Introduction

Alzheimer's disease (AD) is the major neurodegenerative disease of the aging brain and, whereas the underlying pathology remains extremely complex and poorly understood, poses an ever-expanding burden on health services in the context of an aging population. By 2010, it is estimated that there will be half a million AD sufferers in the UK, while currently there are greater than 12 million sufferers worldwide. AD is characterized by a decline in cognitive function that progresses slowly, leaving patients in the later stages of the illness bedridden, incontinent, and dependent on custodial care, with death occurring, on average, 9 years after diagnosis. Although there are currently a few drugs used to help manage the cognitive effects of AD, namely the acetylcholinesterase inhibitors and the V-methyl-D-aspartate receptor antagonist memantine, there is presently no available therapy to arrest or modify the progress of the disease (Vardy, Catto, & Hooper, 2005).

AD is characterized by the deposition in the brain of senile plaques consisting predominantly of the amyloid-P (AP) peptide of 40-42 amino acids that causes, either directly or indirectly, the neurodegeneration seen in AD (Selkoe, 2001). Recent work has indicated that oligomeric forms of AP appear to be the major toxic species in transgenic mouse models of AD (Cleary et al., 2005; Lesne et al., 2006). As part of the process of neurodegeneration, the tau protein is deposited as paired helical filaments in neurofibrillary tangles and dystrophic neurites (LaFerla & Oddo, 2005). AP is derived by proteolytic cleavage of the amyloid precursor protein (APP), a type I integral membrane glycoprotein. In the amyloidogenic pathway, p-secretase cleavage of APP yields a soluble N-terminal fragment of approximately 100 kDa (sAPPP) along with a 12-kDa membrane-bound C-terminal fragment that is subsequently cleaved by y-secretase to release the Ap peptide (Fig. 1). P-secretase has been identified as a membrane-bound aspartic protease termed BACE-1, Asp2, or memapsin (Esler & Wolfe, 2001), while y-secretase is a complex of at least four proteins, presenilin-1 and -2, nicastrin, Aph-1, and Pen-2 (Haass & Steiner, 2002). In the alternative nonamyloido-genic pathway, a-secretase cleaves APP within the Ap sequence, thus precluding the formation of Ap, releasing a soluble N-terminal fragment sAPPa (Fig. 1). Members of the ADAM (a disintegrin and rnetalloprotease)

Membrane

Membrane

g-secretase

AICD

Fig. 1. Proteolytic processing of amyloid precursor protein (APP) by its secretases. APP is a type I integral membrane glycoprotein consisting of a large N-terminal extracellular domain, a transmembrane domain, and a short intracellular cytoplasmic domain. The Ap peptide (shaded box) constitutes part of the transmembrane domain and an adjacent short fragment of the extracellular domain. In the amyloidogenic pathway, P-secretase (BACE-1) cleaves APP at the N terminus of the Ap domain to produce sAPPp and a 99-amino acid C-terminal fragment C99. C99 is further cleaved by the y-secretase complex (presenilin, nicastrin, Aph-1, and Pen-2) within the transmembrane domain to liberate Ap and the APP intracellular domain (AICD). In the alternative nonamyloidogenic pathway, a-secretase (members of the ADAM family) cleaves APP within the Ap sequence to produce sAPPa and an 83-amino acid C-terminal fragment C83, which in turn is cleaved by y-secretase to produce p3 and AICD

family of proteases, such as ADAM-10 and ADAM-17, display a-secretase activity (Hooper & Turner, 2002; Allinson, Parkin, Turner, & Hooper, 2003). Thus inhibition of the P- and y-secretases and activation of a-secretase are currently being considered as therapeutic approaches to AD (Dewachter & Van Leuven, 2002; Vardy et al., 2005).

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