Mutant Presenilin 2 Transgenic Mice

Abstract

A subset of early-onset familial Alzheimer's disease (FAD) 1 is inherited as an autosomal dominant trait, and presenilin (PS) 1 and 2 genes in addition to ß-amyloid precursor protein (APP) gene were identified as the causative genes. PS1 is mapped to chromosome 14 (1,2), while PS2 is mapped to chromosome 1 (3-5). These PS1 and PS2 genes encode multispanned transmembrane proteins showing high degrees of homology (4,5).Both proteins are located predominantly in the endoplasmic reticulum (ER), and partly in the Golgi apparatus and other compartments (6-8), but their physiological functions remain unclear. More than 50 different mutations have thus far been identified in PS1 (9), while only two mutations have been found in PS2 (10). The residue at position 141 (Asn) in PS2, which is conserved in human and mouse PS1 and PS2, is substituted by Ile (N141I) in the Volga German kindred. Another missense mutation (M239V) in PS2 has been found in Italian FAD families (5).Although the pathogenetic mechanism how Alzheimer's disease (AD) is developed by PS mutations remains unknown, mutations of PS1 and PS2 are known to have similar effects on the production of amyloid ß-protein (Aß) 42, the initially deposited Aß species in senile plaques (11)(12)(13)(14): While Aß42 is normally secreted in much lower quantities than Aß40, these aforementioned mutations induce elevation of the Aß42 levels in cultured cells and transgenic mice (15)(16)(17)(18)(19)(20). It has also been reported that in primary neuronal cultures derived from PS1-knockout mouse embryos, Aß secretion was remarkably decreased, concomitant with the accumulation of the C-terminal fragment of APP (21). The mutation in the two particular Asp residues in the PS1-transmembrane domains induced a profound decrease in the Aß production and an increase in the levels of the C-terminal fragment of APP (22). These observations indicate that PS1 may have a direct or indirect role in the γ -cleavage of APP.We previously reported that the mutant PS2 transgenic mice showed increases in the Aß42 levels in the Tris-saline (TS)-soluble fractions in an age-dependent manner during 2 to 8 months of age (20). On the other hand, a series of Aß quantitation studies of autopsied human tissues has clearly shown that Aß42 already accumulates to a significant extent in the TS- In the present study, we sought to obtain further insight into the effects of mutant PS2on the Aß levels in the TS-insoluble, guanidine hydrochloride-solubilized fraction of the mouse brain, and to characterize the intracellular compartmentalization of insoluble Aß. EXPERIMENTAL PROCEDURESTransgenic mice -The heterozygous PS2 transgenic mice used in this study were from the previously established lines W2 (wild-type PS2 transgenic mice), and M1 and M2(N141I mutant PS2 transgenic mice) (20). Each line of transgenic mice was backcrossed to the C57BL/6J strain, and those mice carrying the PS2 transgene were selected using a transgene-specific PCR assay (20). Littermates without PS2 transgenes were used as the nontransge...

Smooth muscle raft-like membranes

“…Previous studies have found considerable variation in phospholipid and cholesterol contents of detergent-resistant LBDM (9,33,(56)(57)(58)(59)(60). These results are shown in Table 4 and compared with data obtained in the current study.…”

A Seed for Alzheimer Amyloid in the Brain

“…Regarding this issue, we favor the possibility that GA␤ is generated in GM1-and cholesterol-rich microdomains such as lipid rafts (Parton, 1994;Simons and Ikonen, 1997), because of the following: (1) lipid rafts contain soluble and insoluble 〈␤s under physiological (Lee et al, 1998;Morishima-Kawashima and Ihara, 1998) and pathological (Sawamura et al, 2000) conditions, respectively; (2) amyloidogenic processing of the amyloid precursor protein is associated with lipid rafts (Ehehalt et al, 2003); and (3) the aggregation of soluble A␤ is readily induced by its interaction with lipid raftlike model membranes (Kakio et al, 2003). We found recently that A␤ binding to GM1 is markedly accelerated in a cholesterolrich environment and that, in such an environment, GM1 forms a cluster that can be recognized by soluble A␤ as a receptor (Kakio et al, 2001).…”

Thematic Review Series: Sphingolipids. Role of ganglioside metabolism in the pathogenesis of Alzheimer's disease—a review

“…Although the amount of gangliosides and their patterns are similar in control and in AD cases (37), an observation was made that the A2B5 antibody reacted with human brain c-series gangliosides and, unexpectedly, sulfatides (38). The brain gangliosides of different transgenic mouse models of AD have been analyzed and compared with those of age-matched wild-type mice (39)(40)(41)(42). Barrier et al (39) observed a marked increase in the simple gangliosides GM2 and GM3 in the cortex of 2-year-old APP SL mice expressing the Swedish (K670N/M671L) and London (V717I) mutations of human APP.…”