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International Journal of Molecular... Feb 2024In this narrative review, we delved into the intricate interplay between alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies... (Review)
Review
In this narrative review, we delved into the intricate interplay between alleles (typically associated with Alzheimer's disease-AD) and alpha-synucleinopathies (aS-pathies), involving Parkinson's disease (PD), Parkinson's disease dementia (PDD), dementia with Lewy bodies (DLB), and multiple-system atrophy (MSA). First, in-vitro, animal, and human-based data on the exacerbating effect of on LB pathology were summarized. We found robust evidence that carriage constitutes a risk factor for PDD-APOE2, and APOE3 may not alter the risk of developing PDD. We confirmed that copies confer an increased hazard towards DLB, as well. Again and appear unrelated to the risk of conversion. Of note, in individuals with DLB , carriage appears to be intermediately prevalent between AD and PDD-PD (AD > DLB > PDD > PD). Less consistency existed when it came to PD; -PD associations tended to be markedly modified by ethnicity. Finally, we failed to establish an association between the gene and MSA. Phenotypic associations (age of disease onset, survival, cognitive-neuropsychiatric- motor-, and sleep-related manifestations) between alleles, and each of the aforementioned conditions were also outlined. Finally, a synopsis of literature gaps was provided followed by suggestions for future research.
Topics: Humans; Alzheimer Disease; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Dementia; Lewy Body Disease; Parkinson Disease; Synucleinopathies
PubMed: 38339074
DOI: 10.3390/ijms25031795 -
Angewandte Chemie (International Ed. in... Jun 2023Apolipoprotein E (ApoE)'s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor...
Apolipoprotein E (ApoE)'s ϵ4 alle is the most important genetic risk factor for late onset Alzheimer's Disease (AD). Cell-surface heparan sulfate (HS) is a cofactor for ApoE/LRP1 interaction and the prion-like spread of tau pathology between cells. 3-O-sulfo (3-O-S) modification of HS has been linked to AD through its interaction with tau, and enhanced levels of 3-O-sulfated HS and 3-O-sulfotransferases in the AD brain. In this study, we characterized ApoE/HS interactions in wildtype ApoE3, AD-linked ApoE4, and AD-protective ApoE2 and ApoE3-Christchurch. Glycan microarray and SPR assays revealed that all ApoE isoforms recognized 3-O-S. NMR titration localized ApoE/3-O-S binding to the vicinity of the canonical HS binding motif. In cells, the knockout of HS3ST1-a major 3-O sulfotransferase-reduced cell surface binding and uptake of ApoE. 3-O-S is thus recognized by both tau and ApoE, suggesting that the interplay between 3-O-sulfated HS, tau and ApoE isoforms may modulate AD risk.
Topics: Humans; Alzheimer Disease; Apolipoprotein E3; Apolipoproteins E; Heparitin Sulfate; Protein Isoforms
PubMed: 37014788
DOI: 10.1002/anie.202212636 -
ELife May 2023Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we...
Mitochondria influence cellular function through both cell-autonomous and non-cell autonomous mechanisms, such as production of paracrine and endocrine factors. Here, we demonstrate that mitochondrial regulation of the secretome is more extensive than previously appreciated, as both genetic and pharmacological disruption of the electron transport chain caused upregulation of the Alzheimer's disease risk factor apolipoprotein E (APOE) and other secretome components. Indirect disruption of the electron transport chain by gene editing of SLC25A mitochondrial membrane transporters as well as direct genetic and pharmacological disruption of either complexes I, III, or the copper-containing complex IV of the electron transport chain elicited upregulation of APOE transcript, protein, and secretion, up to 49-fold. These APOE phenotypes were robustly expressed in diverse cell types and iPSC-derived human astrocytes as part of an inflammatory gene expression program. Moreover, age- and genotype-dependent decline in brain levels of respiratory complex I preceded an increase in APOE in the 5xFAD mouse model. We propose that mitochondria act as novel upstream regulators of APOE-dependent cellular processes in health and disease.
Topics: Animals; Humans; Mice; Apolipoprotein E4; Apolipoproteins E; Astrocytes; Genotype; Mitochondria
PubMed: 37171075
DOI: 10.7554/eLife.85779 -
Trends in Neurosciences Sep 2016Alzheimer disease (AD) research has mainly focused on neurodegenerative processes associated with the classic neuropathologic markers of senile plaques and... (Review)
Review
Alzheimer disease (AD) research has mainly focused on neurodegenerative processes associated with the classic neuropathologic markers of senile plaques and neurofibrillary tangles. Additionally, cerebrovascular contributions to dementia are increasingly recognized, particularly from cerebral small vessel disease (SVD). Remarkably, in AD brains, the apolipoprotein E (ApoE) ɛ4 allele shows male excess for cerebral microbleeds (CMBs), a marker of SVD, which is opposite to the female excess of plaques and tangles. Mouse transgenic models add further complexities to sex-ApoE ɛ4 allele interactions, with female excess of both CMBs and brain amyloid. We conclude that brain aging and AD pathogenesis cannot be understood in humans without addressing major gaps in the extent of sex differences in cerebrovascular pathology.
