. Fasciclin II signals new synapse formation through amyloid precursor protein and the scaffolding protein dX11/Mint. J Neurosci. 2005 Jun 22;25(25):5943-55. PubMed.

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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.

    View all comments by Charles Glabe

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