Presenilin Proteins and the Pathogenesis of Early-Onset Familial Alzheimer’s Disease: β-Amyloid Production and Parallels to Prion Diseases View Full Text


Ontology type: schema:Chapter     


Chapter Info

DATE

1998

AUTHORS

D. Westaway , G. A. Carlson , C. Bergeron , G. Levesque , R. Sherrington , H. Yao , R. Strome , B. Perry , A. Davies , S. Gandy , C. Weaver , P. Davies , D. Shenk , J. Rommens , J. Roder , P. E. Fraser , P. St. George-Hyslop

ABSTRACT

In contrast to rare mutations in the amyloid presursor protein (APP) gene, missense mutations in the presenilin 1 (PS1) and presenilin 2 (PS2) genes, on chromosomes 14 and 1 respectively, are the most common causes of early-onset familial Alzheimer’s disease (AD)(Sherrington et al. 1995)(Rogaev et al. 1995)(Levy-Lahad et al. 1995). Presenilin genes encode proteins with at least seven putative transmembrane domains and an extruded cytoplasmic “loop”, the latter with a preponderance of acidic amino acid residues: these proteins are expressed in a variety of cell types. While the physiologic function of these genes is unknown, their protein products have been demonstrated to accumulate in intracellular sites including the endoplasmic reticulum, and the Golgi apparatus. Similarly, the mechanism by which the 30 different point mutations have been identified in PS1 and PS2 to date cause the clinical and neuropathological hallmarks of Alzheimer disease is unknown. However, fibroblasts from heterozygous carriers of PS1 and PS2 mutations secrete increased levels of the amyloidogenic long-tailed amyloid β-peptides ending at residues 42 or 43 (Aβ42)(Martin 1995)(Scheuner et al. 1996). Increased levels of Aβ42 and other Aβ-peptides can also be measured in postmortem brain tissue from human patients dying with early-onset FAD associated with PS1 mutations(Lemere et al. 1996). To determine whether overproduction of Aβ peptides occurs in brain as an early biochemical event prior to the onset of neurodegeneration, we constructed transgenic mice with either mutant or wild-type human PS1 and mated them with another line of transgenic mice overexpressing wild-type human βAPP695 under the control of the same transcriptional regulatory element. These studies reveal that mutant PS1 transgenes but not wild-type PS1 transgenes act in a dominant fashion to programme over-production of long-tailed Aβ42 peptides in brain, and that this biochemical difference is present by at least 2–4 months of age and in the absence of any detectable neuropathologic lesions. These advances in our understanding of presenilin function are discussed in relation to the two schools of thought on AD pathogenesis, “tau-ist”and “ßaptist”, and also with regards the hypothesis that similarities between AD and prion diseases reflect the existence of shared pathogenic pathways. More... »

PAGES

159-176

References to SciGraph publications

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    http://scigraph.springernature.com/pub.10.1007/978-1-4899-1896-3_17

    DOI

    http://dx.doi.org/10.1007/978-1-4899-1896-3_17

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