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, Yong Hong Chen, Maryam A. Nishtar, David M. Holtzman, Wilhelm Haas, Beverly L. Davidson, Bradley T. Hyman

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish
Pages (from-to)1373-1386
Number of pages14
JournalMolecular Therapy
Volume32
Issue number5
DOIs
StatePublished - May 1 2024

Keywords

  • AAV
  • APOE
  • APOE2
  • Alzheimer disease
  • gene therapy
  • microglia
  • neuroinflammation

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