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Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.
Neurobiol Aging. 2016 08; 44:159-172.NA

Abstract

The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.

Authors+Show Affiliations

Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY, USA. Electronic address: liz2010@med.cornell.edu.Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY, USA.Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY, USA.Department of Neurology, Hope Center Viral Vector Core, Washington University, St. Louis, MO, USA.Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center's Geriatric Research, Education and Clinical Center, Durham, NC, USA.Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY, USA. Electronic address: stp2015@med.cornell.edu.

Pub Type(s)

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

Language

eng

PubMed ID

27318144

Citation

Zhao, Lingzhi, et al. "Intracerebral Adeno-associated Virus Gene Delivery of Apolipoprotein E2 Markedly Reduces Brain Amyloid Pathology in Alzheimer's Disease Mouse Models." Neurobiology of Aging, vol. 44, 2016, pp. 159-172.
Zhao L, Gottesdiener AJ, Parmar M, et al. Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiol Aging. 2016;44:159-172.
Zhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., Sondhi, D., Sullivan, P. M., Holtzman, D. M., Crystal, R. G., & Paul, S. M. (2016). Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. Neurobiology of Aging, 44, 159-172. https://doi.org/10.1016/j.neurobiolaging.2016.04.020
Zhao L, et al. Intracerebral Adeno-associated Virus Gene Delivery of Apolipoprotein E2 Markedly Reduces Brain Amyloid Pathology in Alzheimer's Disease Mouse Models. Neurobiol Aging. 2016;44:159-172. PubMed PMID: 27318144.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models. AU - Zhao,Lingzhi, AU - Gottesdiener,Andrew J, AU - Parmar,Mayur, AU - Li,Mingjie, AU - Kaminsky,Stephen M, AU - Chiuchiolo,Maria J, AU - Sondhi,Dolan, AU - Sullivan,Patrick M, AU - Holtzman,David M, AU - Crystal,Ronald G, AU - Paul,Steven M, Y1 - 2016/04/30/ PY - 2016/03/05/received PY - 2016/04/22/revised PY - 2016/04/23/accepted PY - 2016/6/19/entrez PY - 2016/6/19/pubmed PY - 2017/9/29/medline KW - Adeno-associated virus KW - Alzheimer's disease KW - Amyloid pathology KW - Apolipoprotein E2 KW - Gene delivery SP - 159 EP - 172 JF - Neurobiology of aging JO - Neurobiol. Aging VL - 44 N2 - The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease. SN - 1558-1497 UR - https://www.unboundmedicine.com/medline/citation/27318144/Intracerebral_adeno_associated_virus_gene_delivery_of_apolipoprotein_E2_markedly_reduces_brain_amyloid_pathology_in_Alzheimer's_disease_mouse_models_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0197-4580(16)30057-4 DB - PRIME DP - Unbound Medicine ER -