AAVrh.10 delivery of novel APOE2-Christchurch variant suppresses amyloid and Tau pathology in alzheimer's disease mice
Open accessAbstract
Gene therapy to treat hereditary disorders conventionally delivers the normal allele to compensate for loss-of-function mutations. More effective gene therapy may be achieved using a gain-of-function variant. We tested the hypothesis that AAVrh.10-mediated CNS delivery of the human APOE2 allele with the Christchurch mutation (R136S) (E2Ch) will provide superior protection against APOE4-associated Alzheimer's disease (AD) in mice compared to the unmodified APOE2 allele (E2). The vectors were assessed in two mouse strains with humanized APOE4: APP.PSEN1/TRE4 "amyloid mice" and P301S/TRE4, "tau mice." Both the E2Ch and E2 vectors prevented Aβ42 and Aβ40 accumulation and decreased β-amyloid aggregates in amyloid mice, but only the E2Ch vector suppressed tau tangles in tau mice. Microglial activation and reactive astrocytes were significantly suppressed by both vectors in amyloid mice but only the E2Ch vector mediated significant suppression of Iba1 and glial fibrillary acidic protein (GFAP) in tau mice. In four behavioral assays, the E2 and E2Ch vectors had similar benefits in amyloid mice, but E2Ch outperformed E2 in tau mice. In summary, while E2 is effective in suppressing amyloid pathology, the novel E2 variant E2Ch more effectively treats both the amyloid and tau pathology of murine AD in APOE4 background, supporting the development of AAVrh.10APOE2Ch as a therapy for APOE4-associated AD.
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Multiple studies have demonstrated that APOECh mutation broadly suppresses gliosis, dampens inflammatory gene expression, and modulates DAM phenotypes in an amyloid and tau-context dependent manner.
“Multiple studies have demonstrated that APOECh mutation broadly suppresses gliosis, dampens inflammatory gene expression, and modulates disease-associated microglial (DAM) phenotypes in an amyloid and tau-context dependent manner [4, 5, 7, 42, 50].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [5]
The Results (page unavailable) report reduced microglial and astroglial activation after APOE2-Christchurch treatment in amyloid and tau mouse models, along with altered inflammatory-marker expression. The paper measures markers relevant to glial phenotype, but does not establish the claimed modulation of disease-associated microglial (DAM) phenotypes specifically; its findings are also limited to the tested mouse models. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe Christchurch mutation resulted in decreased tauopathy in an APOE4 background, mouse Apoe background, and in AAV-mediated expression models.
“The Christchurch mutation also resulted in decreased tauopathy in an APOE4 background (Nelson et al., 2023), mouse Apoe background (Tran et al., 2025), and in AAV-mediated expression models (Gunaydin et al., 2024).”
From APOE3-Christchurch variant enhances neurovascular support functions of iPSC-derived mesenchymal stromal cells (2026) · cites this paper as Gunaydin et al., 2024
AAVrh.10-mediated APOE2 and APOE2Ch expressions in the central nervous system result in similar suppression of gliosis in APP/PS1 mice with APOE4.
“the AAVrh.10-mediated APOE2 and APOE2Ch expressions in the central nervous system results in a similar suppression of gliosis in APP/PS1 mice with APOE4 [5].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [5]
Mounting evidence from human-based, in vitro, and in vivo studies has linked APOE3Ch to reduction in tau pathology.
“Mounting evidence from human-based, in vitro, and in vivo studies has linked APOE3Ch to reduction in tau pathology [3–7, 24, 26, 41, 42].”
From Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice (2026) · cites this paper as [5]
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Cited by
Sorted by citations
Astrocytic APOE3-Christchurch expression ameliorates brain amyloid-β pathology in 5xFAD mice
Raulin, A.-C., Alnobani, A., Rodriguez-Martinez, P., Lee, E., Linares, C., Yslas, A. R., Li, M., Ren, Y., Doss, S. V., Roy, B., et al. (2026) · Translational Psychiatry · doi:10.1038/s41398-026-04002-9
Rodriguez Martinez, P. J., Yslas, A. R., Inoue, Y., Parsons, T. M., Baker, S. K., Lu, W., Raulin, A.-C., & Kanekiyo, T. (2026) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2026.1778856
- Authors
- Günaydin, C., Sondhi, D., Kaminsky, S. M., Lephart, H. C., Leopold, P. L., Hackett, N. R., Khanna, R., & Crystal, R. G.
- Affiliations
- Weill Cornell Medicine (US)
- Corresponding author
- Crystal, Ronald G.
- Venue
- Molecular Therapy
- Publisher
- Elsevier BV
- Published
- 2024-12
- Volume
- 32
- Issue
- 12
- Pages
- 4303-4318
- ISSN
- 1525-0016 (ISSN-L)
- PMC
- PMC11638875
- OpenAlex
- W4404095699
- Cited by
- 26
- References
- 27
- Citations by year
- 2026: 16 · 2025: 10
- FWCI
- 6.73
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Molecular Therapy (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alzheimer's Drug Discovery Foundation
- Medical College, Weill Cornell Medicine
- Duke University
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
- Keywords
- gene therapy, amyloid pathology, tau pathology, microglial activation, reactive astrocytes, gain-of-function mutations
- MeSH terms
- Dependovirus, Alleles, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Genetic Vectors, Humans, Mice, Transgenic, Mutation, Genetic Therapy, Amyloid beta-Peptides, tau Proteins, Microglia, Mice, Apolipoprotein E2
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