Alzheimer's Disease

Alzheimer's disease is the commonest form of dementia which affects an increasing number of older people. This neurodegenerative disorder is characterized by the progressive deposition of the 4 kDa amyloid-β (Aβ) peptide in extracellular senile plaques in the brain. Aβ is derived by proteolytic cleavage of the amyloid precursor protein (APP), a Type I integral membrane protein. Cleavage of APP at the N-terminus of the Aβ by β-secretase (BACE1) and at the C-terminus by the γ-secretase complex (presenilins, nicastrin, Aph1 and Pen2) constitutes the amyloidogenic pathway for processing of APP (Figure 1).

Figure 1. Schematic showing the proteolytic processing of the Alzheimer’s amyloid precursor protein (APP). In the amyloidogenic pathway APP is cleaved by β- and g-secretases to release the neurotoxic Ab peptide. In the non-amyloidogenic pathway α-secretase cleaves within the Aβ domain in APP thereby precluding the formation of Aβ.

In addition, APP can be processed by a-secretase which cleaves within the Aβ domain preventing deposition of this intact amyloidogenic peptide (Figure 1). Several members of the ADAM (a disintegrin and metalloprotease) family, namely ADAM10, ADAM9 and ADAM17, display a-secretase activity. The regulation of the APP secretases is important for the development of therapeutic strategies to control the build up of Aβ in the brain and the subsequent pathological effects of Alzheimer's disease. We are currently using a combination of approaches to characterise the molecular and cellular mechanisms underlying the regulation of the α-, β- and γ-secretases. In particular we are interested in the role that cholesterol-rich lipid rafts play in regulating the amyloidogenic processing of APP (Figure 2).

Figure 2. Schematic showing the role of cholesterol-rich lipid rafts in segregating the non-amyloidogenic proteolytic processing of APP by the α-secretase (B) from the amyloidogenic processing by β- and γ-secretases (C).