Presenilin Proteins
59
4.2 Familial Alzheimer's Disease
In the majority of cases AD occurs sporadically with an increasing risk
during aging (Selkoe 1996; Price and Sisodia 1998). However, rare
mutations have been found to cause autosomal-dominant early-onset
familial AD (FAD; Selkoe 1996; Price and Sisodia 1998). Mutations
were found within the genes encoding ~APP, presenilin-l (PS), and PS2
(summarized in Selkoe 1996; Price and Sisodia 1998). The analysis of
these mutations in primary fibroblasts derived from FAD patients, transfected cells, and transgenic animals revealed that they all alter the
production of A~ (Selkoe 1996; Price and Sisodia 1998). Interestingly,
these mutations affect a common pathological mechanism by increasing
the production of the long 42 amino acid version of A~ (A~42). This
peptide is known to aggregate much faster as compared to the more
abundant A~40 (Jarret and Lansbury 1993) and is therefore predominantly found within senile plaques (Lemere et al. 1996; Mann et al.
1996).
4.3 The Presenilin Complex
PS proteins are membrane proteins, which most likely contain eight
transmembrane domains (Doan et al. 1996; De Strooper 1997). Human
presenilins are proteolytic ally processed to an N-terminal-30 kDa fragment (NTF) and a C-terminal -20 kDa fragment (CTF; Thinakaran et al.
1996; Fig. 1). In vivo, these fragments accumulate and almost no fulllength PS can be observed (Thinakaran et al. 1996). PS fragments are
bound to each other (Capell et al. 1998; Thinakaran et al. 1998) and
form a high molecular weight complex (Capell et al. 1998). This complex, consisting of NTF and CTF, and probably other binding proteins as
well (Yu et al. 1998; Zhang et al. 1998), may be the biologically active
unit. Recent evidence indicates that recombinant NTF containing FADassociated mutations does not stimulate A~42 production (Steiner et al.
1998; Citron et al. 1998; Tomita et al. 1998). Furthermore, such recombinant NTFs are also inactive in facilitating Notch signaling (Baumeister et al. 1997; see below) and coimmunoprecipitation experiments
demonstrated that these fragments are not incorporated into the PS
complex (Steiner et al. 1998). This raises the possibility that the PS
59
4.2 Familial Alzheimer's Disease
In the majority of cases AD occurs sporadically with an increasing risk
during aging (Selkoe 1996; Price and Sisodia 1998). However, rare
mutations have been found to cause autosomal-dominant early-onset
familial AD (FAD; Selkoe 1996; Price and Sisodia 1998). Mutations
were found within the genes encoding ~APP, presenilin-l (PS), and PS2
(summarized in Selkoe 1996; Price and Sisodia 1998). The analysis of
these mutations in primary fibroblasts derived from FAD patients, transfected cells, and transgenic animals revealed that they all alter the
production of A~ (Selkoe 1996; Price and Sisodia 1998). Interestingly,
these mutations affect a common pathological mechanism by increasing
the production of the long 42 amino acid version of A~ (A~42). This
peptide is known to aggregate much faster as compared to the more
abundant A~40 (Jarret and Lansbury 1993) and is therefore predominantly found within senile plaques (Lemere et al. 1996; Mann et al.
1996).
4.3 The Presenilin Complex
PS proteins are membrane proteins, which most likely contain eight
transmembrane domains (Doan et al. 1996; De Strooper 1997). Human
presenilins are proteolytic ally processed to an N-terminal-30 kDa fragment (NTF) and a C-terminal -20 kDa fragment (CTF; Thinakaran et al.
1996; Fig. 1). In vivo, these fragments accumulate and almost no fulllength PS can be observed (Thinakaran et al. 1996). PS fragments are
bound to each other (Capell et al. 1998; Thinakaran et al. 1998) and
form a high molecular weight complex (Capell et al. 1998). This complex, consisting of NTF and CTF, and probably other binding proteins as
well (Yu et al. 1998; Zhang et al. 1998), may be the biologically active
unit. Recent evidence indicates that recombinant NTF containing FADassociated mutations does not stimulate A~42 production (Steiner et al.
1998; Citron et al. 1998; Tomita et al. 1998). Furthermore, such recombinant NTFs are also inactive in facilitating Notch signaling (Baumeister et al. 1997; see below) and coimmunoprecipitation experiments
demonstrated that these fragments are not incorporated into the PS
complex (Steiner et al. 1998). This raises the possibility that the PS