Amyloid β interacts with the amyloid precursor protein: a potential toxic mechanism in Alzheimer's disease

Abstract

Amyloid beta protein (Abeta) deposition in the brain is a hallmark of Alzheimer's disease (AD). The fibrillar form of Abeta is neurotoxic, although the mechanism of its toxicity is unknown. We showed that conversion of Abeta to the fibrillar form markedly increased binding to specific neuronal membrane proteins, including amyloid precursor protein (APP). Nanomolar concentrations of fibrillar Abeta bound cell-surface holo-APP in cortical neurons. Reduced vulnerability of cultured APP-null neurons to Abeta neurotoxicity suggested that Abeta neurotoxicity involves APP. Thus Abeta toxicity may be mediated by the interaction of fibrillar Abeta with neuronal membrane proteins, notably APP. An Abeta-APP interaction reminiscent of the pathogenic mechanism of prions may thus contribute to neuronal degeneration in AD.

Neurotoxic effects of thioflavin S-positive amyloid deposits in transgenic mice and Alzheimer's disease

“…In neuropathological studies of human AD brain, ThioS plaques but not non-ThioS plaques are associated with dramatic alterations in neuritic geometry (36,37), which, we have argued, may underlie functional deficits in neural systems in AD. The current results are also consistent with the idea that the ␤-pleated sheet conformation of A␤ is important for toxicity in vivo, perhaps by inducing cross linking or conformational changes of cell surface proteins (38). In vitro data demonstrate that fibrillar A␤ can affect calcium homeostasis, promote freeradical and oxidative injury, and potentiate excitotoxic and apoptotic insult.…”

A rescue factor abolishing neuronal cell death by a wide spectrum of familial Alzheimer's disease genes and Aβ

“…For instance, FAD genes promote A␤-forming processing of APP, resulting in increased A␤ secretion on the one hand and accumulation of the cytoplasmic domains of APP on the other, which can potentially induce neurotoxicity (12,21,26,27). Also, extracellular A␤ binds to cell-surface APP (28), and ligand binding to cell-surface APP generates cytotoxic signals via the cytoplasmic region of APP (25), suggesting that extracellular A␤ may induce cell death through APP and its cytoplasmic domain. Thus, HN might block cytotoxic signals from the cytoplasmic region of APP to commonly attenuate neurotoxicity by FAD genes and A␤.…”

Phosphorylation of Actin-Depolymerizing Factor/Cofilin by LIM-Kinase Mediates Amyloid -Induced Degeneration: A Potential Mechanism of Neuronal Dystrophy in Alzheimer's Disease

“…We demonstrated that A␤ fibrils are needed for LIMK1 activation in vitro; coincidently, conversion of sA␤ to the fibrillar form increases its binding to membrane proteins (Lorenzo et al, 2000). Several membrane proteins have been shown to participate in A␤-induced apoptosis ; in contrast, A␤PP and/or integrins could be the main cell-surface candidates for A␤ fibril-induced neuronal dystrophy.…”

“…Several membrane proteins have been shown to participate in A␤-induced apoptosis ; in contrast, A␤PP and/or integrins could be the main cell-surface candidates for A␤ fibril-induced neuronal dystrophy. Both A␤PP and integrins participate in mechanisms of neuronal plasticity (Breen et al, 1991;Perez et al, 1997;Benson et al, 2000;Sabo et al 2001a), bind to A␤ fibrils (Sabo et al, 1995;Lorenzo et al, 2000;Van Nostrand et al, 2002), colocalize in adhesion sites (Storey et al, 1996;Yamazaki et al, 1997), and cluster around A␤ deposits in aberrant focal adhesion structures (Grace and Busciglio, 2003;Heredia et al, 2004). In fact, A␤ dystrophy requires aberrant activation of focal adhesion proteins, including Paxillin (Grace and Busciglio, 2003), activation of which could also depend on A␤PP or integrins, through their interaction with different cytoplasmic proteins (Sabo et al, 2001b;Zambrano et al, 2001;Martin et al, 2002).…”