. Rab5 mediates an amyloid precursor protein signaling pathway that leads to apoptosis. J Neurosci. 2007 Jul 4;27(27):7141-53. PubMed.

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  1. Studies of Alzheimer disease in Down syndrome (DS) and DS mouse models have shown a close connection between APP triplication, endosome enlargement—one of the earliest manifestations of AD—and neurodegeneration (1,2). Daphna Laifenfeld, with Rachael Neve’s group, now reveals that APP-BP1, a molecule they previously implicated in neurodegeneration, links this chain of pathological events. The findings reinforce the concept that endosomes, a convergence point for the actions of various AD risk factors, may mediate important Aβ-independent toxic effects of APP as well as modulate Aβ production with additional possible toxic consequences (3). In their study, overexpression of mutant APP (V462I) was sufficient to initiate the endosome-mediated cascade, while in the DS mouse model Ts65Dn, wild-type APP triplication triggered this cascade only in the presence of one or more other genes on the trisomic segment of chromosome 16 (1).

    Together, these observations raise the possibility that other factors that increase risk for sporadic AD might also do so by enhancing APP interactions at the level of the APP-BP1/Rab5 complex, especially given that expression of Rab5 and related endosome trafficking molecules is significantly upregulated very early in AD and in DS mouse models (4). The ε4 allele of ApoE, for example, accelerates endosome pathology in SAD and Rab5 expression. It will be interesting to look closely at how risk factors associated with the endocytic pathway, such as ApoE ε4, LRPs, and sortilins may modulate the Rab5-APP-BP1 complex and affect endosome-mediated signaling. The current study should stimulate investigations of less well-studied pathways by which APP contributes to neurodegeneration in AD beyond giving rise to Aβ.

    See also:

    Kovacs KM, Nixon RA, Ginsberg SD. Microarray analysis of hippocampal pyramidal neurons and dentate gyrus granule cells in a murine model of Down’s syndrome (Ts65Dn). Soc. Neurosci Abstr. 169.1.

    References:

    . App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci. 2003 Jul 30;23(17):6788-92. PubMed.

    . Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.

    . Endosome function and dysfunction in Alzheimer's disease and other neurodegenerative diseases. Neurobiol Aging. 2005 Mar;26(3):373-82. PubMed.