Signaling effect of amyloid-beta(42) on the processing of AbetaPP - PubMed (original) (raw)

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Signaling effect of amyloid-beta(42) on the processing of AbetaPP

Massimo Tabaton et al. Exp Neurol. 2010 Jan.

Abstract

The effects of amyloid-beta are extremely complex. Current work in the field of Alzheimer disease is focusing on discerning the impact between the physiological signaling effects of soluble low molecular weight amyloid-beta species and the more global cellular damage that could derive from highly concentrated and/or aggregated amyloid. Being able to dissect the specific signaling events, to understand how soluble amyloid-beta induces its own production by up-regulating BACE1 expression, could lead to new tools to interrupt the distinctive feedback cycle with potential therapeutic consequences. Here we describe a positive loop that exists between the secretases that are responsible for the generation of the amyloid-beta component of Alzheimer disease. According to our hypothesis, in familial Alzheimer disease, the primary overproduction of amyloid-beta can induce BACE1 transcription and drive a further increase of amyloid-beta precursor protein processing and resultant amyloid-beta production. In sporadic Alzheimer disease, many factors, among them oxidative stress and inflammation, with consequent induction of presenilins and BACE1, would activate a loop and proceed with the generation of amyloid-beta and its signaling role onto BACE1 transcription. This concept of a signaling effect by and feedback on the amyloid-beta precursor protein will likely shed light on how amyloid-beta generation, oxidative stress, and secretase functions are intimately related in sporadic Alzheimer disease.

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Figure 1

Figure 1. Schematic of the tentative model of Aβ induced activation of BACE1 transcription

Soluble Aβ (blue dots) could activate G-coupled receptors or ionic (Ca++) channels leading to increase Ca++ entry. The same effect could be achieved intracellularly (green dots) via interaction with the ER, liberating Ca++. This could lead to JNK activation and finally AP1-mediated transcription of BACE1. Inhibition of IRs and Akt pathway by Aβ could liberate the action of JNK on AP1, achieving the same effect. Increased production of BACE1 completes the cycle, enhancing the processing of AβPP (red circle) to form more Aβ. Oligomers and fibrils (aggregated blue dots) are formed as a consequence of enhanced amyloidogenesis, but it is not clear if they have a role in this signalling. Blue dots: Aβ; green dots: Ca++; arrows: stimulation; blunt arrows: inhibition; IRs: insulin receptors; G: G-proteins and G-coupled receptors; β and γ: β-and γ-secretase cleavages; ER: endoplasmic reticulum.

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