Apolipoprotein e and alzheimer disease risk mechanisms and therapy pdf

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apolipoprotein e and alzheimer disease risk mechanisms and therapy pdf

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Herein, we showed that the association between APOE2 and longer lifespan persisted irrespective of AD status, including its neuropathology, by analyzing clinical datasets as well as animal models.

APOE2: protective mechanism and therapeutic implications for Alzheimer’s disease

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. The first allele to emerge was E4. After the primate-human split, there were four amino acid changes in the human lineage, three of which had no effect on protein function VL, A18T, AV. The fourth substitution traded a threonine for an arginine altering the protein's functionality.

This substitution occurred somewhere in the 6 million year gap between the primate-human split and the Denisovan-human split, since exactly the same substitutions were found in Denisovan APOE. About , years ago, an arginine to cysteine substitution took place at amino acid ArgCys of the APOE4 gene, and this resulted in the E3 allele.

Finally, 80, years ago, another arginine to cysteine substitution at amino acid ArgCys of the APOE3 gene created the E2 allele. The APOE gene consists of four exons and three introns , totaling base pairs. According to crystallography studies, a hinge region connects the N- and C-terminal regions of the protein.

The N-terminal region residues 1— forms an anti-parallel four-helix bundle such that the non-polar sides face inside the protein. As of , much remained to be learned about the APOE isoforms, including the interaction of other potentially protective genetic polymorphisms, so caution is advised before making determinant statements about the influence of APOE polymorphisms on cognition and the development of Alzheimer's disease.

As of , there was no evidence that APOE polymorphisms influence cognition in younger age groups other than possible increased episodic memory ability and neural efficiency in younger APOE4 age groups , nor that the APOE4 isoform places individuals at increased risk for any infectious disease. APOE transports lipids , fat-soluble vitamins , and cholesterol into the lymph system and then into the blood. It is synthesized principally in the liver , but has also been found in other tissues such as the brain , kidneys , and spleen.

APOE was initially recognized for its importance in lipoprotein metabolism and cardiovascular disease. In the field of immune regulation, a growing number of studies point to APOE's interaction with many immunological processes, including suppressing T cell proliferation, macrophage functioning regulation, lipid antigen presentation facilitation by CD1 [52] to natural killer T cell as well as modulation of inflammation and oxidation.

As of , the E4 variant was the largest known genetic risk factor for late-onset sporadic Alzheimer's disease AD in a variety of ethnic groups. Nigerian people have the highest observed frequency of the APOE4 allele in world populations, [56] but AD is rare among them.

This may be caused by an interaction with amyloid. Apolipoprotein E enhances proteolytic break-down of this peptide, both within and between cells. Using genotype APOE3,3 as a benchmark with the persons who have this genotype regarded as having a risk level of 1.

Individuals with the APOE3,4 genotype face an odds ratio of 3. Persons with one copy each of the 2 allele and the 3 allele APOE2,3 have an odds ratio of 0.

Persons with two copies of the 2 allele APOE2,2 also have an odds ratio of 0. While ApoE4 has been found to greatly increase the odds that an individual will develop Alzheimer's, a study concluded, that in persons with any combination of APOE alleles, high serum total cholesterol and high blood pressure in mid-life are independent risk factors which together can nearly triple the risk that the individual will later develop AD.

A publication as part of the "Einstein Soccer Study" showed that in adult soccer players those with at least one copy of APOE4 gene allele had a stronger association between a month soccer ball heading experience and worse verbal memory performance than their peers without the allele. Click on genes, proteins and metabolites below to link to respective articles. From Wikipedia, the free encyclopedia.

Cholesterol-transporting protein most notably implicated in Alzheimer's disease. National Center for Biotechnology Information, U. National Library of Medicine. Berlin: Springer. Journal of Lipid Research. Nature Reviews. Nature Neuroscience. March Nature Medicine. Bibcode : PNAS Ageing Research Reviews. Bibcode : PLoSO The Quarterly Review of Biology. January Molecular Cell. December Annals of Human Biology. American Journal of Physical Anthropology. Clinical Cardiogenetics. London: Springer.

Nucleic Acids Research. Behavioral and Brain Functions. The Journal of Biological Chemistry. Human Mutation. Neurobiology of Disease. August Bibcode : Sci June February American Journal of Human Genetics. Hormones and Behavior. The Journals of Gerontology.

September Cerebral Cortex. Genetic Testing and Molecular Biomarkers. Neuron Glia Biology. Current Opinion in Lipidology.

October Bibcode : Natur. A meta-analysis". The effect of the apolipoprotein E polymorphism on quantitative levels of lipoproteins in Nigerian blacks". Journal of Molecular Neuroscience. Annals of Internal Medicine.

Neuroscience Letters. Cell Press. Lay summary — ScienceDaily Current Alzheimer Research. Nature Genetics. A meta-analysis. The Journal of Neuroscience. April JAMA Neurology. Clinical Science. Scientific Reports. Bibcode : NatSR Journal of Medical Genetics. Raber J Neural Plasticity. Ye J August PLOS Pathogens. Annals of the New York Academy of Sciences. Ashford JW Masterman T, Hillert J June The Lancet.

Current Drug Targets.

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

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. Further, whether plasma APOE, by influencing systemic metabolic pathways, can also possibly alter CNS function indirectly is not complete;y understood.

Apolipoprotein E

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.

The diagnosis of AD based on clinical symptoms alone is known to have poor specificity; recently developed diagnostic criteria based on biomarkers that reflect underlying AD neuropathology allow better assessment of the strength of the associations of risk factors with AD. This case—control study included 1, white AD cases A total of 11, dementia-free controls In total,

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

Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy

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.

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. DNA was isolated from peripheral leukocytes of anticoagulated venous blood. The number of elder people has raised with the increase of life expectancy and as consequence, the prevalence of age-related disease.

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 ].


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