Established genetic factors implicated in AD include mutations in APP (chromosome 21), mutations in presenilin 1 (PS1; chromosome 14) and PS2 (chromosome 1), and the susceptibility allele of ApoE4 (chromosome 19; Price et al. 1998; Hardy 2006a; Ghiso and Wisniewski 2004; Bertram and Tanzi 2005). Autosomal dominant mutations in APP, PS1, or PS2 usually cause disease earlier than occurs in sporadic cases, with the maj ority of mutations in APP, PS1 and PS2 influencing BACE1 and y-secretase cleavages of APP to increase the levels of all Ap species or the relative amounts of toxic Ap42 (Ghiso and Wisniewski 2004). Individuals with duplications of APP (Rovelet-Lecrux et al. 2006) or with trisomy 21 (Down's syndrome; Hardy 2006a) have an extra copy of APP and develop AD pathology relatively early in life. The presence of ApoE4 predisposes to later onset AD and some cases of late-onset fAD (Bertram and Tanzi 2005; Corder et al. 1994).
A member of the APP gene family (APP, APLP1 and 2), APP encodes a type I transmembrane protein that is abundant in the nervous system, rich in neurons, transported rapidly anterograde in axons to terminals (Lazarov et al. Buxbaum et al. 1998; Sisodia et al. 1993); its specific functions remain to be defined (Wong et al. 2005; Cao and Sudhof 2001). APP is cleaved by activities of BACE1 (P-site APP cleaving enzyme 1) of the +1 and +11 sites and by the y-secretase complex at a variety of sites (see below) that generate the N- and C- termini of Ap peptides, respectively (Citron 2004; Vassar et al. 1999; Cai et al. 2001; Selkoe and Kopan 2003; Iwatsubo 2004; Laird et al. 2005; Ma et al. 2005; Li et al. 2003). The APPswe mutation enhances many-fold the BACE1 cleavage at the N-terminus of Ap (+1 site), resulting in substantial elevations in levels of all Ap peptides. APP717 mutations influence y-secretase cleavage to increase secretion of Afi42, which is the most toxic peptide. Thus, a variety of APP mutations alter the processing of APP and influence an increase in the production of Ap peptides or the amounts of the more toxic Ap42. In contrast, other mutations may promote local fibril formation and vascular amyloidosis (Ghiso and Wisniewski 2004). This information has been useful in creating transgenic models of amyloidosis (see Savonenko 2006 for a recent review of models).
PS1 and PS2 encode two highly homologous and conserved 43- to 50-kD multipass transmembrane proteins (Price et al. 1998; Sherrington et al. 1995) that are involved in Notch 1 signaling pathways critical for cell fate decisions (Selkoe and Kopan 2003). PS are endoproteolytically cleaved by a "presenilinase" to form an N-terminal ~28-kDa fragment and a C-terminal ~ 18-kDa fragment (Thinakaran et L. 1997); both fragments are critical components of the y-secretase complex (Selkoe and Kopan 2003; Iwatsubo 2004)3. Nearly 50% of early-onset cases of fAD are linked to > 90 different mutations in PS1 (Price et al. 1998; Hardy 2006a; Bertram and Tanzi 2005; Sherrington et al. 1995). A relatively small number of PS2 mutations also cause autosomal dominant fAD (Price et al. 1998; Bertram and Tanzi 2005). The majority of abnormalities in PS genes are missense mutations that enhance y-secretase activities and increase the levels of the Ap42 peptides.
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