4 Presenilin Proteins and Their Function
During Embryonic Development
and Alzheimer's Disease
C. Haass
4.1
Introduction ............................................ 57
4.2
Familial Alzheimer's Disease. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59
4.3
The Presenilin Complex .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 59
4.4
Presenilins Facilitate Amyloid ~-Peptide Production ........... 60
4.5
Presenilins Are Required for Notch Signaling ................. 61
4.6
Presenilins: Targets for Anti-Alzheimer's Drugs? .............. 61
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 62
4.1 Introduction
Aggregation and precipitation of peptides appear to playa major role in
neurodegenerative diseases such as Alzheimer's disease (AD) (Teplow
1998), Parkinson's disease (Mezey et al. 1998), and Huntington's disease (Georgalis et al. 1998). In AD, the aggregating Amyloid B-peptide
(AB) accumulates in highly insoluble senile plaques, which are the
defining pathological symptoms of the disease (Selkoe 1996). AB is
derived by proteolytic processing from the B-Amyloid precursor protein
(BAPP; Selkoe 1996). Two secretases have been postulated, which
either generate the N-terminus (B-secretase) or the C-terminus (y-secretase) of AB (Haass and Selkoe 1993; Fig. 1). AB is produced under
physiological conditions in cultured cells and is secreted into the media.
In vivo, AB is detected in human plasma and cerebrospinal fluid (Haass
and Selkoe 1993).