387. Gene Delivery of APOE2 Reduces Amyloid Pathology in Transgenic Mouse Models of Alzheimer's Disease
Authors: Lingzhi Zhao, Andrew J. Gottesdiener, Mayur Parmar, Christine Grevstad, David Havlicek, Jonathan Rosenberg, Stephen Kaminsky, Maria Chiuchiolo, Dolan Sondhi, Ronald G. Crystal, Steven M. Paul
Journal: Molecular Therapy (2015)

The deposition of amyloid β-peptides (Aβ), cleavage products of the amyloid precursor protein (APP) by β- and γ-secretases, in brain represents a pathological hallmark of Alzheimer's disease (AD). Apolipoprotein E (APOE) ε4 allele carriers have an increased risk to develop AD and an earlier age of onset, whereas carriers of the ε2 allele have reduced risk and a delayed age of onset. APOE is also a major determinant of brain Aβ and amyloid burden in humans and in several transgenic mouse models of AD (E4>E3>E2). We have previously reported that lentivirus-mediated intraparenchymal gene delivery of APOE2 significantly reduces brain Aβ levels and amyloid plaque burden in PDAPP mice. To extend these findings, we administered an rh.10 serotype adeno-associated viral vector expressing the gene (AAVrh.10-APOE2, 1.0X1010 viral genomes (vg)) directly into the hippocampus of 9-month-old PDAPP mice, a mouse model of AD-related amyloidosis. Eight weeks post-injection, AAVrh.10-APOE2 administration resulted in 5-6 times higher levels of APOE2 expression than targeted replacement (wild-type) mice and a marked decrease in both soluble (~33% reduction. P<0.05) and insoluble Aβ42 levels (~70% reduction. P<0.001) compared to control mice. Given the important role of APOE4 in AD risk and amyloid burden, we next assessed how gene delivery of APOE2 affects amyloid pathology in APP.PS1/TRE4 mice where brain Aβ/amyloid deposition is dependent on APOE4 expression. AAVrh.10-APOE2 (0.25X1010, 0.5X1010, or 1×1010 vg) was bilaterally administered into the hippocampus of 2.5-month-old APP.PS1/TRE4 mice. Eight weeks post-injection, there was a dose-dependent increase in APOE expression and a corresponding dose-dependent decrease in insoluble and soluble Aβ levels in the hippocampus of mice treated with AAVrh.10-APOE2, suggesting that overexpression of APOE2 effectively counteracts the detrimental effects of APOE4 on amyloid pathology. We also investigated the effects of AAVrh.10-APOE2 treatment on various proteins associated with Aβ production and clearance by Western analysis. No significant differences were observed in the relative hippocampal levels of APP, β-secretase, C99 (APP cleavage product of β-secretase), or C83 (a non-amyloidogenic APP cleavage product by α-secretase) between mice treated with AAVrh.10-APOE2 or a control vector, suggesting no effect on Aβ production. By contrast, the levels of insulin-degrading enzyme (IDE, an Aβ-degrading enzyme) and ATG5/LC3 (the signaling pathway responsible for autophagy) were significantly (P<0.001 and P<0.05 respectively) elevated in the hippocampus of AAVrh.10-APOE2-treated mice. Taken together, the data demonstrates that AAVrh.10-mediated delivery of APOE2 effectively reduces Aβ pathology in the hippocampus of APP mutant mice expressing either murine Apoe or APOE4. The latter may be due to an enhancement of Aβ metabolism or clearance. Gene delivery of APOE2 may represent a potential therapeutic strategy for treating or preventing AD.