Alzheimers disease ad is a progressive neurodegenerative disease characterised by extracellular amyloid. Apolipoprotein e4 domain interaction mediates detrimental. Review article relationship between apolipoprotein e gene. To investigate associations between cerebrospinal fluid csf and plasma apoa1 levels and clinical progression toward ad in nondemented elderly. Clu, cr1 and picalm genes associate with alzheimersrelated.
Alzheimers disease ad is highly heritable and recent studies have. Earlier age at menopause spontaneous or surgical is associated with an enhanced risk of developing alzheimers disease. Apolipoprotein e4 and sirt1 interaction in alzheimerazs disease. Longitudinal analysis of the effect of apolipoprotein e. Meaning sexspecific treatments for cognitive decline and. Mechanism explains link between apolipoprotein e and alzheimers disease date. Clinical and pathological correlates of apolipoprotein e.
The alzheimers disease risk factors apolipoprotein e and trem2 are linked in a receptor signaling pathway charlotte jendresen1, vibeke arskog1, michael r. Apoe is the strongest risk gene for sporadic alzheimers disease ad so far. Apolipoprotein e genotype and sex risk factors for alzheimer disease. Pp, there is little information available regarding its in vivo clearance. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Human apom cdna 734 base pairs encodes 188amino acid residuelong protein.
Common pathological mechanisms and risk factors for alzheimers disease and type2 diabetes. Low plasma apoa1 concentrations are associated with alzheimers disease ad. The influence of apolipoprotein e genotype on regional. Drug interaction study with a potential alzheimers disease. Apolipoprotein e and its receptors in alzheimers disease. Listing a study does not mean it has been evaluated by the u. A new study finds a link between low plasma levels of apolipoprotein e and the risk for alzheimer s and allcause dementia, but not with cerebrovascular disease, independent of apoe risk genotype. Computational design of apolipoprotein e4 inhibitors for. This protein plays an important role in cholesterol transport to the neurons. According to estimates, people carrying one copy of apoe4 have a 2 to 3fold higher risk of alzheimers than those with none, and people with two copies of apoe4 have 8. Apolipoprotein m lipids in health and disease full text.
It is implicated in alzheimers disease and cardiovascular disease. The modelpredicted cumulative incidence of alzheimer disease ad and rate of cognitive decline based on the entire cohort are illustrated for hypothetical average apoe. Data are drawn from 5447 participants of the whitehall ii study, health behaviors were assessed in 19971999 mean age 55. Here, we investigated whether human apoe mediates signal transduction through human and murine trem2 and sought to identify a trem2binding domain in human apoe. To investigate cell signaling through trem2, a cell line was used which expressed an. The extent to which the effect of risk factors on cognitive ageing is dependent on apoe. However, earlyonset alzheimers disease has a weaker relationship with. The complex role of apolipoprotein e in alzheimers disease.
Physical activity is predictive of better cognitive performance and lower risk of alzheimer s disease ad. A mechanism for the neuroprotective effect of apolipoprotein. Alzheimers disease ad, the most common form of dementia, is a neurodegenerative disorder characterized by the appearance of extracellular senile plaques and intracellular neurofibrillary tangles, accompanying a progressive loss of memory, thinking and language skills, and behavioral changes. Apoe4 assumes a pathological conformation through an intramolecular interaction mediated by arg61 in the aminoterminal domain and glu255 in the carboxylterminal domain, referred to as apoe4 domain interaction. Apoe polymorphic alleles are the main genetic determinants of alzheimer disease ad risk. Apolipoprotein e is a protein involved in the metabolism of fats in the body. Scientists have discovered a previously unknown mechanism by which.
Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein e. A new study finds a link between low plasma levels of apolipoprotein e and the risk for alzheimers and allcause dementia, but not with cerebrovascular disease, independent of. We investigated the associations of senile plaques sp and neurofibrillary tangles nft with the proposed risk genes and apoe, in the tampere autopsy study. Although 14 percent of the worlds population carries this variant, many will not develop the disease. The apolipoprotein e gene apoe is a susceptibility gene for ad with the e4 allele.
The vast majority of alzheimers disease ad cases are lateonset and their development is probably influenced by both genetic and environmental risk factors. One of the primary genetic risk factors for alzheimers disease ad is the presence. The most signifi cant risk factor for nonfamilial ad is the presence of the e4 isoform of the cholesterol transporter apolipoprotein e apoe. Apolipoprotein m apom is a 26kda protein that is mainly associated with highdensity lipoprotein hdl in human plasma, with a small proportion present in triglyceriderich lipoproteins tgrlp and lowdensity lipoproteins ldl. Apolipoprotein e apoe is a protein involved in the metabolism of fats in the body. Solapalmitine, isodesacetyluvaricin, and budmunchiamine l5. The prevalence of alzheimers disease is higher in women than in men. It has been established that e4 confers risk to alzheimers disease, the most common form of neurodegenerative disease. Studies that have examined the link between estrogen replacement therapy, alzheimer s disease and the e4 allele of apoe are inconclusive. To identify the association between apoe gene polymorphism and the risk of pd, we performed. Drug interaction study with a potential alzheimers disease compound the safety and scientific validity of this study is the responsibility of the study sponsor and investigators.
