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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 -
Brain : a Journal of Neurology Jun 2023The risk of developing Alzheimer's disease is mediated by a combination of genetics and environmental factors, such as stress, sleep abnormalities and traumatic brain...
The risk of developing Alzheimer's disease is mediated by a combination of genetics and environmental factors, such as stress, sleep abnormalities and traumatic brain injury. Women are at a higher risk of developing Alzheimer's disease than men, even when controlling for differences in lifespan. Women are also more likely to report high levels of stress than men. Sex differences in response to stress may play a role in the increased risk of Alzheimer's disease in women. In this study, we use in vivo microdialysis to measure levels of Aβ in response to acute stress in male and female mice. We show that Aβ levels are altered differently between female and male mice (APP/PS1 and wild-type) in response to stress, with females showing significantly increased levels of Aβ while most males do not show a significant change. This response is mediated through β-arrestin involvement in Corticotrophin Releasing Factor receptor signalling pathway differences in male and female mice as male mice lacking β-arrestin show increase in Aβ in response to stress similar to females.
Topics: Mice; Female; Male; Animals; Alzheimer Disease; Amyloid beta-Protein Precursor; Mice, Transgenic; Disease Models, Animal; Amyloid beta-Peptides; beta-Arrestins; Presenilin-1
PubMed: 37127299
DOI: 10.1093/brain/awad052 -
Current Gene Therapy 2021Alzheimer's disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic factors.... (Review)
Review
Alzheimer's disease (AD) is the most common form of dementia in the elderly and this complex disorder is associated with environmental as well as genetic factors. Early-onset AD (EOAD) and late-onset AD (LOAD, more common) are major identified types of AD. The genetics of EOAD is extensively understood, with three gene variants such as APP, PSEN1, and PSEN2 leading to the disease. Some common alleles, including APOE, are effectively associated with LOAD identified, but the genetics of LOAD is not clear to date. It has been accounted that about 5-10% of EOAD patients can be explained through mutations in the three familiar genes of EOAD. The APOE ε4 allele augmented the severity of EOAD risk in carriers, and the APOE ε4 allele was considered as a hallmark of EOAD. A great number of EOAD patients, who are not genetically explained, indicate that it is not possible to identify disease-triggering genes yet. Although several genes have been identified by using the technology of next-generation sequencing in EOAD families, including SORL1, TYROBP, and NOTCH3. A number of TYROBP variants are identified through exome sequencing in EOAD patients and these TYROBP variants may increase the pathogenesis of EOAD. The existence of the ε4 allele is responsible for increasing the severity of EOAD. However, several ε4 allele carriers propose the presence of other LOAD genetic as well as environmental risk factors that are not identified yet. It is urgent to find out missing genetics of EOAD and LOAD etiology to discover new potential genetic facets which will assist in understanding the pathological mechanism of AD. These investigations should contribute to developing a new therapeutic candidate for alleviating, reversing and preventing AD. This article, based on current knowledge, represents the overview of the susceptible genes of EOAD, and LOAD. Next, we represent the probable molecular mechanism that might elucidate the genetic etiology of AD and highlight the role of massively parallel sequencing technologies for novel gene discoveries.
Topics: Adaptor Proteins, Signal Transducing; Aged; Alleles; Alzheimer Disease; Amyloid beta-Protein Precursor; Apolipoproteins E; Disease Progression; Genetic Variation; Humans; LDL-Receptor Related Proteins; Membrane Proteins; Membrane Transport Proteins; Mutation; Presenilin-1; Presenilin-2
PubMed: 33231156
DOI: 10.2174/1566523220666201123112822 -
Acta Biochimica Et Biophysica Sinica Jan 2020Dementia, a devastating neurological disorder commonly found in the elderly, is characterized by severe cognitive and memory impairment. Ample clinical and... (Review)
Review
Dementia, a devastating neurological disorder commonly found in the elderly, is characterized by severe cognitive and memory impairment. Ample clinical and epidemiological evidence has depicted a close association between dementia and heart failure. While cerebral blood under perfusion and neurohormonal activation due to the dampened cardiac pump function contribute to the loss of nutrient supply and neuronal injury, Alzheimer's disease (AD), the most common type of dementia, also provokes cardiovascular function impairment, in particular impairment of diastolic function. Aggregation of amyloid-β proteins and mutations of Presenilin (PSEN) genes are believed to participate in the pathological changes in the heart although it is still debatable with regards to the pathological cue of cardiac anomalies in AD process. In consequence, reduced cerebral blood flow triggered by cardiac dysfunction further deteriorates vascular dementia and AD pathology. Patients with atrial fibrillation, heart failure, and other cardiac anomalies are at a higher risk for cognitive decline and dementia. Conclusion: Due to the increased incidence of dementia and cardiovascular diseases, the coexistence of the two will cause more threat to public health, warranting much more attention. Here, we will update recent reports on dementia, AD, and cardiovascular diseases and discuss the causal relationship between dementia and heart dysfunction.
