Intracerebral adeno-associated virus gene delivery of apolipoprotein E2 markedly reduces brain amyloid pathology in Alzheimer's disease mouse models
Abstract
The common apolipoprotein E alleles (ε4, ε3, and ε2) are important genetic risk factors for late-onset Alzheimer's disease, with the ε4 allele increasing risk and reducing the age of onset and the ε2 allele decreasing risk and markedly delaying the age of onset. Preclinical and clinical studies have shown that apolipoprotein E (APOE) genotype also predicts the timing and amount of brain amyloid-β (Aβ) peptide deposition and amyloid burden (ε4 >ε3 >ε2). Using several administration protocols, we now report that direct intracerebral adeno-associated virus (AAV)-mediated delivery of APOE2 markedly reduces brain soluble (including oligomeric) and insoluble Aβ levels as well as amyloid burden in 2 mouse models of brain amyloidosis whose pathology is dependent on either the expression of murine Apoe or more importantly on human APOE4. The efficacy of APOE2 to reduce brain Aβ burden in either model, however, was highly dependent on brain APOE2 levels and the amount of pre-existing Aβ and amyloid deposition. We further demonstrate that a widespread reduction of brain Aβ burden can be achieved through a single injection of vector via intrathalamic delivery of AAV expressing APOE2 gene. Our results demonstrate that AAV gene delivery of APOE2 using an AAV vector rescues the detrimental effects of APOE4 on brain amyloid pathology and may represent a viable therapeutic approach for treating or preventing Alzheimer's disease especially if sufficient brain APOE2 levels can be achieved early in the course of the disease.
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The Paul and Crystal laboratories demonstrated APOE2-mediated efficacy in an Alzheimer's disease E4 transgenic (APP.PS1.TRE4) mouse model with an AAVrh.10 vector encoding the human APOE2 cDNA (AAVrh.10hAPOE2).
“and by the Paul and Crystal laboratories26 demonstrating APOE2-mediated efficacy in an AD E4 transgenic (APP.PS1.TRE4) mouse model with an AAVrh.10 vector encoding the human APOE2 cDNA (AAVrh.10hAPOE2).”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [26]
One strategy to prevent Alzheimer's disease in APOE4 carriers is to modify the central nervous system genetically to express APOE2, providing the CNS with the protective APOE2 to balance the Alzheimer's disease risk associated with expression of APOE4.
“Based on these observations, one strategy to prevent AD in APOE4 carriers is to modify the central nervous system (CNS) genetically to express APOE2, providing the CNS with the protective APOE2 to balance the AD risk associated with expression of APOE4.22–26”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [26]
The efficacy of this approach in AD transgenic mouse models has been demonstrated previously.
“The efficacy of this approach in AD transgenic mouse models has been demonstrated previously.23,24,26”
From AAVrh.10-Mediated APOE2 Central Nervous System Gene Therapy for APOE4-Associated Alzheimer's Disease (2018) · cites this paper as [26]
Exogenous E2 markedly decreases amyloid burden in mice.
“Moving in vivo, other studies have explored vector-mediated delivery to supplement the E4 brain with neuroprotective E2 protein, showing that exogenous E2 markedly decreases amyloid burden in mice9–12.”
From APOE4 to APOE2 allelic switching in mice improves Alzheimer’s disease-related metabolic signatures, neuropathology and cognition (2025) · cites this paper as [11]
In mice, administration of APOE2 was found to be beneficial at reducing plaque deposition even in the presence of APOE4, indicating that APOE2 can reduce some of the negative effects of APOE4.
“in mice, administration of APOE2 was found to be beneficial at reducing plaque deposition even in the presence of APOE4, indicating that APOE2 can reduce some of the negative effects of APOE4 (refs. 202,203).”
From Multifaceted roles of APOE in Alzheimer disease (2024) · cites this paper as [202]
Gene delivery of ApoE2 markedly reduced brain amyloid pathology in an Alzheimer's disease mouse model.
“Gene delivery of ApoE2 markedly reduced brain amyloid pathology in an AD mouse model (Zhao et al., 2016).”
From Human ApoE Isoforms Differentially Modulate Brain Glucose and Ketone Body Metabolism: Implications for Alzheimer's Disease Risk Reduction and Early Intervention (2018) · cites this paper as Zhao et al., 2016
Viral-vector mediated overexpression of APOE4 isoforms in AD mouse brains accelerates plaque formation.
“This has also been observed with viral-vector mediated overexpression of APOE4 isoforms in AD mouse brains (Dodart et al, 2005; Hudry et al, 2013; Zhao et al, 2016).”
From APOE from astrocytes restores Alzheimer’s Aβ-pathology and DAM-like responses in APOE deficient microglia (2024) · cites this paper as Zhao et al, 2016
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- Authors
- Zhao, L., Gottesdiener, A. J., Parmar, M., Li, M., Kaminsky, S. M., Chiuchiolo, M. J., Sondhi, D., Sullivan, P. M., Holtzman, D. M., Crystal, R. G., & Paul, S. M.
- Affiliations
- Cornell University (US)
- Washington University in St. Louis (US)
- Veterans Health Administration (US)
- Corresponding author
- Zhao, Lingzhi
- Paul, Steven M.
- ORCID
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2016-08
- Volume
- 44
- Pages
- 159-172
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2344986694
- Cited by
- 107
- References
- 52
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 26 · 2023: 8 · 2022: 9 · 2021: 13 · 2020: 13 · 2019: 6 · 2018: 8 · 2016: 1
- FWCI
- 4.02
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- NSUWorks (Nova Southeastern University) (submittedVersion)
- Funders
- Eli Lilly and Company
- Hope Center for Neurological Disorders
- National Institutes of Health
- National Institute on Aging (R01AG047644)
- National Institute of Neurological Disorders and Stroke (R01NS090934)
- 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
- apolipoprotein E2, APOE ε4, Alzheimer's disease, amyloid-beta, brain amyloid burden, AAV gene delivery, APOE genotype, gene replacement therapy
- MeSH terms
- Dependovirus, Alleles, Alzheimer Disease, Animals, Brain, Disease Models, Animal, Genetic Vectors, Genotype, Risk Factors, Genetic Therapy, Amyloid beta-Peptides, Age of Onset, Gene Transfer Techniques, Mice, Knockout, Apolipoprotein E2, Molecular Targeted Therapy
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