Therapeutic approaches targeting apolipoprotein e function in. Apolipoprotein a1 in cerebrospinal fluid and plasma and. Apolipoprotein e apo e is the major genetic risk factor in the causation of alzheimer s disease ad. Alzheimers disease, apolipoprotein e and hormone replacement therapy. Apolipoprotein e, receptors, and modulation of alzheimers. Modification of the relationship of the apolipoprotein e. Abstract apolipoprotein e apoe has been found in association with several differents types of systemic and cerebral amyloid deposits and the presence of the e4 allele constitutes a risk factor for alzheimers disease. Apolipoprotein e apoe is a major cholesterol carrier that supports lipid transport and injury repair in the brain. A strong genetic risk factor for lateonset ad is the presence of the. Apolipoprotein e4 apoe4, the most prevalent genetic risk factor of ad, is expressed in more than half of ad patients and is thus an important possible ad therapeutic target. Bloodbrain barrier anatomy, including its tight junction proteins and neurovascular unit, will be discussed. To investigate cell signaling through trem2, a cell line was used which expressed an nfatinducible. Mechanism explains link between apolipoprotein e and. Apolipoprotein e4 apoe4, the most prevalent genetic risk factor of ad, is expressed in more than half of ad patients and is thus an important.
Genomewide metaanalysis identifies new loci and functional. Focus on inflammation current alzheimer research the impact of angiotensinconverting enzyme gene on behavioral and psychological symptoms of dementia in alzheimers disease. In both sexes, carriers of the apoe4 allele harbor a dosedependent increase in risk of ad development, compared with those with the neutral apoe3 or protective apoe2. The alzheimers disease risk factors apolipoprotein e and. Apoe belongs to a family of fatbinding proteins called apolipoproteins. The hypothesis holds that an amyloidrelated mechanism that prunes. In this study we utilize virtual screening of the world s largest traditional chinese medicine tcm database and investigate potential compounds for the inhibition of apoe. The strongest genetic risk factor for lateonset alzheimer s disease is the e4 variant of apolipoprotein e apoe, meaning that two of the amino acid building blocks of the protein are different. Apolipoprotein e influences amyloidbeta clearance from the. Apolipoprotein apo e4 is the major genetic risk factor for lateonset alzheimer disease ad. The pathophysiologic basis of this genetic influence is unknown.
The apoe4 allele of apolipoprotein e apoe is the greatest genetic risk factor for alzheimers disease ad compared to apoe2 and apoe3. Although several studies have shown significant differences in ad pathology among. About 70% of the risk is believed to be inherited from a persons parents, with many genes. Physical activity is predictive of better cognitive performance and lower risk of alzheimers disease ad. Little is known about apoa1 levels in the predementia stages of ad. The objective of this study is to examine whether apoe. Alzheimers disease ad, also referred to simply as alzheimers, is a chronic. The apolipoprotein e apoe gene, with its 3 common isoforms e2, e3 and e4, was such a candidate risk gene in parkinsons disease explored by many casecontrol studies, but the conclusion still remains contradictory and inconclusive. Isisapoarx results in potent, dosedependent, selective reductions of plasma lpa. Research article computational design of apolipoprotein e4. The safety and tolerability support continued clinical development of isisapoarx as a potential therapeutic drug to reduce the risk of cardiovascular disease and calcific aortic. Alzheimers disease ad is the most common neurodegenerative disease. Alzheimers disease ad is a neurodegenerative disorder whose exact causes are still unknown. We investigated the associations of senile plaques sp and neurofibrillary tangles nft with the proposed risk genes and apoe, in the tampere autopsy.
Jun, 2008 mechanism explains link between apolipoprotein e and alzheimer s disease date. The e4 allele of apoe is recognized as a major risk factor for. Apolipoprotein e increases the fibrillogenic potential of. A mechanism by which apoe4 confers risk to alzheimers. Apolipoprotein e apoe is a major cholesterol carrier that supports lipid. Sep 19, 2016 apolipoprotein e apoe plays a crucial role in the homeostatic control of lipids in both the periphery and the central nervous system cns. Alzheimers disease, apolipoprotein e and hormone replacement. We also discuss a betadependent and a betaindependent mechanisms that link apo e4 status with ad risk, and consider how to design effective strategies for ad therapy by targeting apo e. The safety and tolerability support continued clinical development of isisapoarx as a potential therapeutic drug to reduce the risk of cardiovascular disease and calcific aortic valve stenosis in patients with elevated lpa concentration. Guojun bu and colleagues describe the pathogenic links between apoe4 and. To examine changes in cognitive function in elderly people as a function of the apoe. Apolipoprotein e apoe plays a crucial role in the homeostatic control of lipids in both the periphery and the central nervous system cns. However, the mechanisms underlying how apoe contributes to.
The strongest genetic risk factor for lateonset alzheimers disease is the e4 variant of apolipoprotein e apoe, meaning that two of the amino acid building blocks of the protein are different. The vast majority of alzheimers disease ad cases are lateonset and their development is likely influenced by both genetic and environmental risk factors. Savage 1,48, kyoko watanabe1, julien bryois3, dylan m. Triggering receptor expressed on myeloid cells 2 trem2 and apolipoprotein e apoe are genetically linked to alzheimers disease. In the circulation, it is present as part of several classes of lipoprotein particles, including chylomicron remnants, vldl, idl, and some hdl apoe interacts significantly with the lowdensity lipoprotein receptor, which is essential for the normal processing of triglycerideric. In humans, apoe exists in three different isoforms. Apolipoprotein e and the neuropathology of dementia nejm.
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