Topics: Adult; Aged; Aged, 80 and over; Aging; Alzheimer Disease; Amyloid beta-Peptides; Animals; Cardiovascular Diseases; Comorbidity; Disease Models, Animal; Humans; Mice; Middle Aged; Mutation; Presenilins; Risk Factors
PubMed: 31897470
DOI: 10.1093/abbs/gmz115 -
Current Drug Targets 2021In neurodegenerative disorders, there is a progressive degeneration of the body, leading to the death of nerve cells. In this state, a patient gets affected day by day... (Review)
Review
In neurodegenerative disorders, there is a progressive degeneration of the body, leading to the death of nerve cells. In this state, a patient gets affected day by day with mental weakness, dementia, and ataxia. Alzheimer's disease (AD) is the most common irreversible neurodegenerative brain disorder mainly affecting people over the age of 65. Many types of research suggest that the main culprit for AD is the aggregated form of a (39-43) amino acid peptide called amyloid beta. Amyloid beta (Aβ) is generated by the action of beta-secretase and gamma-secretase on the larger glycoprotein. Gamma (γ) secretase is an intra-membrane protease complex that cleaves the single-- pass transmembrane protein, the amyloid precursor protein, and Notch. The γ-secretase complex contains presenilin, presenilin enhancer-2, anterior pharynx defective-1, and nicastrin. Any mutation in presenilin-1 or the cleavage of amyloid precursor protein by γ-secretase directly or indirectly is associated with AD. Therefore, the prevention of this enzyme is one of the solutions for AD. In this article, we discuss the γ-secretase complex and its inhibitors that can contribute to the prevention of AD.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Humans; Presenilin-1
PubMed: 33390127
DOI: 10.2174/1389450121999201230203709 -
Journal of Alzheimer's Disease : JAD 2021Transgenic mouse models serve a better understanding of Alzheimer's disease (AD) pathogenesis and its consequences on neuronal function. Well-known and broadly used AD... (Review)
Review
Transgenic mouse models serve a better understanding of Alzheimer's disease (AD) pathogenesis and its consequences on neuronal function. Well-known and broadly used AD models are APPswe/PS1dE9 mice, which are able to reproduce features of amyloid-β (Aβ) plaque formations as well as neuronal dysfunction as reflected in electrophysiological recordings of neuronal hyperexcitability. The most prominent findings include abnormal synaptic function and synaptic reorganization as well as changes in membrane threshold and spontaneous neuronal firing activities leading to generalized excitation-inhibition imbalances in larger neuronal circuits and networks. Importantly, these findings in APPswe/PS1dE9 mice are at least partly consistent with results of electrophysiological studies in humans with sporadic AD. This underscores the potential to transfer mechanistic insights into amyloid related neuronal dysfunction from animal models to humans. This is of high relevance for targeted downstream interventions into neuronal hyperexcitability, for example based on repurposing of existing antiepileptic drugs, as well as the use of combinations of imaging and electrophysiological readouts to monitor effects of upstream interventions into amyloid build-up and processing on neuronal function in animal models and human studies. This article gives an overview on the pathogenic and methodological basis for recording of neuronal hyperexcitability in AD mouse models and on key findings in APPswe/PS1dE9 mice. We point at several instances to the translational perspective into clinical intervention and observation studies in humans. We particularly focus on bi-directional relations between hyperexcitability and cerebral amyloidosis, including build-up as well as clearance of amyloid, possibly related to sleep and so called glymphatic system function.
Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Mice; Neurons; Presenilin-1
PubMed: 33843674
DOI: 10.3233/JAD-201540 -
Advances in Experimental Medicine and... 2020Alzheimer's disease (AD) is the most common type of dementia caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain. In addition to... (Review)
Review
Alzheimer's disease (AD) is the most common type of dementia caused by severe neurodegeneration in the hippocampus and neocortical regions of the brain. In addition to neurodegeneration, AD brains contain high levels of amyloid plaques (APs) and neurofibrillary tangles (NFTs) which are used as neuropathological hallmarks of the disorder. Despite intense research efforts, the mechanism(s) of the AD neurodegeneration are imperfectly understood, hampering efforts for the development of efficient therapeutics. Furthermore, failure of clinical trials to benefit AD patients suggests that AD hallmarks are poor therapeutic targets and supports the suggestion that these hallmarks are sequelae of neurodegeneration. Although genetic evidence seem to support the amyloid theory of AD, additional empirical observations and experimental data are inconsistent with the amyloid/Aβ theories of AD [Robakis and Neve (1998), TINS vol. 21 pp.15-19; Robakis (2011) NBA vol. 32, pp 372-379]. This possibility is further supported by data that amyloid plaques and neurofibrillary tangles are found in a number of distinct neurodegenerative disorders and that animal models expressing high levels of AD pathological structures show little neuronal loss. Furthermore, genetic evidence linking genetic loci to disease reveal little about the molecular mechanisms involved. Mutants of APP, PS1, and PS2 cause familial AD (FAD) suggesting these mutants can be used as models to study mechanisms of neurodegeneration. Recent reports show that the ability of efnB1 and BDNF (factors) to rescue neurons from excitotoxicity depends on PS1 but is independent of γ-secretase. Interestingly, PS1 FAD mutations block the ability of factors to protect neurons from toxicity suggesting that FAD mutants may increase neuronal death by blocking neuroprotective activities of brain neurotrophins. Other reports also suggest that proteins involved in FAD have Aβ-/γ-secretase-independent functions that can play important roles in AD. Furthermore, non-neuronal brain cells like microglia are implicated in AD pathology.
Topics: Alzheimer Disease; Amyloid Precursor Protein Secretases; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Brain; Clinical Trials as Topic; Disease Models, Animal; Humans; Plaque, Amyloid; Presenilin-1; Presenilin-2; Treatment Failure
PubMed: 32468473
DOI: 10.1007/978-3-030-32633-3_23 -
CNS Neuroscience & Therapeutics Feb 2024Alzheimer's disease (AD) is the most common form of dementia. Depression is one of the most critical psychiatric complications of AD, and 20%-30% of patients with AD...
INTRODUCTION
Alzheimer's disease (AD) is the most common form of dementia. Depression is one of the most critical psychiatric complications of AD, and 20%-30% of patients with AD experience symptoms of depression. Phospho-glycogen synthase kinase-3 beta (GSK3β) is known to be associated with AD and depression. Furthermore, the role of disheveled (DVL) is known to regulate GSK3β. Moreover, presenilin-2 (PS2) and DVL have cross-talk with each other. Also, it is widely hypothesized that stress leads to hypersecretion of cortisol and is thus associated with depression. Dickkopf WNT signaling pathway inhibitor-1 (DKK-1) is a crucial factor regulating depression and both amyloid beta (Aβ) and phosphorylation of tau are widely known as a biomarker of AD.
METHODS
To investigate the relationship between AD and depression, and possible pathways connecting the two diseases, we examined memory function and depression-related behavior test results in PS2 knock-in AD mice (PS2 MT). Next, we confirmed that there are relationships between DVL, depression, and cognitive disease through the comparative toxicogenomics database (https://ctdbase.org) and STRING (https://string-db.org) database.
RESULTS
PS2 knock-in mice showed much more severe memory impairment and depression than PS2 wild-type mice (PS2 WT). In AD-related behavioral experiments, PS2 MT mice showed more memory dysfunction compared with PS2 WT group mice. Moreover, Aβ and phosphorylation of tau showed higher expression in PS2 MT mice than in PS2 WT mice. Depression-related behavioral tests showed that PS2 MT mice exhibited more depressive behaviors than PS2 WT mice. Furthermore, both higher cortisol levels and higher expression of DKK-1 were found in PS2 MT mice relative to PS2 WT mice. The results indicated that there is a relationship between DVL and the release of AD-related mediators and expression of the depression-related glucocorticoid receptor and DKK-1. In the PS2 knock-in group, DVL was significantly decreased compared with the PS2 WT group.
CONCLUSION
Depression increases the risk of developing AD and other forms of dementia. Recent evidence indicates that depression symptoms could trigger changes in memory and thinking over time. However, it is recognized that there are no drugs to facilitate a full recovery for both AD and depression. However, our results suggest that AD and depression could be associated, and DVL could be a significant target for the association between AD and depression.
Topics: Animals; Mice; Alzheimer Disease; Amyloid beta-Peptides; Dishevelled Proteins; Down-Regulation; Glycogen Synthase Kinase 3 beta; Hydrocortisone; Mice, Transgenic; Presenilin-1; Presenilin-2
PubMed: 37501340
DOI: 10.1111/cns.14370