and its role in Alzheimer disease, the normal function of this transmembrane molecule is largely a mystery. Drosophila studies yielded an important clue when researchers showed that APPL, the fly homolog of APP, can promote synapse formation at the neuromuscular junction (NMJ) (see ARF related news story). Extending this work, Vivian Budnik and colleagues from the University of Massachusetts in Worcester now show that APPL is needed for signaling by the cell adhesion molecule Fasciclin II during synapse development. The work, published in the Journal of Neuroscience on June 22, puts APP smack in the middle of a signal transduction pathway that controls synaptic formation and remodeling in flies—two processes that have been implicated in AD pathology in humans.

Drosophila motor neurons continuously sprout new synaptic boutons during muscle growth and development. Bouton expansion is regulated by local changes in FasII, a homotypic Ig family adhesion molecule, and co-first authors James Ashley and Mary Packard showed they could double the number of bouton buds in a given axon by overexpressing FasII. Since the budding was reminiscent of what they had previously seen in APPL-overexpressing flies, they wondered whether APPL might be responsible for FasII signaling.

By using fly strains that over- or underexpressed a variety of FasII or APPL alleles, Ashley and Packard determined that APPL was in fact required for FasII to increase the formation of boutons at the NMJ, and that APPL functioned downstream of the adhesion molecule in a signaling pathway. Increased bouton formation also required the PDZ domain-containing protein dX11, the fly homolog of a mammalian cytosolic adaptor protein that associates with the APP cytoplasmic domain. Immunoprecipitation experiments showed that FasII, APPL, and dX11 were in direct association with each other in muscle cell extracts.

From their own analysis and work of others, Ashley et al. propose a model where homophilic binding of FasII located on the pre- and postsynaptic cells brings dX11 and APPL to presynaptic sites of cell adhesion. dX11 carries with it exocytic machinery which could add new membrane to the bud, while APPL might function via G proteins to stimulate microtubule extension.

In support of this model, the researchers show that FasII overexpression only increases synapse formation when the protein is present on both sides of the neuromuscular junction—imbalanced elevation of FasII in neurons only interfered with synapse formation, and prevented APPL-induced synapse development. Interestingly, imbalanced expression of FasII, especially in concert with a gain-of-function APPL allele, caused formation of large, morphologically abnormal boutons. These giant boutons contained excess internal membrane structures, abnormal microtubule clusters, and aberrantly accumulated APPL and FasII. “These internal APPL accumulations within the boutons seem reminiscent of intraneuronal amyloid-β accumulation,” the authors write, and may “provide additional clues toward a mechanism by which interference with normal APP function could lead to pathological events and subsequent symptoms of Alzheimer’s disease.”—Pat McCaffrey.

Reference:
Ashley J, Packard M, Ataman B, Budnik V. Fasciclin II signals new synapse formation through amyloid precursor protein and the scaffolding protein dX11/Mint. Journal of Neuroscience. 2005 June 22; 25:5943-5955.

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  1. This report by Vivian Budnik and coworkers provides some new insight into the normal roles of FasII, APPL and X11 in synapse formation, but it is especially interesting for AD researchers because of its potential insight into the mechanism of dystrophic neurite formation.

    The authors report that overexpressing both FasII and APPL leads to the abnormal accumulation of APPL in presynaptic boutons, which is reminiscent of what is seen in dystrophic neurites in AD. This suggests that dysregulation of FasII/APPL/X11 function at the presynaptic terminus may initiate neuritic dystrophy and intracellular APP and Aβ accumulation. Electron micrographs show that APPL accumulates in abnormal boutons containing concentric membrane vesicles that resemble the autophagic vesicles described in dystrophic neurites reported by Ralph Nixon. Normally, you might discount the significance of this type of observation because overexpression of many proteins leads to abnormal accumulation. However, in this report the authors have convincingly ruled this artifactuous interpretation out—the abnormal accumulation of APPL is abolished by the symmetric overexpression of FasII and APPL in both pre- and postsynaptic compartments.

    APPL accumulation also requires the presence of the APPL intracellular domain and it is exacerbated by the expression of mutant X11 in which the PTB domain is deleted. These observations suggest a mechanism whereby interference with the function or trafficking of APP could initiate intracellular accumulation of APP, Aβ, and neuritic dystrophy.

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  1. APP Has a Role in Synaptic Development

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