Role of Apolipoprotein E in β-Amyloidogenesis

Abstract

Background: ApoE is a genetic risk factor for Alzheimer disease. Results: As compared with apoE2/3, apoE4 failed to inhibit the conversion of A␤ protofibrils to fibrils in vitro. Intracerebral injection of A␤ protofibrils with apoE3 attenuated A␤ deposition, whereas apoE4 did not. Conclusion: ApoE3, not apoE4, impedes ␤-amyloid formation. Significance: Interaction between A␤ and apoE is a critical determinant of ␤-amyloid formation.

Apolipoprotein E and clusterin inhibit the early phase of amyloid-β aggregation in an in vitro model of cerebral amyloid angiopathy

“…Although apoE is considered as a key player in the pathogenesis of Alzheimer’s disease (AD) and CAA [16, 32], the effects of apoE on the aggregation of Aβ in vitro and in vivo are controversial. While some groups reported that apoE accelerates Aβ fibril formation in vitro [31, 35], we and other groups reported that apoE inhibits Aβ aggregation in vitro [6, 8, 15, 24, 37]. These opposite effects may be partly due to the difference in the concentrations of Aβ used in each experiment.…”

“…In contrast, when 300 μM Aβ(1–40) was incubated with 3 μM apoE, apoE slightly enhanced Aβ aggregation. Similarly, while some groups reported that apoE promotes Aβ amyloid deposition in vivo [12], other groups showed that apoE delays Aβ amyloid deposition in vivo [4, 7, 13, 15, 32]. LaDu and coworkers produced EFAD mice, which are a tractable familial AD-transgenic (FAD-Tg) mouse model expressing human APOE rather than mouse APOE [32].…”

Protofibrils of Amyloid-β are Important Targets of a Disease-Modifying Approach for Alzheimer’s Disease

“…It was recently revealed that curvilinear fibrils inhibit fibril formation not only by slowing fibril nucleation and elongation, but also by actively disrupting either process based on combined thioflavin kinetics and AFM imaging data [26]. On the other hand, Iwatsubo's group showed that Aβ 1-42 PF injection induced Aβ deposition in the brains of A7 mice overexpressing human APP695 and harboring the K670N, M671L, and T714I familial AD neuronal mutations, suggesting that Aβ PFs may act as a seed for Aβ aggregation in vivo [27]. The injection of Aβ PFs mixed with apoE3 significantly attenuated Aβ deposition, whereas apoE4 did not, suggesting that the suppressive effect of apoE3 on the structural conversion of Aβ PFs to fibrils is stronger than that of apoE4, thereby impeding Aβ deposition in vivo [27].…”

Passive immunotherapies targeting Aβ and tau in Alzheimer's disease

“…Individuals carrying APOE ε 2/ ε 2 or ε 2/ ε 3 (8.4% of the population) are at decreased risk of AD ( Liu et al (2013) ). In vitro and in vivo evidence in APP transgenic mice has shown that APOE- ε 3, but not APOE- ε 4, attenuates A β protofibril-induced aggregation, by forming stabilizing complexes with A β ( Hori et al (2015) ). As well, the APOE- ε 4 isoform is not as effective as the others at clearing A β ( Jiang et al (2008) ; Castellano et al (2011) ), and carriers of two copies of the ε 4 allele have on average 20× the risk of developing AD ( Hauser and Ryan (2013) ).…”