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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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.

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. HDL-associated proteins include complement factors and acute phase proteins suggesting that HDL plays an important role in the innate immune response.

Therapeutic approaches targeting Apolipoprotein E function in Alzheimer’s disease

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. Notably, APOE2 was associated with preserved activity during aging, which also associated with lifespan. In animal models, distinct apoE isoform levels, where APOE2 has the highest, were correlated with activity levels, while some forms of cholesterol and triglycerides were associated with apoE and activity levels. Preserved activity would be an early-observable feature of APOE2 -mediated longevity, where higher levels of apoE2 and its-associated lipid metabolism might be involved. Additionally, both APOE alleles are also associated with longevity. Several case-control studies have shown higher frequencies of APOE2 in elderly individuals and centenarians compared to younger populations, whereas the frequency of APOE4 is lower in the older individuals Cauley et al.

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.

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

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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 ].

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