The second most frequent mutation is a Dutch mutation (Glu693Gln),

which has been seen in four families.43 Other reports include a Swedish mutation at codon 670/671 ,48 a Flemish mutation at codon 692,49 and others. APP mutations can result in both FAD and SAD, but the majority of AD cases caused by APP mutations are FAD.6,50 Not all APP mutations are pathogenic.6,17,51 It has been estimated that the AD caused by APP mutations accounts for only about 0.5% of all cases of AD.32 The current hypothesis about the role of APP in AD is the amyloid cascade theory.52-54 The principle of this theory is that certain Aβ peptides (which are derived from APP) Inhibitors,research,lifescience,medical are neurotoxic, and that the accumulation of these peptides in the brain is the central event for triggering the pathoanatomical and pathophysiological changes in the brain of AD

patients, including the formation of Inhibitors,research,lifescience,medical neuritic plaques and neuronal loss. The finding of APP mutations in AD dramatically strengthened this hypothesis. The APP gene encodes for a transmembrane protein Inhibitors,research,lifescience,medical containing 770 amino acids, which is extensively expressed on the cell surface.34,55,56 The function of APP is not yet clearly understood. It is generally considered that APP undergoes a series of endoproteolytic cleavages during its processing.53,57 Three kinds of cleavage events are involved, α, β, and γ cleavage: α cleavage cleaves Lys687 and Lcu688 to generate Aβ peptides with 16 to 17 amino acids (Aβ16 and β17), while β cleavage cleaves Met671 and Asp672 to generate Aβ40 to Aβ42.58 Aβ40 is the dominant product of the normal cleavage of APP and is found in the normal aged brain.51,59-61 Inhibitors,research,lifescience,medical In contrast, y cleavage cleaves Ile712, Thr714, or 5-Fluoracil Val715 to generate Aβ40, Aβ42, and Aβ43, respectively,62,63 and the latter two forms are the major components of the neuritic plaques observed in the AD brain.51,54,64,65 Since they are more fibrillogenic and neurotoxic than Aβ40, Aβ42 and Aβ43 are currently considered to play a central role in the pathological processes of AD.66,67 Therefore, enhancement of y cleavage is thought Inhibitors,research,lifescience,medical to be a primary reason

for why mutant APP causes AD. It has been shown that most of the A PP mutations found in AD are located in the molecular region around the secte second tase sites, suggesting that these mutations lead to changes in the substrate in proteolytic processing. Indeed, it has been found that many APP mutations in AD significantly enhance APP cleavage, especially y cleavage.63,65,68-72 All these findings suggest that Aβ metabolism is a key pathway and should be targeted for therapy. Indeed, a compound that can inhibit γ cleavage of APP, a small molecule that can bind to Aβ to prevent its deposition, or an antiinflammatory agent that can diminish the toxic response associated with Aβ have been the major focuses of our attempts to cure this illness.