Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer’s disease mouse models
- Authors: 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.
- Year: 2016
- Journal: Neurobiol Aging 44 159-72
- Applications: in vitro / DNA / PEIpro
- Cell type: HEK-293T
Description: Human embryonic kidney Fibroblast
Known as: HEK293T, 293T
HEK-293T cells were plated at 30% - 40% confluence in CellSTACKS for 24 hours (or when at 70% - 80% confluence) followed by transfection with plasmids using the PEIpro procedure. The cells were incubated at 37°C for 3 days before harvesting and lysed by 5 freeze/thaw cycles.
The common apolipoprotein E alleles (epsilon4, epsilon3, and epsilon2) are important genetic risk factors for late-onset Alzheimer's disease, with the epsilon4 allele increasing risk and reducing the age of onset and the epsilon2 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-beta (Abeta) peptide deposition and amyloid burden (epsilon4 >epsilon3 >epsilon2). 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 Abeta 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 Abeta burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Abeta and amyloid deposition. We further demonstrate that a widespread reduction of brain Abeta 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.