title: Perlecan Domain V Inhibits Amyloid-β Induced Activation of the α2β1 Integrin-Mediated Neurotoxic Signaling Cascade.
abstract: Alzheimer's disease (AD) is characterized by neuronal death, neurofibrillary tangles, and senile plaques. Amyloid-beta (Aβ) is the major component of plaques and consists of two prominent isoforms, Aβ40 and Aβ42. As many risk factors for AD are vascular in origin and blood vessel defects in clearing Aβ 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 α2 integrin and Aβ is a ligand for both α2β1 and αvβ1. Due to the known interaction of DV with α2β1 and α2β1's requirement for Aβ 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 α2β1 binding by Aβ. Our study suggests that α2β1 mediates Aβ-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 α2β1 mediated neurotoxic effects suggesting that they or other α2β1 integrin modulators could represent a novel approach to treat AD. Finally, our results suggest different neurotoxicity susceptibilities between cortical and hippocampal neurons to Aβ40 and Aβ42 as further underscored by differing neuroprotective potencies of LG3 in each cell type.
authors.affiliation: Texas A&M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA.
authors.forename: Christi L
authors.initials: CL
authors.lastname: Parham
authors.affiliation: Texas A&M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Shaw
authors.affiliation: Texas A&M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Auckland
authors.affiliation: Vanderbilt University, Nashville, TN, USA.
authors.forename: S Kent
authors.initials: SK
authors.lastname: Dickeson
authors.affiliation: Imago Pharmaceuticals, Jackson Hole, WY, USA.
authors.forename: Irene
authors.initials: I
authors.lastname: Griswold-Prenner
authors.affiliation: Texas A&M Health Science Center, Department of Molecular and Cellular Biology, College Station, TX, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Bix
mesh_terms: D000544:Alzheimer Disease / Q000378:metabolism / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000818:Animals; D002470:Cell Survival / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D005260:Female; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D038982:Integrin alpha2beta1 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D011247:Pregnancy; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016229:Amyloid beta-Peptides; D019812:Heparan Sulfate Proteoglycans; D038982:Integrin alpha2beta1; C071927:perlecan
keywords: Amyloid-β; cortical neurons; extracellular matrix; hippocampal neurons; integrins; signaling