The role of focal adhesion signaling in Alzheimer's disease
Date of Completion
Alzheimer's disease (AD) is a late onset neurodegenerative disease characterized by memory loss and dementia. AD is distinguished by the presence of amyloid plaques and neurofibrillary tangles (NFT) in hippocampal and cortical regions in the brain. Amyloid plaques are extracellular lesions composed of a core of fibrillar amyloid β (Aβ) surrounded by dystrophic neurons sprouting into the plaque. NFT are intracellular lesions composed of paired helical filaments of hyperphosphorylated tau. AD is one of many neurodegenerative diseases that present with protein deposition, cytoskeletal alterations, and aberrant plastic changes. Therefore, understanding the pathological process in AD may lead to the characterization of pathological mechanisms common to other late onset neurodegenerative conditions. ^ The goal of this research is to understand the cellular and molecular mechanisms involved in maladaptive neuronal plasticity that seem to be part of the AD pathology. We have analyzed the pathological relationship between Aβ-induced neuronal dystrophy, neurotoxicity and synaptic loss, and partially characterized the molecular pathways mediating Aβ-induced neuronal dystrophy and neurotoxicity. Fibrillar Aβ-induced neuronal dystrophy occurs prior to neurotoxicity and at lower concentrations, suggesting that independent molecular pathways are involved. Neuronal dystrophy was closely associated with a reduction in synaptic density, suggesting that fibrillar Aβ deposition promotes synaptic loss in the AD brain. ^ Focal Adhesion (FA) proteins are involved in transducing extracellular signals to generate cellular responses including cytoskeletal changes. We demonstrated that fibrillar Aβ activates FA signaling, leading to the formation of aberrant FA contacts proximal to fibrillar Aβ deposits. We found strikingly similar alterations in the AD brain where dystrophic neurons containing activated FA proteins surrounded amyloid plaques, frequently co-localizing with hyper-phosphorylated tau. These results suggest a pathological role for the aberrant activation of FA in AD. ^ Deletion experiments demonstrated the involvement of the carboxy terminus domain of paxillin and protein tyrosine phosphatase PEST (PTP-PEST) in Aβ-induced neuronal dystrophy and toxicity, while focal adhesion kinase (FAK) is involved only in Aβ-induced neurotoxicity. Our results indicate that aberrant activation of FA signaling by fibrillar Aβ leads to neuronal dystrophy and synaptic loss, and underscores the role of “maladaptive neuronal plasticity” in the AD neuropathology. ^
Grace, Elizabeth Ann, "The role of focal adhesion signaling in Alzheimer's disease" (2002). Doctoral Dissertations. AAI3062080.