Tags

Type your tag names separated by a space and hit enter

Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice.
Mol Neurodegener. 2015 Mar 05; 10:6.MN

Abstract

BACKGROUND

Human apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. In the brain, apoE is produced mostly by astrocytes and transports cholesterol to neurons via apoE receptors. Among the gene alleles encoding the three isoforms, the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), whereas APOE2 is protective. ApoE4 confers a gain of toxic function, a loss of neuroprotective function or a combination of both in AD pathogenesis. Given that therapeutic impacts of modulating apoE expression may be isoform-dependent, we sought to investigate the relationship between overexpressing apoE isoform and apoE-related functions in apoE-targeted replacement (TR) mice. Specifically, apoE isoform expression driven by the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter was built into an adeno-associated virus serotype 8 (AAV8) vector and injected into the ventricles of postnatal day 2 (P2) apoE3-TR or apoE4-TR mice. Upon confirmation of apoE isoform expression, effects on apoE lipidation and the levels of amyloid-β (Aβ) in the brain were assessed.

RESULTS

AAV8-GFAP-apoE isoforms were specifically expressed in astrocytes throughout all brain regions, which led to overall increased apoE levels in the brain. Viral mediated overexpression of apoE4 in the apoE4-TR background increased poorly-lipidated apoE lipoprotein particles and decreased apoE-associated cholesterol in apoE4-TR mice. Conversely, apoE2 overexpression in apoE4-TR mice enhanced apoE lipidation and associated cholesterol. Furthermore, overexpression of apoE4 elevated the levels of endogenous Aβ, whereas apoE2 overexpression trended to lower endogenous Aβ.

CONCLUSIONS

Overexpression of apoE isoforms induces differential effects in the apoE4-TR background: apoE4 decreases apoE lipidation and enhances Aβ accumulation, whereas apoE2 has the opposite effects. Our findings suggest that increasing apoE2 in APOE4 carriers is a beneficial strategy to treat AD, whereas increasing apoE4 in APOE4 carriers is likely harmful. We have also established novel methods to express apoE isoforms in mouse brain to study apoE-related pathways in AD and related dementia.

Authors

No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25871773

Citation

Hu, Jin, et al. "Opposing Effects of Viral Mediated Brain Expression of Apolipoprotein E2 (apoE2) and apoE4 On apoE Lipidation and Aβ Metabolism in apoE4-targeted Replacement Mice." Molecular Neurodegeneration, vol. 10, 2015, p. 6.
Hu J, Liu CC, Chen XF, et al. Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice. Mol Neurodegener. 2015;10:6.
Hu, J., Liu, C. C., Chen, X. F., Zhang, Y. W., Xu, H., & Bu, G. (2015). Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice. Molecular Neurodegeneration, 10, 6. https://doi.org/10.1186/s13024-015-0001-3
Hu J, et al. Opposing Effects of Viral Mediated Brain Expression of Apolipoprotein E2 (apoE2) and apoE4 On apoE Lipidation and Aβ Metabolism in apoE4-targeted Replacement Mice. Mol Neurodegener. 2015 Mar 5;10:6. PubMed PMID: 25871773.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Opposing effects of viral mediated brain expression of apolipoprotein E2 (apoE2) and apoE4 on apoE lipidation and Aβ metabolism in apoE4-targeted replacement mice. AU - Hu,Jin, AU - Liu,Chia-Chen, AU - Chen,Xiao-Fen, AU - Zhang,Yun-Wu, AU - Xu,Huaxi, AU - Bu,Guojun, Y1 - 2015/03/05/ PY - 2014/12/23/received PY - 2015/01/26/accepted PY - 2015/4/15/entrez PY - 2015/4/15/pubmed PY - 2015/9/26/medline SP - 6 EP - 6 JF - Molecular neurodegeneration JO - Mol Neurodegener VL - 10 N2 - BACKGROUND: Human apolipoprotein E (apoE) exists in three major isoforms: apoE2, apoE3 and apoE4. In the brain, apoE is produced mostly by astrocytes and transports cholesterol to neurons via apoE receptors. Among the gene alleles encoding the three isoforms, the APOE4 allele is the strongest genetic risk factor for late-onset Alzheimer's disease (AD), whereas APOE2 is protective. ApoE4 confers a gain of toxic function, a loss of neuroprotective function or a combination of both in AD pathogenesis. Given that therapeutic impacts of modulating apoE expression may be isoform-dependent, we sought to investigate the relationship between overexpressing apoE isoform and apoE-related functions in apoE-targeted replacement (TR) mice. Specifically, apoE isoform expression driven by the astrocyte-specific glial fibrillary acidic protein (GFAP) promoter was built into an adeno-associated virus serotype 8 (AAV8) vector and injected into the ventricles of postnatal day 2 (P2) apoE3-TR or apoE4-TR mice. Upon confirmation of apoE isoform expression, effects on apoE lipidation and the levels of amyloid-β (Aβ) in the brain were assessed. RESULTS: AAV8-GFAP-apoE isoforms were specifically expressed in astrocytes throughout all brain regions, which led to overall increased apoE levels in the brain. Viral mediated overexpression of apoE4 in the apoE4-TR background increased poorly-lipidated apoE lipoprotein particles and decreased apoE-associated cholesterol in apoE4-TR mice. Conversely, apoE2 overexpression in apoE4-TR mice enhanced apoE lipidation and associated cholesterol. Furthermore, overexpression of apoE4 elevated the levels of endogenous Aβ, whereas apoE2 overexpression trended to lower endogenous Aβ. CONCLUSIONS: Overexpression of apoE isoforms induces differential effects in the apoE4-TR background: apoE4 decreases apoE lipidation and enhances Aβ accumulation, whereas apoE2 has the opposite effects. Our findings suggest that increasing apoE2 in APOE4 carriers is a beneficial strategy to treat AD, whereas increasing apoE4 in APOE4 carriers is likely harmful. We have also established novel methods to express apoE isoforms in mouse brain to study apoE-related pathways in AD and related dementia. SN - 1750-1326 UR - https://www.unboundmedicine.com/medline/citation/25871773/Opposing_effects_of_viral_mediated_brain_expression_of_apolipoprotein_E2__apoE2__and_apoE4_on_apoE_lipidation_and_Aβ_metabolism_in_apoE4_targeted_replacement_mice_ L2 - https://molecularneurodegeneration.biomedcentral.com/articles/10.1186/s13024-015-0001-3 DB - PRIME DP - Unbound Medicine ER -