Exploring the Role of PSEN Mutations in the Pathogenesis of Alzheimer’s Disease (original) (raw)
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Mutations in amyloid precursor protein affect its interactions with presenilin/γ-secretase
Molecular and Cellular Neuroscience, 2009
Alzheimer's disease is characterized by accumulation of toxic β-amyloid (Aβ) in the brain and neuronal death. Several mutations in presenilin (PS1) and β-amyloid precursor protein (APP) associate with an increased Aβ 42/40 ratio. Aβ 42 , a highly fibrillogenic species, is believed to drive Aβ aggregation. Factors shifting γ-secretase cleavage of APP to produce Aβ 42 are unclear. We investigate the molecular mechanism underlying altered Aβ 42/40 ratios associated with APP mutations at codon 716 and 717. Using FRET-based fluorescence lifetime imaging to monitor APP-PS1 interactions, we show that I716F and V717I APP mutations increase the proportion of interacting molecules earlier in the secretory pathway, resulting in an increase in Aβ generation. A PS1 conformation assay reveals that, in the presence of mutant APP, PS1 adopts a conformation reminiscent of FAD-associated PS1 mutations, thus influencing APP binding to PS1/γ-secretase. Mutant APP affects both intracellular location and efficiency of APP-PS1 interactions, thereby changing the Aβ 42/40 ratio.
Biochimica Et Biophysica Acta-molecular Cell Research, 2008
gamma-Secretase mediates the intramembranous proteolysis of amyloid precursor protein (APP), Notch and other cellular substrates and is considered a prime pharmacological target in the development of therapeutics for Alzheimer's disease (AD). We describe here an efficient, new, simple, sensitive and rapid assay to quantify gamma-secretase activity in living cells by flow cytometry using two membrane-bound fluorescent probes, APP-GFP or C99-GFP, as substrates for gamma-secretase. The principle of the assay is based on the fact that the soluble intracellular domain of GFP-tagged APP (AICD-GFP) is released from the membrane into the cytosol following gamma-secretase cleavage. Using this feature, enzymatic activity of gamma-secretase could be deduced from the extent of the membrane retention of the probe observed after plasma membrane permeabilization and washout of the cleaved fraction. By applying two well-known gamma-secretase inhibitors (DAPT and L-685,458), we validated our assay showing that the positional GFP-based probes for gamma-secretase activity behave properly when expressed in different cell lines, providing the basis for the further development of a high-throughput and high content screening for AD targeted drug discovery. Moreover, by co-expression of different familial AD-linked mutated forms of presenilin--the key component of the gamma-secretase complex--in cells devoid of any endogenous gamma-secretase, our method allowed us to evaluate in situ the contribution of different presenilin variants to the modulation of the enzyme.
Journal of Neurochemistry, 2002
Recent reports indicate that missense mutations on presenilin (PS) 1 are likely responsible for the main early-onset familial forms of Alzheimer's disease (FAD). Consensual data obtained through distinct histopathological, cell biology, and molecular biology approaches have led to the conclusion that these PSi mutations clearly trigger an increased production of the 42amino-acid-long species of /1-amyloid peptide (A/I). Here we show that overexpression of wild-type PSi in HK293 cells increases A/I40 secretion. By contrast, FAD-linked mutants of PSi trigger increased secretion of both A/340 and A/342 but clearly favor the production of the latter species. We also demonstrate that overexpression of the wild-type PSi augments the a-secretase-derived C-terminally truncated fragment of /3-amyloid precursor protein (APPc~)recovery, whereas transfectants expressing mutated PSi secrete drastically lower amounts of APPcr when compared with cells expressing wild-type PSi . This decrease was also observed when comparing double transfectants overexpressing wild-type /3-amyloid precursor protein and either PSi or its mutated congener Ml 46V-PS1. Altogether, our data indicate that PS mutations linked to FAD not only trigger an increased ratio of A/342 over total A/I secretion but concomitantly downregulate the production of APPa. Key Words: Familial Alzheimer's disease-Presenilin 1 -a-Secretase-APPa-~3-Amyloidpeptide-/3-Amyloid precursor protein.
Presenilin structure, function and role in Alzheimer disease
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, 2000
Numerous missense mutations in the presenilins are associated with the autosomal dominant form of familial Alzheimer disease. Presenilin genes encode polytopic transmembrane proteins, which are processed by proteolytic cleavage and form high-molecular-weight complexes under physiological conditions. The presenilins have been suggested to be functionally involved in developmental morphogenesis, unfolded protein responses and processing of selected proteins including the L-amyloid precursor protein. Although the underlying mechanism by which presenilin mutations lead to development of Alzheimer disease remains elusive, one consistent mutational effect is an overproduction of long-tailed amyloid L-peptides. Furthermore, presenilins interact with L-catenin to form presenilin complexes, and the physiological and mutational effects are also observed in the catenin signal transduction pathway.
Journal of Biological Chemistry, 2002
Presenilin 1 (PS1) plays an essential role in intramembranous "␥-secretase" processing of several type I membrane proteins, including the -amyloid precursor proteins (APP) and Notch1. In this report, we examine the activity of two familial Alzheimer's disease-linked PS1 variants on the production of secreted A peptides and the effects of L-685,458, a potent ␥-secretase inhibitor, on inhibition of A peptides from cells expressing these PS1 variants. We now report that PS1 variants enhance the production and secretion of both A1-42 and A1-40 peptides. More surprisingly, whereas the IC 50 for inhibition of A1-40 peptide production from cells expressing wild-type PS1 is ϳ1.5 M, cells expressing the PS1⌬E9 mutant PS1 exhibit an IC 50 of ϳ4 M. Immunoprecipitation and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry reveal that the levels of A1-43 peptides are elevated in medium of PS1⌬E9 cells treated with higher concentrations of inhibitor. The differential effects of wild-type and mutant PS1 on ␥-secretase production of A peptides and the disparity in sensitivity of these peptides to a potent ␥-secretase suggest that PS may be necessary, but not sufficient, to catalyze hydrolysis at the scissile bonds that generate the termini of A1-40 and A1-42 peptides.
