Proteolytic cascades in the brain and their cholinergic regulation: role in neurodegeneration
Progressive dysfunction of cholinergic neurotransmission in selected brain regions contributes to the cognitive and behavioural disturbances in Alzheimer’s disease although the underlying mechanisms remain unclear. The amyloid β-peptide (Aβ) is a major player in Alzheimer progression and its levels are modulated by the cholinergic system. The level of Aβ in the brain represents a dynamic equilibrium state as a result of its biosynthesis from the amyloid precursor protein (APP) by β- and γ-secretases, its alternative processing by α-secretases and its degradation by a team of amyloid-degrading enzymes. The fi rst and rate-limiting step in amyloid synthesis, mediated by the membrane-bound β-secretase occurs in lipid raft domains and is modulated by other interacting proteins, e.g. the prion protein. Alternatively, and by far the major metabolic route for APP, is its processing in non-raft domains, to release the soluble extracellular domain, sAPPα, in a process mediated by a cohort of ADAMs zinc metalloproteases and regulated through cholinergic signalling pathways. We have used a variety of biochemical and genetic techniques to identify the proteases involved in these processes, their regulation and their subcellular localizations. Manipulation of cholinergic signalling could provide one strategy for reducing amyloid burden alongside direct targeting of the amyloid-forming and -degrading enzymes. This work was supported by the UK Medical Research Council.