What is APOE2?

Abstract. Although the ε2 allele of apolipoprotein E (APOE2) benefits longevity, its mechanism is not understood. The protective effects of the APOE2 on Alzheimer’s disease (AD) risk, particularly through their effects on amyloid or tau accumulation, may confound APOE2 effects on longevity.

How does APOE cause Alzheimer’s?

Pathogenic Mechanisms of ApoE in Alzheimer’s Disease Evidence suggests that the major effect of apoE isoforms on the risk of developing AD is via its effect on Aβ aggregation and clearance, influencing the onset of Aβ deposition.

Why is APOE2 protective?

Viral-mediated APOE*ε2 overexpression Given APOE2 protects against AD likely due to its greater neuroprotective functions than that of APOE3 and APOE4 (Fig. 3), introducing APOE2 into the brain of AD patients who lack APOE*ε2 may have therapeutic effects.

Does APOE bind to LDLR?

Although lipid-free apoE is unable to bind LDLR, lipid association induces the protein to adopt a receptor active conformation [5,6]. Human apoE exists as one of three major isoforms, apoE2, apoE3 and apoE4. ApoE3 and apoE4 bind to LDLR with high affinity while apoE2 binding is much weaker [7].

What does the ApoE2 gene do?

Collectively, these findings suggest that ApoE2 may play a positive role in preserving the structural integrity of the brain, which could account for its cognition-favoring properties in aging brains as well as for the increased resistance to pathological development in early-stage AD brains.

What does APO A2 do?

Low apolipoprotein-A2 is associated with metastatic renal cell cancer. ApoA-II plays a crucial role in triglyceride catabolism by regulating lipoprotein lipase activity, at least in part, through HDL proteome modulation.

What does APOE do in the brain?

As the major component of HDL-like particles in the brain, ApoE facilitates the transfer of cholesterol and phospholipid between cells. ApoE serves as a ligand in the receptor-mediated endocytosis of HDL-like particles through LDL receptor family. There are three major isoforms (ApoE2, ApoE3, and ApoE4) in humans.

Is APOE4 dominant or recessive?

To date, only dominant genes have been linked with Alzheimer’s disease. The epsilon 4 allele of the apolipoprotein E gene, or APOE-4, accounts for nearly all of the currently identified genetic risk associated with the most common form of Alzheimer’s.

How common is APOE2?

ApoE2 is relatively rare, with only 5% incidence, and is considered to be a protective variant against AD. By contrast, as the most potent genetic risk factor for AD, ApoE4 exists in only about 20% of the population; however, it is present in nearly 50% of AD patients.

What chromosome is APOE4 on?

The apolipoprotein E (APOE) gene on chromosome 19q13. 32, was the first, and remains the strongest, genetic risk factor for Alzheimer’s disease (AD). Additional signals associated with AD have been located in chromosome 19, including ABCA7 (19p13.

What’s the difference between APOE2 and APOE3?

ApoE2 has a much lower binding affinity for low-density lipoprotein (LDL) receptors compared to ApoE3 and ApoE4. Furthermore, ApoE2 and ApoE3 preferentially bind to small, phospholipid-enriched high-density lipoproteins (HDL) whereas ApoE4 preferentially binds to larger, triglyceride-enriched lipoproteins.

What is the protective effect of ApoE * ε2?

The mechanism underlying the protective effect of APOE*ε2 against AD remains unclear. Human studies show that APOE*ε2 is associated with reduced Aβ deposition in the brains of non-demented aged individuals and AD patients [ 7, 8, 9, 10, 11 ], suggesting that APOE*ε2 reduces AD risk at least partially through Aβ-dependent pathways.

How does ApoE * ε2 protect against Alzheimer’s disease?

Despite increased understanding of the detrimental effect of APOE*ε4, it remains unclear how APOE*ε2 confers protection against AD. Accumulating evidence suggests that APOE*ε2 protects against AD through both amyloid-β (Aβ)-dependent and independent mechanisms.

Which is the triggering receptor for APOE2 in the brain?

In addition, recent studies show the triggering receptor expressed on myeloid cells 2 (TREM2), which is specifically expressed by microglia in the brain, is a receptor for APOE [ 62, 63, 64 ].