The many substrates of presenilin/γ-secretase
Journal of Alzheimer's disease : JAD, 2011
The Alzheimer's disease (AD)-associated amyloid-β protein precursor (AβPP) is cleaved by α-, β-, and presenilin (PS)/γ-secretases through sequential regulated proteolysis. These proteolytic events control the generation of the pathogenic amyloid-β (Aβ) peptide, which excessively accumulates in the brains of individuals afflicted by AD. A growing number of additional proteins cleaved by PS/γ-secretase continue to be discovered. Similarly to AβPP, most of these proteins are type-I transmembrane proteins involved in vital signaling functions regulating cell fate, adhesion, migration, neurite outgrowth, or synaptogenesis. All the identified proteins share common structural features, which are typical for their proteolysis. The consequences of the PS/γ-secretase-mediated cleavage on the function of many of these proteins are largely unknown. Here, we review the current literature on the proteolytic processing mediated by the versatile PS/γ-secretase complex. We begin by discussing th...
Clinical Interventions in Aging, 2015
Alzheimer's disease (AD) is the most common form of dementia. Mutations in the genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2), and amyloid precursor protein have been identified as the main genetic causes of familial AD. To date, more than 200 mutations have been described worldwide in PSEN1, which is highly homologous with PSEN2, while mutations in PSEN2 have been rarely reported. We performed a systematic review of studies describing the mutations identified in PSEN2. Most PSEN2 mutations were detected in European and in African populations. Only two were found in Korean populations. Interestingly, PSEN2 mutations appeared not only in AD patients but also in patients with other disorders, including frontotemporal dementia, dementia with Lewy bodies, breast cancer, dilated cardiomyopathy, and Parkinson's disease with dementia. Here, we have summarized the PSEN2 mutations and the potential implications of these mutations in dementia-associated disorders.
Early-onset Alzheimer's disease with a de novo mutation in the presenilin 1 gene
Experimental Neurology, 2007
A 32-year-old woman diagnosed with very rapidly progressing early-onset Alzheimer's disease (EOAD), age of onset 29 years, and S170F mutation in presenilin 1 gene (PSEN1) is presented. Neuroimaging conducted 2 years after the first symptoms was typical for the advanced stage of Alzheimer's disease (AD), showing cortical brain atrophy, particularly within hippocampus, frontal and temporal cortex. The unaffected parents of the proband are not carriers of the mutation. The paternity was confirmed by microsatellite typing, strongly suggesting de novo origin of S170F mutation. In silico modeling of S170F mutation impact on presenilin 1 (PS1) transmembrane structure indicates that the mutation considerably alters putative interactions of PS1 with other proteins within γ-secretase complex.
Journal of Neurochemistry, 2005
Gene knockout studies in mice suggest that presenilin 1 (PS1) is the major γ-secretase and that it contributes disproportionately to amyloid β (Aβ) peptide generation from β-amyloid precursor protein (APP), whereas PS2 plays a more minor role. Based on this and other observations we hypothesized that familial Alzheimer's disease (FAD) mutations in PS2 would have a dramatic effect on function in order to have an observable effect on Aβ levels in the presence of normal PS1 alleles. Only four of the eight reported FAD mutations in PS2 have altered function in vitro suggesting that the other variants represent rare polymorphisms rather than disease-causing mutations. In support of our hypothesis, the four verified PS2 FAD mutations cause substantial changes in the Aβ 42/40 ratio, comparable with PS1 mutations that cause very-early-onset FAD. Most of the PS2 mutations also cause a significant decrease in Aβ 40, APP C-terminal fragment (CTF)γ and Notch intracellular domain (NICD) production suggesting that they are partial loss of function mutations. PS2 M239V, its PS1 homolog M233V, and other FAD mutations within transmembrane (TM) 5 of PS1 differentially affect CTFγ and NICD production suggesting that TM5 of PS are important for γ-secretase cleavage of APP but not Notch.
Journal of Biological Chemistry, 2000
Presenilins (PSs) are polytopic membrane proteins that have been implicated as potential therapeutic targets in Alzheimer's disease because of their role in regulating the ␥-secretase cleavage that generates the amyloid  protein (A). It is not clear how PSs regulate ␥-secretase cleavage, but there is evidence that PSs could be either essential cofactors in the ␥-secretase cleavage, ␥-secretase themselves, or regulators of intracellular trafficking that indirectly influence ␥-secretase cleavage. Using presenilin 1 (PS1) mutants that inhibit A production in conjunction with transmembrane domain mutants of the amyloid protein precursor that are cleaved by pharmacologically distinct ␥-secretases, we show that PS1 regulates multiple pharmacologically distinct ␥-secretase activities as well as inducible ␣-secretase activity. It is likely that PS1 acts indirectly to regulate these activities (as in a trafficking or chaperone role), because these data indicate that for PS1 to be ␥-secretase it must either have multiple active sites or exist in a variety of catalytically active forms that are altered to an equivalent extent by the mutations we have studied.