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Mechanisms of memory loss and Neuro-degeneration caused by loss of Presenilin Function in Alzheimer's disease


In recent years, and as a result of extended life expectancy, the number of people affected by Alzheimer’s disease (AD), a neurodegenerative disorder that slowly and progressively impairs memory and intellectual abilities, has dramatically increased . AD affects usually people of advanced ages and its origin in most cases is unknown.

However, the majority of pre-senile AD cases (< 65 years of age), are caused by inherited familial mutations in the Presenilin genes. Presenilins are the catalytic components of g-secretase, a multiprotein complex that generates the b-amyloid (Ab) peptides, which aggregates and accumulate into amyloid plaques in the AD brain. The accumulation and deposition of Ab is thought to be a key event in the pathogenesis of AD.

The toxic effects of Ab on cultured neurons and transgenic mice have been extensively studied. However, the molecular mechanisms by which mutant presenilins cause memory loss and neurodegeneration are largely unknown. To study the biological function of presenilins in the adult brain we generated recently neuronal-specific presenilin conditional knockout mice.

We found that presenilin inactivation in the adult mouse brain causes synaptic dysfunction and neurodegeneration by altering CREB/CBP-mediated gene expression. This raises the possibility that loss of presenilin function may cause memory deficits and neurodegeneration in AD. In this project, we will investigate the molecular mechanisms, by which presenilins regulate CREB-dependent signalling, which is essential for neuronal function and survival.

Based on the analysis of the mouse genome, we will examine how normal and mutant presenilins regulate CREB/CBP signalling. These studies will integrate genomic approaches into our knowledge of human diseases and will facilitate the design of therapeutic strategies for the treatment of Alzheimer’s and related disorders.

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