Final Activity Report Summary - PRESENILIN-ALZHEIMER (Mechanisms of memory loss and Neuro-degeneration caused by loss of Presenilin Function in Alzheimer's disease) Alzheimer's disease (AD) is a neurodegenerative disorder that slowly and progressively impairs memory and intellectual abilities. AD brain is characterised neuropathologically by the presence of amyloid plaques, composed of b-amyloid (Ab) peptides, neurofibrillary tangles, synapse degeneration and neuron loss. Loss of synapses is associated with early memory impairments in animal models of AD and ageing indicating that neuronal and synaptic failure may underlie cognitive dysfunction and neurodegeneration. The majority of inherited familial AD cases are caused by mutations in the presenilin (PS) genes. Presenilins are components of g-secretase, a multiprotein protease complex that is required for normal processing of the b-amyloid precursor protein (APP) and Ab generation. Since the ultimate goal of AD research is to develop therapies that prevent neurodegeneration and memory loss, it is important to understand the molecular mechanisms implicated in neuron survival in AD. Indeed, at the moment the cellular and molecular mechanisms underlying memory loss and neuronal degeneration caused by loss of PS function are unknown. We recently raised the possibility that PS mutations might cause the disease by a loss-of-function pathogenic mechanism (Saura et al., 2004). Indeed, loss of PS in mutant engineered mice causes synaptic dysfunction, memory loss and neurodegeneration (Saura et al., 2004; Beglopoulos et al., 2004). To further study the molecular mechanisms regulated by PS on cell survival we used molecular biology and biochemical approaches to examine possible cellular mechanisms implicated in PS-dependent cell survival and death. We first examined whether PS are implicated in cell survival by examining the proliferation of cells expressing or lacking PS. We found that absence of PS increases cell proliferation in culture conditions of low serum. The proliferation of PS-deficient cells was inhibited by using an inhibitor of the epidermal growth factor receptor (EGFR), suggesting that the effect of PS on cell proliferation was dependent on EGFR signalling. Indeed, the EGFR has extensively been involved in cell survival and differentiation of different cell types. Our studies indicate that PS negatively regulates the expression of EGFR by affecting its constitutive and ligand-dependent degradation. Specifically, PS regulates a posttranslational step, called ubiquitination, that is a signal for EGFR degradation. One consequence of PS inactivation is that EGFR is increased, which leads to abnormal proliferation of PS-deficient cells. These results suggest that PS are important to maintain a correct balance of EGFR signalling, which is crucial for cell survival. In addition, our studies may provide critical information to elucidate the molecular mechanisms by which PS-dependent EGFR signalling regulates neuronal survival. These studies will be important to elucidate whether PS regulate neuronal survival and memory by regulating the EGFR pathway in PS mutant mice. In summary, the study of the cellular mechanisms controlling neuronal function and survival in the adult brain are directly relevant for our understanding of cognitive dysfunction and neurodegeneration in Alzheimer's disease. Importantly, genetic and pharmacological manipulation of signalling cascades involved in memory and neurodegeneration can be explored as novel therapeutic strategies for neurodegenerative disorders.