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. 2015 Oct 27;21 Suppl 1(Suppl 1):S41-8.
doi: 10.2119/molmed.2015.00163.

Twenty Years of Presenilins--Important Proteins in Health and Disease

Jochen Walter  1
Affiliations

Twenty Years of Presenilins--Important Proteins in Health and Disease

Jochen Walter. Mol Med. .

Abstract

Alzheimer's disease (AD) is characterized by progressive decline in cognitive functions associated with depositions of aggregated proteins in the form of extracellular plaques and neurofibrillary tangles in the brain. Extracellular plaques contain characteristic fibrils of amyloid β peptides (Aβ); tangles consist of paired helical filaments of the microtubuli-associated protein tau. Although AD manifests predominantly at ages above 65 years, rare cases show a much earlier onset of disease symptoms with very similar neuropathological characteristics. In 1995, two homologous genes were identified, in which mutations are associated with dominantly inherited familial forms of early onset AD. The genes therefore were dubbed presenilins (PS) and encode polytopic transmembrane proteins. At this time the role of these proteins in the pathogenesis of AD and their biological function in general were completely unknown. However, individuals carrying PS mutations showed alterations in the composition of different length variants of Aβ peptides in blood and cerebrospinal fluid, which indicated the potential involvement of presenilins in the metabolism of Aβ. After 20 years of intense research, the roles of presenilins in Aβ generation as well as important functions in biological processes have been identified. Presenilins represent the catalytic components of protease complexes that directly cleave the amyloid precursor protein (APP) but also many other proteins with important physiological functions. Here, the progress in presenilin research from basic characterization of their cellular functions to the targeting in clinical trials for AD therapy, and potential future directions, will be discussed.

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Figures

Figure 1
Figure 1
Schematic showing the proteolytic processing of APP and the composition of the γ-secretase complex. (A) APP is a type I transmembrane protein. β-Secretase cleaves at the N-terminus of the Aβ domain (red), resulting in the secretion of soluble APP (APPs-β) and generation of a C-terminal fragment (APP CTFβ). Subsequent cleavage of this fragment by γ-secretase liberates Aβ and the APP intracellular domain (AICD) from cellular membranes. (B) Composition of the γ-secretase complex. Presenilins represent the catalytically active proteins in the complex. Critical aspartate residues within the active site of presenilins are indicated by yellow stars. Nicastrin, Aph-1 and Pen-2 mediate assembly, substrate recognition and subcellular transport of the γ-secretase complex. See text for details.
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