Perlecan Domain V Inhibits Amyloid-Beta Induced Activation Of The Alpha 2 Beta 1 Integrin-Mediated Neurotoxic Signaling Cascade

Alzheimer's disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (A beta) is the major component of plaques and consists of two prominent isoforms, A beta(40) and A beta(42). As many risk factors for AD are vascular in origin and blood vessel defects in clearing A beta from the brain are a potential key component of AD pathology, we have focused on the neuron-blood vessel interface, and in particular, the vascular basement membrane, which coats blood vessels and physically separates them from neurons. A prominent component of the vascular basement membrane is the extracellular matrix proteoglycan perlecan. Domain V (DV) is the C-terminal domain and is generated by perlecan proteolysis. DV interacts with the alpha 2 integrin and A beta is a ligand for both alpha beta 21 and alpha v beta 1. Due to the known interaction of DV with alpha 2 beta 1 and alpha 2 beta 1's requirement for A beta deposition and neurotoxicity, we hypothesized that DV and/or its C-terminal domain, LG3, might alter neurotoxic signaling pathways by directly blocking or otherwise interfering with alpha 2 beta 1 binding by A beta. Our study suggests that alpha 2 beta 1 mediates A beta-induced activation of c-Jun and caspase-3, key components of the neurotoxic pathway, in primary cortical and hippocampal neurons. We further demonstrate that DV and/or LG3 may therapeutically modulate these alpha 2 beta 1 mediated neurotoxic effects suggesting that they or other alpha 2 beta 1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to A beta(40) and A beta(42) as further underscored by differing neuroprotective potencies of LG3 in each cell type.