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Cellular Signalling Jan 2016The presenilins are the catalytic subunit of the membrane-embedded tetrameric γ-secretase protease complexes. More that 90 transmembrane proteins have been reported to... (Review)
Review
The presenilins are the catalytic subunit of the membrane-embedded tetrameric γ-secretase protease complexes. More that 90 transmembrane proteins have been reported to be γ-secretase substrates, including the widely studied amyloid precursor protein (APP) and the Notch receptor, which are precursors for the generation of amyloid-β peptides and biologically active APP intracellular domain (AICD) and Notch intracellular domain (NICD). The diversity of γ-secretase substrates highlights the importance of presenilin-dependent γ-secretase protease activities as a regulatory mechanism in a range of biological systems. However, there is also a growing body of evidence that supports the existence of γ-secretase-independent functions for the presenilins in the regulation and progression of an array of cell signalling pathways. In this review, we will present an overview of current literature that proposes evolutionarily conserved presenilin functions outside of the γ-secretase complex, with a focus on the suggested role of the presenilins in the regulation of Wnt/β-catenin signalling, protein trafficking and degradation, calcium homeostasis and apoptosis.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Humans; Presenilins; Wnt Signaling Pathway
PubMed: 26498858
DOI: 10.1016/j.cellsig.2015.10.006 -
Journal of Alzheimer's Disease : JAD 2023Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is...
Probabilistic and parsimony-based arguments regarding available genetics data are used to propose that Hardy and Higgin's amyloid cascade hypothesis is valid but is commonly interpreted too narrowly to support, incorrectly, the primacy of the amyloid-β peptide (Aβ) in driving Alzheimer's disease pathogenesis. Instead, increased activity of the βCTF (C99) fragment of AβPP is the critical pathogenic determinant altered by mutations in the APP gene. This model is consistent with the regulation of APP mRNA translation via its 5' iron responsive element. Similar arguments support that the pathological effects of familial Alzheimer's disease mutations in the genes PSEN1 and PSEN2 are not exerted directly via changes in AβPP cleavage to produce different ratios of Aβ length. Rather, these mutations likely act through effects on presenilin holoprotein conformation and function, and possibly the formation and stability of multimers of presenilin holoprotein and/or of the γ-secretase complex. All fAD mutations in APP, PSEN1, and PSEN2 likely find unity of pathological mechanism in their actions on endolysosomal acidification and mitochondrial function, with detrimental effects on iron homeostasis and promotion of "pseudo-hypoxia" being of central importance. Aβ production is enhanced and distorted by oxidative stress and accumulates due to decreased lysosomal function. It may act as a disease-associated molecular pattern enhancing oxidative stress-driven neuroinflammation during the cognitive phase of the disease.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Presenilin-1; Mutation; Iron
PubMed: 37718800
DOI: 10.3233/JAD-230313 -
Swiss Medical Weekly 2015Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause for dementia, which affects approximately 120 thousand people in Switzerland and 35... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disorder and the most common cause for dementia, which affects approximately 120 thousand people in Switzerland and 35 million worldwide. Aging is a major risk factor for developing AD and thus, as our societies are growing older, we face great challenges to find treatment strategies. The disease is characterised by loss of memory, deposition of extracellular amyloid plaques containing Aβ peptides and intraneuronal tangles of the tau protein. To date, there is no effective treatment and the cause of the disease is still debated. The Schweizerische Alzheimervereinigung states that we need "continuous manifold research" into all possible causes of AD to find a cure for this disease. Fitting this proposition, a recent publication by Xia et al. (2015) described a novel mouse model that for the first time reproduces cortical neuron death as observed in human AD cases. At the same time, this publication questions the major theory of AD pathogenesis and points towards different treatment avenues that should be followed to find a cure for AD.
Topics: Aging; Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Humans; Mice; Neurons; Presenilins; Switzerland
PubMed: 26701700
DOI: 10.4414/smw.2015.14233 -
Aging Cell Aug 2023Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates... (Observational Study)
Observational Study
Although pathogenic variants in PSEN1 leading to autosomal-dominant Alzheimer disease (ADAD) are highly penetrant, substantial interindividual variability in the rates of cognitive decline and biomarker change are observed in ADAD. We hypothesized that this interindividual variability may be associated with the location of the pathogenic variant within PSEN1. PSEN1 pathogenic variant carriers participating in the Dominantly Inherited Alzheimer Network (DIAN) observational study were grouped based on whether the underlying variant affects a transmembrane (TM) or cytoplasmic (CY) protein domain within PSEN1. CY and TM carriers and variant non-carriers (NC) who completed clinical evaluation, multimodal neuroimaging, and lumbar puncture for collection of cerebrospinal fluid (CSF) as part of their participation in DIAN were included in this study. Linear mixed effects models were used to determine differences in clinical, cognitive, and biomarker measures between the NC, TM, and CY groups. While both the CY and TM groups were found to have similarly elevated Aβ compared to NC, TM carriers had greater cognitive impairment, smaller hippocampal volume, and elevated phosphorylated tau levels across the spectrum of pre-symptomatic and symptomatic phases of disease as compared to CY, using both cross-sectional and longitudinal data. As distinct portions of PSEN1 are differentially involved in APP processing by γ-secretase and the generation of toxic β-amyloid species, these results have important implications for understanding the pathobiology of ADAD and accounting for a substantial portion of the interindividual heterogeneity in ongoing ADAD clinical trials.
