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International Journal of Molecular... Mar 2020Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients... (Review)
Review
Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive cognitive dysfunction and behavioral impairment. In China, the number of AD patients is growing rapidly, which poses a considerable burden on society and families. In recent years, through the advancement of genome-wide association studies, second-generation gene sequencing technology, and their application in AD genetic research, more genetic loci associated with the risk for AD have been discovered, including , and , which provides new ideas for the etiology and treatment of AD. This review summarizes three early-onset AD causative genes (, , and ) and some late-onset AD susceptibility genes and their mutation sites newly discovered in China, and briefly introduces the potential mechanisms of these genetic susceptibilities in the pathogenesis of AD, which would help in understanding the genetic mechanisms underlying this devastating disease.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Asian People; China; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Mutation; Presenilin-1; Presenilin-2
PubMed: 32235595
DOI: 10.3390/ijms21072381 -
Seizure Oct 2018Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and represents the most common form of dementia in the elderly. Mutations in genes encoding... (Review)
Review
Alzheimer's disease (AD) is a heterogeneous neurodegenerative disorder and represents the most common form of dementia in the elderly. Mutations in genes encoding presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP) are responsible for early-onset familial AD (EOFAD). Several pieces of evidence report that patients with rare autosomal dominant forms of AD carry a significant risk to develop seizures. However, the molecular mechanisms linking epilepsy and AD are needed to be clarified: the pathophysiology of seizures in AD may be related to an increased production of amyloid-β (Aβ) peptide or structural alterations in neurons probably due to cerebrovascular changes, neurotransmitter or cytoskeletal dysfunctions. Seizures have traditionally been related to neuronal loss in the late stages of AD as a consequence of neurodegeneration, however, recent studies indicated that seizures may contribute to the emergence of AD symptoms in early stages of the disease, mainly in familial AD. So, a better understanding of possible common neural mechanisms might help to improve the clinical management of both conditions. This review aims to give a comprehensive overview and to analyze the association between epilepsy and EOFAD, focusing on possible overlapping pathological mechanisms.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Humans; Mutation; Presenilin-1; Presenilin-2; Seizures
PubMed: 30041064
DOI: 10.1016/j.seizure.2018.07.015 -
Journal of Alzheimer's Disease : JAD 2019The 'amyloid hypothesis' dominates Alzheimer's disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP) and presenilin-1...
The 'amyloid hypothesis' dominates Alzheimer's disease (AD) research but has failed to deliver effective therapies. Amyloid precursor protein (APP) and presenilin-1 (PSEN1) genetic mutations are undoubtedly pathogenic, albeit by unclear mechanisms. Conversely, high dose B-vitamins convincingly slow brain atrophy in a pre-stage state of sporadic AD. Here we suggest a link between sporadic and genetic AD: 1) Increased serum homocysteine, a marker of B-vitamin deficiencies, is a significant risk factor for sporadic AD. It also correlates with elevated levels of antichymotrypsin, a serine protease inhibitor. 2) Family members with codon 717 APP mutations and dementia have low serum vitamin B12 values. Overexpression of the APP domain coding for a Kunitz type serine protease inhibitor might explain this. 3) PSEN1 mutations disrupt lysosomal function due to reduced proteolytic activity. They also trap cobalamin (B12) within lysosomes, leading to intracellular deficiency of the vitamin. In summary, APP and PSEN1 mutations both confer a risk for reduced protease activity and B12 bio-availability. Comparably, sporadic AD features a constellation of increased protease inhibition and B-vitamin deficiencies, the central part of which is believed to be B12. These concordant observations in three disparate AD etiologies suggest a common neuropathogenic pathway. This hypothesis is evaluable in laboratory and clinical trials.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Genetic Predisposition to Disease; Humans; Models, Biological; Presenilin-1; Vitamin B 12
PubMed: 30814347
DOI: 10.3233/JAD-181007 -
Journal of Neuroinflammation Jan 2024Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a...
BACKGROUND
Widescale evidence points to the involvement of glia and immune pathways in the progression of Alzheimer's disease (AD). AD-associated iPSC-derived glial cells show a diverse range of AD-related phenotypic states encompassing cytokine/chemokine release, phagocytosis and morphological profiles, but to date studies are limited to cells derived from PSEN1, APOE and APP mutations or sporadic patients. The aim of the current study was to successfully differentiate iPSC-derived microglia and astrocytes from patients harbouring an AD-causative PSEN2 (N141I) mutation and characterise the inflammatory and morphological profile of these cells.
