Signaling mechanisms that mediate Aβ induced neuronal dysfunction

Abstract

In this chapter, we present a set of mechanisms by which Aβ can compromise neuronal function in the absence of degeneration. Aβ has an ability to impair NMDA and BDNF/TrkB signal transduction, two mechanisms critical for neuronal communication and brain plasticity such as learning and memory. Chronic exposure to Aβ also can cause the development of neuronal dystrophy. The mechanism involves aberrant activation of focal adhesion signals. Aβ1-42 impairs BDNF-TrkB transcriptional activity and neuron survival probably by a mechanism involving regulation of the TrkB docking proteins. The regulation of docking proteins has also been shown to participate in insulin resistance and may induce a similar state of neurotrophin resistance in brain. Aβ can also impair NMDA transcriptional activity of genes such as CREB. The mechanism appears to involve Aβ activated internalization of NMDA receptor mediated via α-7 nicotinic receptors. Aβ can also cause neuronal dystrophy and the loss of synaptic connectivity via focal adhesion signaling pathways. Alterations in the composition of the extracellular environment in the AD brain, e.g. accumulation of Aβ fibrils, may stimulate cellular responses consistent with misregulation of FA signaling. Thus Aβ accesses normal signaling pathways to cause aberrant signaling which can compromise neuronal function dysfunction in the absence of cell death. Taken together, these normal signaling pathways-compromised NMDA, TrkB and focal adhesion signaling-may contribute to early functional losses prior to the manifestation of classical AD pathology. In addition, these same Aβ-mediated mechanisms may also exacerbate brain dysfunction by similar processes once pathology develops. In a sense, Aβ literally high jacks key plasticity mechanisms to impair neuronal function. © 2007 Springer Science+Business Media, LLC. All rights reserved.