Topics: Aging; Alzheimer Disease; Animals; Apolipoproteins E; Brain; Humans; Peptide Fragments; Reactive Oxygen Species; Sex Characteristics
PubMed: 27546867
DOI: 10.1016/j.tins.2016.07.002 -
Journal of Clinical Neuroscience :... Aug 2015We performed an updated meta-analysis to obtain a more precise estimation of the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility to... (Meta-Analysis)
Meta-Analysis Review
We performed an updated meta-analysis to obtain a more precise estimation of the relationship between apolipoprotein E (ApoE) gene polymorphism and susceptibility to depression, as previous reports have been inconsistent. Twenty studies with 2286 depression patients and 3845 controls were included. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to assess the association between ApoE gene polymorphism and depression using a random effects model. Results showed a significant association between ApoE gene polymorphism and susceptibility to depression in the overall population (ε2/ε3 genotype versus ε3/ε3: OR 0.76, 95% CI 0.59-0.99). Subgroup analyses indicated an association in the Caucasian population (ε2 allele versus ε3: OR 0.75, 95% CI 0.58-0.97) as well as in late-life depression (LLD) patients (ε3/ε4 genotype versus ε3/ε3: OR 1.34, 95% CI 1.07-1.68, and ε4 allele versus ε3: OR 1.30, 95% CI 1.06-1.59). We concluded that the ε2/ε3 genotype likely provided a protective effect against depression in the overall population and the ε2 allele acted as a protective factor for depression in the Caucasian population while the ε4 allele and ε3/ε4 genotype were associated with an increased risk of depression in the LLD subjects.
Topics: Alleles; Apolipoproteins E; Depression; Genotype; Humans; Polymorphism, Genetic
PubMed: 25979253
DOI: 10.1016/j.jocn.2015.02.012 -
Archives of Oral Biology Feb 2019The association between cardiovascular and periodontal diseases is characterized by chronic inflammatory processes, with a high prevalence worldwide and complex... (Review)
Review
The association between cardiovascular and periodontal diseases is characterized by chronic inflammatory processes, with a high prevalence worldwide and complex genetic-environment interactions. Although apolipoprotein E4 (ApoE4), one of the isoforms coded by a polymorphic APOE gene, has been widely recognized as a risk factor for cardiovascular diseases and as an immunoinflammatory factor, less is known regarding how ApoE4 affects atherosclerosis in periodontitis patients. The aim of this review was to investigate the potential underlying mechanisms related to APOE4 that could increase the risk of periodontal disease and, ultimately, of atherosclerosis. There have only been a few studies addressing apoE polymorphisms in patients with chronic periodontitis. To date, no studies have been performed that have assessed how ApoE4 affects atherosclerotic disease in chronic periodontitis patients. Although clinical studies are warranted, experimental studies have consistently documented the presence of periodontal pathogens, which are usually found in the oral cavity and saliva, in the atherosclerotic plaques of ApoE-deficient mice. In addition, in this review, the potential role of the APOE4 allele as an example of antagonistic pleiotropy during human evolution and its relation to oral health is discussed.
Topics: Animals; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Atherosclerosis; Cardiovascular Diseases; Genetic Pleiotropy; Humans; Inflammation; Mice; Microbiota; Mouth; Periodontal Diseases; Polymorphism, Genetic; Protein Isoforms; Risk Factors
PubMed: 30503976
DOI: 10.1016/j.archoralbio.2018.11.009 -
Journal of Alzheimer's Disease : JAD 2023Mitochondria can trigger Alzheimer's disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE; apoE) is not well known.
BACKGROUND
Mitochondria can trigger Alzheimer's disease (AD)-associated molecular phenomena, but how mitochondria impact apolipoprotein E (APOE; apoE) is not well known.
OBJECTIVE
Consider whether and how mitochondrial biology influences APOE and apoE biology.
METHODS
We measured APOE expression in human SH-SY5Y neuronal cells with different forms of mitochondrial dysfunction including total, chronic mitochondrial DNA (mtDNA) depletion (ρ0 cells); acute, partial mtDNA depletion; and toxin-induced mitochondrial dysfunction. We further assessed intracellular and secreted apoE protein levels in the ρ0 cells and interrogated the impact of transcription factors and stress signaling pathways known to influence APOE expression.
RESULTS
SH-SY5Y ρ0 cells exhibited a 65-fold increase in APOE mRNA, an 8-fold increase in secreted apoE protein, and increased intracellular apoE protein. Other models of primary mitochondrial dysfunction including partial mtDNA-depletion, toxin-induced respiratory chain inhibition, and chemical-induced manipulations of the mitochondrial membrane potential similarly increased SH-SY5Y cell APOE mRNA. We explored potential mediators and found in the ρ0 cells knock-down of the C/EBPα and NFE2L2 (Nrf2) transcription factors reduced APOE mRNA. The activity of two mitogen-activated protein kinases, JNK and ERK, also strongly influenced ρ0 cell APOE mRNA levels.
