B5 - Neurologic Diseases (excluding Ophthalmic and Auditory Diseases)
1130: Ependyma-Derived ApoE2 Protects Against Alzheimer’s Disease Phenotypes in the Presence of ApoE4
Type: Poster Session
Poster Board Number: 1130
Presentation Details
Session Title: Thursday Posters: Neurologic Diseases
Dementia and more specifically Alzheimer’s Disease (AD) currently pose a global health crisis with more than 3 million cases of AD in the US alone. Inheritance of the ε4 allele of apolipoprotein E (ApoE) is the strongest genetic risk factor associated with the sporadic form of AD, whereas the rare ApoE ε2 allele has the opposite effect. However, the mechanisms whereby ApoE confers risk and protection remain uncertain. ApoEε4 genotype has been associated with worsening plaque deposition, increased speed of cognitive decline and neurodegeneration as well as increased neuroinflammatory phenotype in microglia. We have previously shown that the introduction of ApoE4 or ApoE2 into the ependymal lining via AAV in amyloid plaque-bearing transgenic mice (expressing wild type murine apoE) exacerbated or reduced amyloid plaque burden, respectively (Hudry, et al. 2013 Sci Trans Med). Here a novel, capsid-modified AAV with restricted ependyma expression was used to evaluate ApoE2 replacement in plaque-bearing mice expressing human ApoE4 (mouse apoe negative; APP/PS1/ApoE4).
Following intracerebroventricular (ICV) delivery, ependyma-derived ApoE2 expression accounted for ~20-30% of total ApoE protein in the CSF, a level sufficient to reduce the size and density of cortical amyloid plaques, the concentration of oligomeric Aβ in brains and notably, levels of activated microglia near plaques. Finally, we found that ApoE2 can prevent or lessen synapse loss near Aβ plaques. Together these data support the therapeutic efficacy of ependyma-derived ApoE2 in ApoE4 carriers by improving the classical lesions of AD (eg plaque deposition and neurodegeneration) as well as the increased neuroinflammation and synapse loss observed in sporadic AD. Studies to address translatability of our approach in non-human primates are ongoing.
Rosemary J. Jackson1,2, Ellie Carrell3, Megan S. Keiser3, Jonah C. Meltzer1,2, Dustin P. Fykstra1,2, Steven E. Dierksmeier1,2,4, Soroush Hajizadeh5,6,7, Johannes Kreuzer5,8, Robert Morris5, Alexandra Melloni1, Tsuneo Nakajima1,2, Luis Tecedor9, Paul T. Ranum9, Yonghong Chen9, David M. Holtzman10, Wilhelm Haas5,8, Beverly L. Davidson3,11, Bradley T. Hyman1,2
1Alzheimer Research Unit, The Massachusetts General Hospital Institute for Neurodegenerative Disease, Charlestown, MA,2Department of Neurology, Harvard Medical School, Boston, MA,3The Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA,4Medical Sciences Division, University of Oxford, Oxford, United Kingdom,5Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA,6Broad Institute of MIT and Harvard, Cambridge, MA,7Institute of Molecular Biosciences, University of Graz, Graz, Austria,8Department of Medicine, Harvard Medical School, Boston, MA,9Children's Hospital of Philadelphia, Philadelphia, PA,10Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research, Washington University, St. Louis, MO,11Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA"
Find This Session