METHODS
iPSCs from three healthy control individuals and three familial AD patients harbouring a heterozygous PSEN2 (N141I) mutation were used to derive astrocytes and microglia-like cells and cell identity and morphology were characterised through immunofluorescent microscopy. Cellular characterisation involved the stimulation of these cells by LPS and Aβ and analysis of cytokine/chemokine release was conducted through ELISAs and multi-cytokine arrays. The phagocytic capacity of these cells was then indexed by the uptake of fluorescently-labelled fibrillar Aβ.
RESULTS
AD-derived astrocytes and microglia-like cells exhibited an atrophied and less complex morphological appearance than healthy controls. AD-derived astrocytes showed increased basal expression of GFAP, S100β and increased secretion and phagocytosis of Aβ while AD-derived microglia-like cells showed decreased IL-8 secretion compared to healthy controls. Upon immunological challenge AD-derived astrocytes and microglia-like cells showed exaggerated secretion of the pro-inflammatory IL-6, CXCL1, ICAM-1 and IL-8 from astrocytes and IL-18 and MIF from microglia.
CONCLUSION
Our study showed, for the first time, the differentiation and characterisation of iPSC-derived astrocytes and microglia-like cells harbouring a PSEN2 (N141I) mutation. PSEN2 (N141I)-mutant astrocytes and microglia-like cells presented with a 'primed' phenotype characterised by reduced morphological complexity, exaggerated pro-inflammatory cytokine secretion and altered Aβ production and phagocytosis.
Topics: Humans; Astrocytes; Microglia; Induced Pluripotent Stem Cells; Interleukin-8; Alzheimer Disease; Cytokines; Phenotype; Amyloid beta-Peptides; Presenilin-2
PubMed: 38178159
DOI: 10.1186/s12974-023-02951-2 -
Journal of Cellular and Molecular... Feb 2018The two presenilin-1 (PS1) and presenilin-2 (PS2) homologs are the catalytic core of the γ-secretase complex, which has a major role in cell fate decision and...
The two presenilin-1 (PS1) and presenilin-2 (PS2) homologs are the catalytic core of the γ-secretase complex, which has a major role in cell fate decision and Alzheimer's disease (AD) progression. Understanding the precise contribution of PS1- and PS2-dependent γ-secretases to the production of β-amyloid peptide (Aβ) from amyloid precursor protein (APP) remains an important challenge to design molecules efficiently modulating Aβ release without affecting the processing of other γ-secretase substrates. To that end, we studied PS1- and PS2-dependent substrate processing in murine cells lacking presenilins (PSs) (PS1KO, PS2KO or PS1-PS2 double-KO noted PSdKO) or stably re-expressing human PS1 or PS2 in an endogenous PS-null (PSdKO) background. We characterized the processing of APP and Notch on both endogenous and exogenous substrates, and we investigated the effect of pharmacological inhibitors targeting the PSs activity (DAPT and L-685,458). We found that murine PS1 γ-secretase plays a predominant role in APP and Notch processing when compared to murine PS2 γ-secretase. The inhibitors blocked more efficiently murine PS2- than murine PS1-dependent processing. Human PSs, especially human PS1, expression in a PS-null background efficiently restored APP and Notch processing. Strikingly, and contrary to the results obtained on murine PSs, pharmacological inhibitors appear to preferentially target human PS1- than human PS2-dependent γ-secretase activity.
