Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models.
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.
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.
Lingzhi
L
Zhao
Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Andrew J
AJ
Gottesdiener
Appel Alzheimer's Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Mayur
M
Parmar
Department of Neurology, Hope Center Viral Vector Core, Washington University, St. Louis, MO, USA.
Mingjie
M
Li
Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Stephen M
SM
Kaminsky
Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Maria J
MJ
Chiuchiolo
Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Dolan
D
Sondhi
Department of Medicine, Duke University Medical Center, Durham Veterans Health Administration Medical Center's Geriatric Research, Education and Clinical Center, Durham, NC, USA.
Patrick M
PM
Sullivan
Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO, USA.
David M
DM
Holtzman
Department of Genetic Medicine, Weill Cornell Medical College of Cornell University, New York, NY, USA.
Ronald G
RG
Crystal
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.
Steven M
SM
Paul
D017668:Age of Onset; D000483:Alleles; D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D000818:Animals; D053329:Apolipoprotein E2 / Q000235:genetics*; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D000229:Dependovirus; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005838:Genotype; D018345:Mice, Knockout; D058990:Molecular Targeted Therapy; D012307:Risk Factors
D016229:Amyloid beta-Peptides; D053329:Apolipoprotein E2
Adeno-associated virus; Alzheimer's disease; Amyloid pathology; Apolipoprotein E2; Gene delivery