Topics: Humans; Male; Female; Adult; Brain; Positron-Emission Tomography; Magnetic Resonance Imaging; Presenilin-1; Mutation; Alzheimer Disease; Cognition; Amyloid beta-Peptides; tau Proteins; Longitudinal Studies; Cross-Sectional Studies; Biomarkers
PubMed: 37291760
DOI: 10.1111/acel.13871 -
Neurochemical Research Aug 2021Early-onset Alzheimer's disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized... (Review)
Review
Early-onset Alzheimer's disease (AD) is associated with variants in amyloid precursor protein (APP) and presenilin (PSEN) 1 and 2. It is increasingly recognized that patients with AD experience undiagnosed focal seizures. These AD patients with reported seizures may have worsened disease trajectory. Seizures in epilepsy can also lead to cognitive deficits, neuroinflammation, and neurodegeneration. Epilepsy is roughly three times more common in individuals aged 65 and older. Due to the numerous available antiseizure drugs (ASDs), treatment of seizures has been proposed to reduce the burden of AD. More work is needed to establish the functional impact of seizures in AD to determine whether ASDs could be a rational therapeutic strategy. The efficacy of ASDs in aged animals is not routinely studied, despite the fact that the elderly represents the fastest growing demographic with epilepsy. This leaves a particular gap in understanding the discrete pathophysiological overlap between hyperexcitability and aging, and AD more specifically. Most of our preclinical knowledge of hyperexcitability in AD has come from mouse models that overexpress APP. While these studies have been invaluable, other drivers underlie AD, e.g. PSEN2. A diversity of animal models should be more frequently integrated into the study of hyperexcitability in AD, which could be particularly beneficial to identify novel therapies. Specifically, AD-associated risk genes, in particular PSENs, altogether represent underexplored contributors to hyperexcitability. This review assesses the available studies of ASDs administration in clinical AD populations and preclinical studies with AD-associated models and offers a perspective on the opportunities for further therapeutic innovation.
Topics: Aging; Alzheimer Disease; Animals; Anticonvulsants; Comorbidity; Epilepsy; Humans; Mutation; Presenilin-1; Presenilin-2; Seizures
PubMed: 33929683
DOI: 10.1007/s11064-021-03332-y -
The FEBS Journal Dec 2023More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase-like (SPPL) proteases have been identified based on their... (Review)
Review
More than 20 years ago, signal peptide peptidase (SPP) and its homologues, the signal peptide peptidase-like (SPPL) proteases have been identified based on their sequence similarity to presenilins, a related family of intramembrane aspartyl proteases. Other than those for the presenilins, no high-resolution structures for the SPP/SPPL proteases are available. Despite this limitation, over the years bioinformatical and biochemical data have accumulated, which altogether have provided a picture of the overall structure and topology of these proteases, their localization in the cell, the process of substrate recognition, their cleavage mechanism, and their function. Recently, the artificial intelligence-based structure prediction tool AlphaFold has added high-confidence models of the expected fold of SPP/SPPL proteases. In this review, we summarize known structural aspects of the SPP/SPPL family as well as their substrates. Of particular interest are the emerging substrate recognition and catalytic mechanisms that might lead to the prediction and identification of more potential substrates and deeper insight into physiological and pathophysiological roles of proteolysis.
