Apolipoprotein E isoform-dependent effects on the processing of Alzheimer's amyloid-β
Autor: | Ingrid C. Gelissen, Maaike Kockx, Hin Hei Julian Lam, Amanda B. Chai |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Apolipoprotein E Gene isoform Amyloid beta Lipid-anchored protein Biology 03 medical and health sciences 0302 clinical medicine Apolipoproteins E In vivo Alzheimer Disease Humans Protein Isoforms Allele Molecular Biology Lipid Transport Alleles Amyloid beta-Peptides Brain Cell Biology In vitro Cell biology 030104 developmental biology biology.protein lipids (amino acids peptides and proteins) 030217 neurology & neurosurgery |
Zdroj: | Biochimica et biophysica acta. Molecular and cell biology of lipids. 1866(9) |
ISSN: | 1879-2618 |
Popis: | Since the identification of the apolipoprotein E (apoE) *e4 allele as a major genetic risk factor for late-onset Alzheimer's disease, significant efforts have been aimed at elucidating how apoE4 expression confers greater brain amyloid-β (Aβ) burden, earlier disease onset and worse clinical outcomes compared to apoE2 and apoE3. ApoE primarily functions as a lipid carrier to regulate cholesterol metabolism in circulation as well as in the brain. However, it has also been suggested to interact with hydrophobic Aβ peptides to influence their processing in an isoform-dependent manner. Here, we review evidence from in vitro and in vivo studies extricating the effects of the three apoE isoforms, on different stages of the Aβ processing pathway including synthesis, aggregation, deposition, clearance and degradation. ApoE4 consistently correlates with impaired Aβ clearance, however data regarding Aβ synthesis and aggregation are conflicting and likely reflect inconsistencies in experimental approaches across studies. We further discuss the physical and chemical properties of apoE that may explain the inherent differences in activity between the isoforms. The lipidation status and lipid transport function of apoE are intrinsically linked with its ability to interact with Aβ. Traditionally, apoE-oriented therapeutic strategies for Alzheimer's disease have been proposed to non-specifically enhance or inhibit apoE activity. However, given the wide-ranging physiological functions of apoE in the brain and periphery, a more viable approach may be to specifically target and neutralise the pathological apoE4 isoform. |
Databáze: | OpenAIRE |
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