CONCLUSION
Primary mitochondrial dysfunction either directly or indirectly activates APOE expression in a neuronal cell model by altering transcription factors and stress signaling pathways. These studies demonstrate mitochondrial biology can influence the biology of the APOE gene and apoE protein, which are implicated in AD.
Topics: Humans; Neuroblastoma; Mitochondria; DNA, Mitochondrial; Apolipoproteins E; Transcription Factors; Alzheimer Disease; RNA, Messenger; Biology; Cell Line, Tumor
PubMed: 36776072
DOI: 10.3233/JAD-221177 -
Acta Clinica Croatica Dec 2021Apolipoprotein E (APOE) plays an important role in lipid metabolism and is a proven risk factor for development of dementia and other neurodegenerative diseases. The aim...
Apolipoprotein E (APOE) plays an important role in lipid metabolism and is a proven risk factor for development of dementia and other neurodegenerative diseases. The aim of the study was to determine the possible connection between particular APOE alleles, blood lipid profile and different types of epilepsy in children. Alleles of the APOE gene, blood cholesterol (total, high-density lipoprotein and low-density lipoprotein (LDL) cholesterol, and triglyceride levels were analyzed in blood samples of 111 children with epilepsy and 118 age- and sex-matched children without epilepsy. Distribution of APOE genotypes was the same in children of both groups. Significantly increased levels of total cholesterol and LDL cholesterol were found in control group (Z=3.49 and 3.52 respectively, p<0.01). No statistically significant difference was found between the genotypes of children with idiopathic and symptomatic epilepsy (χ=1.96; df=2; p>0.05). There were statistically significant differences in the levels of total cholesterol (Z=2.09; p<0.05) and LDL cholesterol (Z=2.05; p<0.05) according to the type of epilepsy in favor of symptomatic epilepsy. The study confirmed that there was no connection between APOE and type of epilepsy in children and showed the children with epilepsy to have lower total cholesterol and LDL cholesterol levels. Interestingly, this also held true for children with idiopathic epilepsy compared to those with symptomatic condition.
Topics: Apolipoproteins E; Child; Cholesterol; Cholesterol, LDL; Epilepsy; Genotype; Humans; Triglycerides
PubMed: 35734486
DOI: 10.20471/acc.2021.60.04.05 -
Trends in Endocrinology and Metabolism:... Nov 2020Apolipoprotein E (ApoE) is a glycoprotein consisting of 299 amino acids, highly produced in the mammalian ovaries. The main function of the ApoE is to transport... (Review)
Review
Apolipoprotein E (ApoE) is a glycoprotein consisting of 299 amino acids, highly produced in the mammalian ovaries. The main function of the ApoE is to transport cholesterol from the peripheral tissues to be metabolized in the liver. In humans, the ApoE gene is polymorphic, with three alleles in a single chromosome-19 locus: APOE2, APOE3, and APOE4. ApoE has also been implicated in cholesterol transport within ovarian follicles to regulate steroidogenesis. Ovarian thecal and granulosa cell cholesterol uptake requires ApoE either by participating in the lipoprotein-receptor complex or lipid endocytosis. In this review, we summarize ApoE role on mammalian ovarian steroidogenesis and on human fertility and discuss recent findings of ApoE4 as an antagonistic pleiotropy gene under adverse environments.
Topics: Animals; Apolipoprotein E2; Apolipoprotein E3; Apolipoprotein E4; Apolipoproteins E; Chromosomes, Human, Pair 19; Female; Humans; Ovary
PubMed: 32684408
DOI: 10.1016/j.tem.2020.06.003 -
Journal of Medicinal Food Dec 2017Alzheimer's disease (AD) is an age-related neurodegenerative disorder of the brain. The presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), loss of... (Review)
Review
Alzheimer's disease (AD) is an age-related neurodegenerative disorder of the brain. The presence of amyloid-beta (Aβ) plaques, neurofibrillary tangles (NFTs), loss of neurons, synapses, and altered sensory perceptions, including memory loss, delineate AD. However, the cause of AD is not clearly known. Several genetic and nongenetic factors have been implicated in the disease. Of the genes, the ɛ4 allele of apolipoprotein E is the largest known genetic risk factor of AD. This review article focuses on the various genetic and other predisposing factors that account for AD, pathophysiology of the disease, and the mechanisms by which Aβ plaques and NFTs are formed and could affect AD brain. In addition, recent advances and current diagnostics available for AD patients are detailed. As oxidative stress has been implicated in the etiology of the disease, special emphasis is given for nutrition based antioxidant therapies and interventional strategies for reducing/treating AD.
Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Apolipoproteins E; Disease Progression; Humans; Oxidative Stress
PubMed: 29131706
DOI: 10.1089/jmf.2017.0093