Alzheimer's disease (AD) is the most common cause of neurodegeneration and dementia. Mutations in presenilin 1 (PS1) and presenilin 2 (PS2) account for ~90% of all identified causative mutations in familial AD (FAD), highlighting the importance of presenilins (PS) in AD pathogenesis. However, the molecular mechanisms by which PS mutations lead to neuronal dysfunction and death in FAD is a key unresolved question. Pathogenic mutations have been found to impair PS function and promote overproduction of -amyloid peptides in cell culture systems, but the relative contributions of loss-of-function and gain-of-function mechanisms to FAD pathogenesis have not been fully defined. Through the generation and analysis of conditional knockout mice lacking PS function in the adult brain, we previously identified essential roles for PS in synaptic function, memory and neuronal survival in the adult brain. Based on these and other observations, we recently proposed that loss of essential neuronal functions of PS may be a primary cause of dementia and neurodegeneration in FAD. In this new competing R01 application, we test this hypothesis by examining the impact of FAD mutations on essential PS functions in the developing and adult brains. We recently identified a PS1 mutation (L435F) in an early-onset FAD pedigree with cotton wool plaque neuropathology, and found that this mutation causes a nearly complete loss of ?-secretase activity in PS-deficient mouse embryo fibroblasts. Moreover, we recently found that PS1 harboring pathogenic mutations can modulate the activity of wild-type PS1 in a dominant-negative manner. In the first Specific Aim, we propose a multidisciplinary analysis of the effects of the PS1 L435F mutation on neurogenesis in the developing mouse brain and synaptic function, memory and neuronal survival in the adult brain. In particular, we will determine whether this mutation can rescue the defects in these processes caused by complete PS inactivation, and we will also assess the role of PS gene dosage in determining the phenotypic consequences of the mutation. In the second Specific Aim, we will investigate whether the mutant PS1 bearing the L435F mutation can modulate the activity of wild-type PS1 in the developing and adult brains. We will compare the relative effects of PS1 L435F and null mutations on ?-secretase activity, A production and A deposition in cultured neurons and/or the adult brain. We will then extend our analysis to the effects of additional FAD mutations on ?-secretase activity and synaptic function in a primary neuronal culture system. Completion of our proposed Specific Aims will provide mechanistic insight into the effects of pathogenic mutations on PS function in the brain, where the pathogenesis of AD ultimately occurs. Our long-term goal is to understand how pathogenic mutations alter PS function to provoke dementia and neurodegeneration in AD, and to unravel the mechanisms by which loss of PS function produces synaptic dysfunction, cognitive decline and neurodegeneration.

Public Health Relevance

Alzheimer's disease (AD) is the most common neurodegenerative disorder, and mutations in the presenilin genes are the most common cause of inherited forms of the disease. Pathogenic presenilin mutations have been proposed to cause dementia and neurodegeneration through loss-of-function and gain-of-function mechanisms, but the impact of pathogenic mutations on presenilin function in the brain remains unclear. In this application, we propose a multidisciplinary investigation of the mechanisms by which pathogenic presenilin mutations lead to dementia and neurodegeneration, focusing on essential neuronal functions of presenilins in the developing and adult brain. Completion of our proposed study will provide important insights into AD pathogenesis and may identify novel approaches to therapy for this devastating disease.

National Institute of Health (NIH)
Research Project (R01)
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Cell Death and Injury in Neurodegeneration Study Section (CDIN)
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Corriveau, Roderick A
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Massachusetts General Hospital
United States
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Heilig, Elizabeth A; Gutti, Usha; Tai, Tara et al. (2013) Trans-dominant negative effects of pathogenic PSEN1 mutations on ýý-secretase activity and A* production. J Neurosci 33:11606-17