A study of the role of presenilin (1) in regulating synaptic function at hippocampal synapses

• Main Author: Yu, L. M. Y.
• Published: University College London (University of London) 2010
• Online Access: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.587588

Synapse dysfunction is emerging as a major factor in the pathogenesis of Alzheimer’s disease (AD). Key insights into the pathological mechanisms have been provided through studies of familial AD (FAD) genes. Mutations in the PSEN1 gene account for the vast majority of FAD cases, which are typified by the formation of amyloid plaques, neurofibrillary tangles and neuronal loss. The PSEN1 gene encodes presenilin 1, a polytopic transmembrane protein, which is the catalytic core of a proteolytic enzyme complex known as γ-secretase. γ-secretase mediates the generation of amyloid-β (Aβ) peptides, key constituents of amyloid plaques, and hence it is central to AD pathology. γ-secretase has also been implicated in the proteolysis of a wide range of transmembrane proteins associated with different cellular signalling pathways and functions. However, the precise role that presenilins play in regulating synapse function is not clear. The aim of this thesis is to gain an understanding of the physiological role of presenilin 1 at hippocampal synapses in anticipation that this may provide a greater understanding of the mechanisms that underlie synaptic dysfunction during AD. This study provides evidence that presenilin is implicated in modulating spontaneous excitatory synaptic transmission in hippocampal neurons in dissociated and slice cultures. Further experiments have revealed a role for presenilin in modulating synapse number but not neurotransmitter release probability, and calcium imaging suggests that γ-secretase activity is dispensable for regulation of cellular calcium homeostasis. In addition, experiments using pharmacological inhibitors of Aβ precursor protein processing and Aβ peptide generation have uncovered synaptic roles for γ-secretase that are potentially distinct from those of β-secretase. Together these findings suggest a role for presenilin in regulating basal glutamatergic synaptic transmission and synapse structure of hippocampal neurons.