Topics: Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Animals; Biocatalysis; Fibroblasts; Humans; Mice, Knockout; Presenilin-1; Presenilin-2; Receptors, Notch; Substrate Specificity
PubMed: 28994238
DOI: 10.1111/jcmm.13364 -
Proceedings of the National Academy of... Jan 2017
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Humans; Mutation; Presenilin-1; Presenilin-2
PubMed: 28082723
DOI: 10.1073/pnas.1619574114 -
Gene Jul 2014Alzheimer's disease (AD) is the most common form of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia in the elderly and represents an important and increasing clinical challenge in terms of diagnosis and treatment. Mutations in the genes encoding amyloid precursor protein (APP), presenilin 1 (PSEN1) and presenilin 2 (PSEN2) are responsible for early-onset autosomal dominant AD. The ε4 allele of the apolipoprotein E (APOE) gene has been recognized as a major genetic risk factor for the more common, complex, late-onset AD. Fibrillar deposits by phosphorylated tau are also a key pathological feature of AD. The retromer complex also has been reported to late-onset AD. More recently, genome-wide association studies (GWASs) identified putative novel candidate genes associated with late-onset AD. Lastly, several studies showed that circulating microRNAs (miRNAs) in the cerebrospinal fluid (CSF) and blood serum of AD patients can be used as biomarkers in AD diagnosis. This review addresses the advances and challenges in determining genetic and diagnostic markers for complex AD pathogenesis.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Protein Precursor; Animals; Apolipoproteins E; Genetic Markers; Genome-Wide Association Study; Humans; MicroRNAs; Multiprotein Complexes; Presenilins; Protein Binding; tau Proteins
PubMed: 24838203
DOI: 10.1016/j.gene.2014.05.031 -
Human Molecular Genetics Nov 2019The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the... (Review)
Review
The failure of recent clinical trials in Alzheimer's disease has highlighted the need for the development of a more complete understanding of the pathogenesis of the disorder and also a belief that therapies may only work if given very early in the disease process before overt symptoms occur. The rare, early onset forms of the disease are all caused by mutations which make amyloid deposition a more likely event. Here we discuss the recent data showing that, in contrast, much of the risk of late onset disease is encoded by loci involved in lipid metabolism and/or encoded by microglia. We discuss these finding and suggest that amyloid induced membrane damage may be a key factor in disease and also review the evidence that genome wide genetic analysis can substantially help in the prediction of those individuals at high risk of disease in the general population.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Apolipoproteins E; Brain; Epistasis, Genetic; Genetic Predisposition to Disease; Genome-Wide Association Study; Humans; Lipid Metabolism; Presenilin-1; Presenilin-2; Risk Factors; White People
PubMed: 31332445
DOI: 10.1093/hmg/ddz163 -
International Journal of Molecular... Sep 2022Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer's disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to... (Review)
Review
Presenilin-1 (PSEN1) has been verified as an important causative factor for early onset Alzheimer's disease (EOAD). PSEN1 is a part of γ-secretase, and in addition to amyloid precursor protein (APP) cleavage, it can also affect other processes, such as Notch signaling, β-cadherin processing, and calcium metabolism. Several motifs and residues have been identified in PSEN1, which may play a significant role in γ-secretase mechanisms, such as the WNF, GxGD, and PALP motifs. More than 300 mutations have been described in PSEN1; however, the clinical phenotypes related to these mutations may be diverse. In addition to classical EOAD, patients with PSEN1 mutations regularly present with atypical phenotypic symptoms, such as spasticity, seizures, and visual impairment. In vivo and in vitro studies were performed to verify the effect of PSEN1 mutations on EOAD. The pathogenic nature of PSEN1 mutations can be categorized according to the ACMG-AMP guidelines; however, some mutations could not be categorized because they were detected only in a single case, and their presence could not be confirmed in family members. Genetic modifiers, therefore, may play a critical role in the age of disease onset and clinical phenotypes of PSEN1 mutations. This review introduces the role of PSEN1 in γ-secretase, the clinical phenotypes related to its mutations, and possible significant residues of the protein.
Topics: Humans; Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Cadherins; Calcium; Mutation; Presenilin-1; Presenilin-2
PubMed: 36142879
DOI: 10.3390/ijms231810970 -
Neurotoxicity Research Dec 2020Alzheimer's disease (AD) is the most common cause of dementia. Mutations of presenilin (PSEN) genes that encode presenilin proteins have been found as the vital causal... (Review)
Review
Alzheimer's disease (AD) is the most common cause of dementia. Mutations of presenilin (PSEN) genes that encode presenilin proteins have been found as the vital causal factors for early-onset familial AD (FAD). AD pathological features such as memory loss, synaptic dysfunction, and formation of plaques have been successfully mimicked in the transgenic mouse models that coexpress FAD-related presenilin and amyloid precursor protein (APP) variants. γ-Secretase (GS) is an enzyme that plays roles in catalyzing intramembranous APP proteolysis to release pathogenic amyloid beta (Aβ). It has been found that presenilins can play a role as the GS's catalytic subunit. FAD-related mutations in presenilins can modify the site of GS cleavage in a way that can elevate the production of longer and highly fibrillogenic Aβ. Presenilins can interact with β-catenin to generate presenilin complexes. Aforesaid interactions have also been studied to observe the mutational and physiological activities in the catenin signal transduction pathway. Along with APP, GS can catalyze intramembrane proteolysis of various substrates that play a vital role in synaptic function. PSEN mutations can cause FAD with autosomal dominant inheritance and early onset of the disease. In this article, we have reviewed the current progress in the analysis of PSENs and the correlation of PSEN mutations and AD pathogenesis.
Topics: Alzheimer Disease; Animals; Humans; Mutation; Presenilin-1; Presenilin-2; Proteolysis; Signal Transduction
PubMed: 32556937
DOI: 10.1007/s12640-020-00232-x