Skip to main content
U.S. flag

An official website of the United States government

Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models

Bibliographic

Year of Publication:
2016
Contact PI Name:
Steven M. Paul
Contact PI Affiliation:
Appel Alzheimer’s Disease Research Institute, Feil Family Brain and Mind Research Institute, Weill Cornell Medical College of Cornell University, New York, New York, USA
Co-Authors:
Lingzhi Zhao, Andrew J. Gottesdiener, Mayur Parmar, Mingjie Li, Stephen M. Kaminsky, Maria J. Chiuchiolo, Dolan Sondhi, Patrick M. Sullivan, David M. Holtzman, Ronald G. Crystal
Primary Reference (PubMED ID):
Funding Source:
Alzheimer's Drug Discovery Foundation (ADDF)
Appel Alzheimer’s Disease Research Institute
Study Goal and Principal Findings:

In this study the authors assessed the effects of various levels of APOE2 expression, routes of delivery, and the extent of pre-existing amyloid pathology on AAV-APOE2-mediated alteration of amyloid pathology using a widely used mouse model of brain amyloidosis (PDAPP mice) as well as a mouse model that develops APOE4-dependent amyloid deposition (APP.PS1/TRE4 mice). This study shows that direct intracerebral gene delivery of APOE2 via an AAV vector significantly reduces brain Abeta and amyloid deposition in these transgenic mouse models of AD and rescues the detrimental effects of both APOE4 as well as murine Apoe on brain amyloid pathology.  The data also demonstrate that the “efficacy” of AAV-APOE2 gene delivery to decrease amyloid pathology in these mouse models strongly depends on the level of APOE2 expression and pre-existing amyloid pathology at the time of vector administration, rather than the cellular source of APOE2 or the route of administration. In addition, the results show that intrathalamic delivery of APOE2 using an AAV vector results in widespread brain distribution of APOE2 and a broad reduction of brain Abeta burden following a single injection in APP.PS1/TRE4 mice. In conclusion this study provides direct evidence for a qualitative “protective” effect of APOE2 on brain amyloid burden and shows that raising (rather than reducing) brain APOE2 to a sufficient level effectively reduces amyloid pathology in mice where the latter is primarily due to APOE4 expression. Thus, gene delivery of APOE2 may represent a promising therapeutic strategy especially if used early in the course of the disease.

Therapeutic Agent

Therapeutic Information:
Therapy Type:
Biologic - Gene
Therapeutic Agent:
AAVrh.10- APOE2
Therapeutic Target:
Multi Target
Therapy Type:
Biologic - Gene
Therapeutic Agent:
AAV9-APOE2
Therapeutic Target:
Multi Target
Therapy Type:
Biologic - Gene
Therapeutic Agent:
AAV9-CAG-APOE2
Therapeutic Target:
Multi Target

Animal Model

Model Information:
Species:
Mouse
Model Type:
APPxPS1xApoE
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
APP
Strain/Genetic Background:
Not Reported
Species:
Mouse
Model Type:
Mouse ApoE KO
Strain/Genetic Background:
Not Reported
Species:
Mouse
Strain/Genetic Background:
Not Reported
Animal Model Notes:
No reference given for EKO mice. Authors listed Taconic Biosciences Inc as their source of these mice.

Experimental Design

Is the following information reported in the study?:
Power/Sample Size Calculation
Randomized into Groups
Blinded for Treatment
Blinded for Outcome Measures
Pharmacokinetic Measures
Pharmacodynamic Measures
Toxicology Measures
ADME Measures
Biomarkers
Dose
Formulation
Route of Delivery
Duration of Treatment
Frequency of Administration
Age of Animal at the Beginning of Treatment
Age of Animal at the End of Treatment
Sex as a Biological Variable
Study Balanced for Sex as a Biological Variable
Number of Premature Deaths
Number of Excluded Animals
Statistical Plan
Genetic Background
Inclusion/Exclusion Criteria Included
Conflict of Interest

Outcomes

Outcome Measured
Outcome Parameters
Histopathology
beta Amyloid Load
Biochemical
Apolipoprotein E2 (ApoE2)
Brain-Detergent Soluble beta Amyloid Peptide 40
Brain-Guanidine Insoluble beta Amyloid Peptide 40
Brain-Guanidine Insoluble beta Amyloid Peptide 42
Brain-beta Amyloid Oligomers
Immunochemistry
Apolipoprotein E2 (ApoE2)
Glial Fibrillary Acidic Protein (GFAP)
beta Amyloid Load
Neuronal Marker NeuN
Neuronal Damage Markers
Microscopy
Cell Count