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Apolipoprotein E And Alzheimer Disease Risk Mechanisms And Therapy Pdf

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Cases included thirty patients with probable AD. Controls were constituted by 29 individuals without dementia according to neuropsychological tests paired to age, sex, race and educational level.

Metrics details. These pathways likely involve the neuroprotective effect of APOE2 and the regulatory roles of APOE2 in lipid metabolism and synaptic functions [ 15 , 16 , 17 , 18 ]. Structurally, APOE has two independently-folded domains referred to as the N-terminal domain and the C-terminal domain [ 35 , 36 ] Fig. These two domains are linked by a flexible loop region that is thrombolytically cleavable [ 37 , 38 ]. The N-terminal domain contains the receptor-binding site residues [ 39 ], whereas the C-terminal domain contains the lipid-binding region residues [ 4 , 40 ].

Plasma Apolipoprotein E Levels and Risk of Dementia—You Are the Company You Keep

Koch and colleagues 1 report on the relationship between apolipoprotein E apoE levels within distinct high-density lipoproteins HDL fractions in plasma samples and risk of dementia in participants in the Ginkgo Evaluation of Memory Study GEMS. Using a case-cohort design to assay archived plasma samples from GEMS participants, the investigators found that higher plasma apoE levels within the HDL fraction lacking apolipoprotein C-III apoC3 were associated with both better cognition at baseline as well as reduced risk of incident all-cause dementia and Alzheimer disease AD. This novel finding is provocative and raises additional questions about the potential role of apoE in the pathogenesis of dementia. The protective role of HDL in cardiovascular disease is believed to be mediated by its actions in enhancing cholesterol efflux from macrophage foam cells in the arterial wall as well as by anti-inflammatory and antithrombotic effects. However, these physiological roles of HDL can be disrupted by its associations with proinflammatory proteins such as apoC3, lipoprotein-associated phospholipase A2 Lp-PLA2 , and serum amyloid A1. Understanding the HDL-proteome has already provided intriguing clues about its complex roles in cardiovascular disease.

Apolipoprotein E

Metrics details. APOE is a polymorphic lipoprotein that is a major cholesterol carrier in the brain. It is also involved in various cellular functions such as neuronal signaling, neuroinflammation and glucose metabolism. The presence of the E4 allele is associated with increased risk of AD whereas E2 reduces the risk. To understand the molecular mechanisms that underlie APOE -related genetic risk, considerable effort has been devoted towards developing cellular and animal models.

Genes control the function of every cell in your body. Some genes determine basic characteristics, such as the color of your eyes and hair. Other genes can make you more likely to develop certain diseases, including Alzheimer's disease. Researchers have identified a number of genes associated with Alzheimer's disease. Some genes increase your likelihood of developing the disease risk genes. Others guarantee that you will develop a disease deterministic genes , though these are rare.

A subtype is implicated in Alzheimer's disease and cardiovascular disease. APOE belongs to a family of fat-binding proteins called apolipoproteins. In the central nervous system , APOE is mainly produced by astrocytes and transports cholesterol to neurons via APOE receptors, which are members of the low density lipoprotein receptor gene family. Apolipoproteins are not unique to mammals. Many terrestrial and marine vertebrates have versions of them. The three major human alleles E4 , E3 , E2 arose after the primate-human split around 7. These alleles are the by-product of non-synonymous mutations which led to changes in functionality.

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

The science of aging is considered the most dynamic and provocative in modern biology. The search for the determinants of successful aging and longevity has been continuously growing, exploiting the major advances in genomic tools and technologies. In this regard, human apolipoprotein E ApoE gene ranks foremost among influential genes in the aging process with a strong association with exceptional longevity and age-related diseases 1—5.

Metrics details. These pathways likely involve the neuroprotective effect of APOE2 and the regulatory roles of APOE2 in lipid metabolism and synaptic functions [ 15 , 16 , 17 , 18 ]. Structurally, APOE has two independently-folded domains referred to as the N-terminal domain and the C-terminal domain [ 35 , 36 ] Fig. These two domains are linked by a flexible loop region that is thrombolytically cleavable [ 37 , 38 ].


The APOE gene alleles modify human aging and the response to the diet at many levels with diverse pleotropic effects from gut to brain. To understand the interactions of APOE isoforms and diet, we analyze how cellular trafficking of apoE proteins affects energy metabolism, the immune system, and reproduction. The age-accelerating APOE4 allele alters the endosomal trafficking of cell surface receptors that mediate lipid and glucose metabolism. Under conditions of high infection, uncertain food, and shorter life expectancy, APOE4 may be adaptive for reducing mortality. As humans transitioned into modern less-infectious environments and longer life spans, APOE4 increased risks of aging-related diseases, particularly impacting arteries and the brain. The association of APOE4 with glucose dysregulation and body weight promotes many aging-associated diseases. Additionally, the APOE gene locus interacts with adjacent genes on chromosome 19 in haplotypes that modify neurodegeneration and metabolism, for which we anticipate complex gene-environment interactions.

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Jatopannai 03.05.2021 at 23:45

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Chia-​Chen Liu, Takahisa Kanekiyo, Huaxi Xu and Guojun Bu. Abstract.