Mutations in the genes encoding presenilins 1 and 2 (PS-1 and PS-2) and the ?-amyloid precursor protein (APP) are the leading cause of familial Alzheimer's disease (FAD). Overexpression of these gene mutations in transgenic mice recapitulates pathological and behavioral features of AD. It has supported the hypothesis that aggregation of the amyloid A?42 protein is an important trigger for disease onset and progression, and fostered the development of therapeutic strategies based on reducing A?42 aggregates. However, the utility of transgenic models for investigating AD pathogenesis and evaluating candidate therapies is constrained by the dependence on ectopic overexpression. As an alternative, we introduced mouse lines in which gene targeting was used to "knock-in" disease-causing mutations into their endogenous genes. Our studies established the only mouse model for AD-type amyloid, tau, and neuroinflammatory pathologies that does not rely on ectopic overexpression, and identified neurobiological and molecular mechanisms central to AD pathogenesis. The proposed research would extend these findings by delineating at the molecular level a key mechanism for A?42 overproduction, defining neurobiological roles for amyloid, tau, and neuroinflammatory pathologies in impairing forms of adaptive plasticity in hippocampal circuits known to be both important for long-term memory and severely impacted in AD, and identifying therapies that reverse these pathologies and rescue the plasticity deficits.
Specific Aim 1 will identify structural and functional changes caused by mutant PS-1 in the mouse brain ?-secretase, the protease that forms the amyloid A?42 protein, and test the hypothesis that mutant PS-1 confers a pathogenic conformation on the protease.
Specific Aim 2 will test the hypothesis that the amyloid and tau pathologies impair synaptic plasticity in the entorhino-hippocampal perforant pathway, and evaluate multiple pharmacologic strategies for reversing the pathology and impaired plasticity.
Specific Aim 3 will test the hypothesis that mutant PS-1 hinders neurogenesis in the adult hippocampus through amyloid-triggered neuroinflammation, and determine its reversibility. The proposed research will advance our understanding of molecular and neurobiological mechanisms of FAD-linked gene mutations and evaluate several therapeutic strategies aimed at reducing neuroplasticity deficits in a faithful mouse genetic model of FAD. Project Narrative: "Pathogenic mechanisms of presenilin mutation": The proposed research will use a novel and faithful mouse genetic model to advance our understanding mechanisms by which certain gene mutations cause inherited Alzheimer's disease. It will promote basic understanding of the neurobiological mechanisms underlying the cognitive and behavioral syndrome of AD, and evaluate multiple candidate therapeutic strategies that target these neurobiological processes. This translational research in a disease-relevant preclinical model is crucial to the development of therapies aimed at delaying the onset and slowing the progression of AD with a high likelihood of success in the clinic.
|Zhang, Chen; McNeil, Elizabeth; Dressler, Lindsay et al. (2007) Long-lasting impairment in hippocampal neurogenesis associated with amyloid deposition in a knock-in mouse model of familial Alzheimer's disease. Exp Neurol 204:77-87|
|Siman, R; Salidas, S (2004) Gamma-secretase subunit composition and distribution in the presenilin wild-type and mutant mouse brain. Neuroscience 129:615-28|
|Siman, Robert; Velji, Jamel (2003) Localization of presenilin-nicastrin complexes and gamma-secretase activity to the trans-Golgi network. J Neurochem 84:1143-53|
|Siman, R; Flood, D G; Thinakaran, G et al. (2001) Endoplasmic reticulum stress-induced cysteine protease activation in cortical neurons: effect of an Alzheimer's disease-linked presenilin-1 knock-in mutation. J Biol Chem 276:44736-43|