Alzheimer’s disease (AD) is the most common form of dementia in elderly people and the fifth leading cause of death for people who are 65 years or older (Alz. Assoc. Facts and Figures 2011). Neuropathologically, depositions of amyloid beta (Aβ) plaques in the brain interstitial and phosphorylation of microtubule-associated protein tau (MAPT) within axons are the hallmarks of AD (Hardy and Selkoe 2002). Aβ peptide, which is the proteolytic cleaved product of the transmembrane amyloid precursor protein (APP), is released by enzymatic cleavage by several secretase enzymes. APP is first cleaved by β-secretase (or BACE-1) to produce sAPPβ and a 99 amino acid fragment, which is further cleaved by γ-secretase to produce Aβ peptides (39-44 amino acids residue) (Sambamurti et al. 2002). Alternatively, APP can also be cleaved by another enzyme, α-secretase, to produce sAPPα and a 83 amino acid residue fragment (C83), which is further cleaved by γ-secretase to produce P3 fragment and precludes Aβ production (Lahiri et al. 2003; Marlow et al. 2003). Decreasing the levels of APP and the activities of BACE-1 and γ-secretase has already been identified as potential therapeutic strategies for the treatment of AD (Lahiri et al. 2007a; Imbimbo and Giardina 2011; Vassar and Kandalepas 2011). The schematic diagram in Figure 11.1 shows the major APP processing pathways.
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)