Focal adhesions regulate Abeta signaling and cell death in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder that results from a loss of synaptic transmission and ultimately cell death. The presenting pathology of AD includes neuritic plaques composed of beta-amyloid peptide (Abeta) and neurofibrillary tangles composed of hyperphosphorylated tau, with neuronal loss in specific brain regions. However, the mechanisms that induce neuronal cell loss remain elusive. Focal adhesion (FA) proteins assemble into intracellular complexes involved in integrin-mediated communication between the extracellular matrix and the actin cytoskeleton, regulating many cell physiological processes including the cell cycle. Interestingly, recent studies report that integrins bind to Abeta fibrils, mediating Abeta signal transmission from extracellular sites of Abeta deposits into the cell and ultimately to the nucleus. In this review, we will discuss the Abeta induced integrin/FA signaling pathways that mediate cell cycle activation and cell death.

Figure 1. Early signaling pathways mobilized at focal adhesion formation

Integrin activation/adhesion promotes FAK autophosphorylation site recruits SH2 domain proteins including Src and Fyn leading to further FAK phosphorylation and other FA proteins including paxillin. Phosphorylated paxillin then binds to p130^CAS forming the FA unit. Integrin receptor binding to fibrillar Aβ mimics early ECM/integrin signaling.

Figure 2. Focal adhesions regulate cell cycle progression

Fibrillar Aβ binds to integrin and activates FA signaling pathway to regulate cell cycle through different pathways including MAPK, PI3-K, and GSK-3β kinases (see text for details). The FA also receives input by growth factor receptors and cell-cell adhesions (cadherins). The sum of all inputs determines gene expression for cell survival and/or cell cycle progression through numerous transcriptional regulators. Signaling inputs from the ECM, growth factor receptors, and cadherins to the FA unit in the cytoplasm regulates cell cycle progression. Transcriptional regulators and nuclear events are denoted in black boxes.