APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Rosemary J Jackson; Megan S Keiser; Jonah C Meltzer; Dustin P Fykstra; Steven E Dierksmeier; Soroush Hajizadeh; Johannes Kreuzer; Robert Morris; Alexandra Melloni; Tsuneo Nakajima; Luis Tecedor; Paul T Ranum; Ellie Carrell; YongHong Chen; Maryam A Nishtar; David M Holtzman; Wilhelm Haas; Beverly L Davidson; Bradley T Hyman

doi:10.1016/j.ymthe.2024.03.024

APOE2 gene therapy reduces amyloid deposition and improves markers of neuroinflammation and neurodegeneration in a mouse model of Alzheimer disease

Mol Ther. 2024 Mar 19:S1525-0016(24)00165-5. doi: 10.1016/j.ymthe.2024.03.024. Online ahead of print.

Authors

Rosemary J Jackson¹, Megan S Keiser², Jonah C Meltzer³, Dustin P Fykstra³, Steven E Dierksmeier⁴, Soroush Hajizadeh⁵, Johannes Kreuzer⁶, Robert Morris⁷, Alexandra Melloni⁸, Tsuneo Nakajima³, Luis Tecedor², Paul T Ranum², Ellie Carrell², YongHong Chen², Maryam A Nishtar³, David M Holtzman⁹, Wilhelm Haas⁶, Beverly L Davidson¹⁰, Bradley T Hyman³

Affiliations

¹ Alzheimer Research Unit, Massachusetts General Hospital Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA; Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02114, USA. Electronic address: rjackson12@mgh.harvard.edu.
² Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³ Alzheimer Research Unit, Massachusetts General Hospital Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA; Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02114, USA.
⁴ Alzheimer Research Unit, Massachusetts General Hospital Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA; Department of Neurology, Massachusetts General Hospital and NeuroDiscovery Center, Harvard Medical School, Boston, MA 02114, USA; Medical Sciences Division, University of Oxford, Oxford OX3 9DU, UK.
⁵ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, UK; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Institute of Molecular Biosciences, University of Graz, 8010 Graz, Austria.
⁶ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, UK; Department of Medicine, Harvard Medical School, Boston, MA 02115, USA.
⁷ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA 02114, UK.
⁸ Alzheimer Research Unit, Massachusetts General Hospital Institute for Neurodegenerative Disease, Charlestown, MA 02129, USA.
⁹ Department of Neurology, Hope Center for Neurological Disorders, Knight Alzheimer's Disease Research Center, Washington University in St. Louis, St. Louis, MO 63108, USA.
¹⁰ Raymond G. Perelman Center for Cellular and Molecular Therapeutics, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.

PMID: 38504517
DOI: 10.1016/j.ymthe.2024.03.024

Abstract

Epidemiological studies show that individuals who carry the relatively uncommon APOE ε2 allele rarely develop Alzheimer disease, and if they do, they have a later age of onset, milder clinical course, and less severe neuropathological findings than people without this allele. The contrast is especially stark when compared with the major genetic risk factor for Alzheimer disease, APOE ε4, which has an age of onset several decades earlier, a more aggressive clinical course and more severe neuropathological findings, especially in terms of the amount of amyloid deposition. Here, we demonstrate that brain exposure to APOE ε2 via a gene therapy approach, which bathes the entire cortical mantle in the gene product after transduction of the ependyma, reduces Aβ plaque deposition, neurodegenerative synaptic loss, and, remarkably, reduces microglial activation in an APP/PS1 mouse model despite continued expression of human APOE ε4. This result suggests a promising protective effect of exogenous APOE ε2 and reveals a cell nonautonomous effect of the protein on microglial activation, which we show is similar to plaque-associated microglia in the brain of Alzheimer disease patients who inherit APOE ε2. These data increase the potential that an APOE ε2 therapeutic could be effective in Alzheimer disease, even in individuals born with the risky ε4 allele.

Keywords: AAV; APOE; APOE2; Alzheimer disease; gene therapy; microglia; neuroinflammation.