Topics: Peptide Hydrolases; Membrane Proteins; Artificial Intelligence; Aspartic Acid Endopeptidases; Presenilins
PubMed: 37786993
DOI: 10.1111/febs.16968 -
Clinical Interventions in Aging 2016Alzheimer's disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD... (Review)
Review
Alzheimer's disease (AD), the most common form of senile dementia, is a genetically complex disorder. In most Asian countries, the population and the number of AD patients are growing rapidly, and the genetics of AD has been extensively studied, except in Japan. However, recent studies have been started to investigate the genes and mutations associated with AD in Korea, the People's Republic of China, and Malaysia. This review describes all of the known mutations in three early-onset AD (EOAD) causative genes (, , and ) that were discovered in Asian countries. Most of the EOAD-associated mutations have been detected in , and several novel mutations were recently identified in patients from various parts of the world, including Asia. Until 2014, no mutations were found in Asian patients; however, emerging studies from Korea and the People's Republic of China discovered probably pathogenic mutations. Since several novel mutations were discovered in these three genes, we also discuss the predictions on their pathogenic nature. This review briefly summarizes genome-wide association studies of late-onset AD and the genes that might be associated with AD in Asian countries. Standard sequencing is a widely used method, but it has limitations in terms of time, cost, and efficacy. Next-generation sequencing strategies could facilitate genetic analysis and association studies. Genetic testing is important for the accurate diagnosis and for understanding disease-associated pathways and might also improve disease therapy and prevention.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Asia; Asian People; Genetic Testing; Genome-Wide Association Study; Humans; Mutation; Presenilin-1; Presenilin-2
PubMed: 27799753
DOI: 10.2147/CIA.S116218 -
Current Protein & Peptide Science 2020Locating remedies for Alzheimer's disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of... (Review)
Review
Locating remedies for Alzheimer's disease (AD) has been majorly restricted by the inefficiency to establish a definitive detection model for early-stage diagnosis of pathological events. This current lapse in AD diagnosis also limits the therapeutic efficiency of the drugs, which might have been effective if given at the earlier stages of the disease. The indicated situation directs towards the burgeoned need for an effective biomarker technique that will help in early detection of AD and would be imminently useful to facilitate improved diagnosis and stimulate therapeutic trials. Till date, the major biomarkers, specifically associated with AD detection, may help in determining the early-stage AD diagnosis and identifying alterations in the cellular proteome, offering deeper insight into disease etiology. Currently existing multidisciplinary clinical diagnosis of AD is a very tedious, expensive procedure and requires highly trained and skilled professionals who are rarely available outside the specialty clinics. Mutations in amyloid precursor protein (APP) or Presenilin 1 and 2 (PSEN1 and PSEN2) are some biomarkers acting as critical checkpoints for AD diagnosis. However, the presence of some associated biomarkers in cerebrospinal fluid (CSF) such as total-Tau (tTau), phosphorylated- Tau (pTau) 181 and Amyloid-β (Aβ) 1-42 using structural or functional imaging techniques is considered for confirmatory diagnosis of AD. Furthermore, the molecular diagnosis of AD incorporates various sophisticated techniques including immuno-sensing, machine learning, nano conjugation-based detections, etc. In the current review description, we have summarized the various diagnostic approaches and their relevance in mitigating the long-standing urgency of targeted diagnostic tools for detection of AD.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Biomarkers; Dementia; Diagnostic Tests, Routine; Gene Expression Regulation; Humans; Immunoassay; Neurogranin; Neurons; Phosphorylation; Presenilin-1; Presenilin-2; Proteomics; Signal Transduction; tau Proteins
PubMed: 32538723
DOI: 10.2174/1389203721666200615173213 -
International Journal of Molecular... Apr 2022Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD...
Presenilin-1 (PS-1), a component of the gamma (γ)-secretase catalytic complex, has been implicated in Alzheimer's disease (AD) and in tumorigenesis. Interestingly, AD risk is inversely related to melanoma, suggesting that AD-related factors, such as PS-1, may affect melanomagenesis. PS-1 has been shown to reduce Wnt activity by promoting degradation of beta-catenin (β-catenin), an important Wnt signaling partner. Since Wnt is known to enhance progression of different cancers, including melanoma, we hypothesized that PS-1 could affect Wnt-associated melanoma aggressiveness. Western blot results showed that aggressive melanoma cells expressed significantly lower levels of both PS-1 and phosphorylated-β-catenin (P-β-catenin) than nonaggressive melanoma cells. Immunohistochemistry of human melanoma samples showed significantly reduced staining for PS-1 in advanced stage melanoma compared with early stage melanoma. Furthermore, γ-secretase inhibitor (GSI) treatment of aggressive melanoma cells was followed by significant increases in PS-1 and P-β-catenin levels, suggesting impaired Wnt signaling activity as PS-1 expression increased. Finally, a significant reduction in cell migration was associated with the higher levels of PS-1 and P-β-catenin in the GSI-treated aggressive melanoma cells. We demonstrate for the first time that PS-1 levels can be used to assess melanoma aggressiveness and suggest that by enhancing PS-1 expression, Wnt-dependent melanoma progression may be reduced.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Humans; Melanoma; Presenilin-1; Wnt Signaling Pathway; beta Catenin
PubMed: 35563300
DOI: 10.3390/ijms23094904 -
Current Neurology and Neuroscience... Nov 2014Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a... (Review)
Review
Since the original publication describing the illness in 1907, the genetic understanding of Alzheimer's disease (AD) has advanced such that it is now clear that it is a genetically heterogeneous condition, the subtypes of which may not uniformly respond to a given intervention. It is therefore critical to characterize the clinical and preclinical stages of AD subtypes, including the rare autosomal dominant forms caused by known mutations in the PSEN1, APP, and PSEN2 genes that are being studied in the Dominantly Inherited Alzheimer Network study and its associated secondary prevention trial. Similar efforts are occurring in an extended Colombian family with a PSEN1 mutation, in APOE ε4 homozygotes, and in Down syndrome. Despite commonalities in the mechanisms producing the AD phenotype, there are also differences that reflect specific genetic origins. Treatment modalities should be chosen and trials designed with these differences in mind. Ideally, the varying pathological cascades involved in the different subtypes of AD should be defined so that both areas of overlap and of distinct differences can be taken into account. At the very least, clinical trials should determine the influence of known genetic factors in post hoc analyses.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Genetic Heterogeneity; Humans; Membrane Proteins; Presenilin-1; Presenilin-2
PubMed: 25217249
DOI: 10.1007/s11910-014-0499-8