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5xFAD-NSG mice: a preclinical Alzheimer model for human cell therapy studies
David J Graber1, Marie-Louise Sentman1, W James Cook1
1Center for Synthetic Immunity, Department of Microbiology and Immunology, the Geisel School of Medicine at Dartmouth, Lebanon, NH 03756 USA.
Abstract:
Cellular therapies are one class of medicine being developed to treat Alzheimer's disease (AD), a neurodegenerative disease with memory loss, aberrant protein accumulation in the brain, and neuroinflammation. One challenge for development of human cell therapeutics is to have preclinical animal models that allow the use of human cells without immune-mediated rejection of those cells. The 5xFAD transgenic mouse model is a robust disease model for AD that expresses human amyloid precursor protein and presenilin-1 with multiple familial AD mutations, develops microglia-mediated neuroinflammation, accumulates amyloid-beta (Aβ) in the brain, and shows behavior changes with age. To create a mouse model for AD that permits the transplantation of human cells without immune-mediated rejection, we bred the 5xFAD transgenes onto the NOD-SCID-IL-2Rγ-deficient (NSG) mouse model to create 5xFAD-NSG mice. We report that 5xFAD-NSG mice develop Aβ plaques in the brain, microgliosis, neuroinflammation, and behavior changes that increase with age. We demonstrate that injection of CAR engineered human T regulatory cells are detected in the cerebral cortex and spleen after eight days. This 5xFAD-NSG mouse model for AD will be helpful to develop human cell-based therapies for AD.
Insights
A new 5xFAD-NSG mouse model allows human cell transplantation for Alzheimer's disease (AD) research. These mice exhibit AD-like pathology, enabling the development of novel human cell-based therapies for AD.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Alzheimer's disease (AD) is a neurodegenerative disorder characterized by memory loss, protein accumulation, and neuroinflammation.
- Developing human cell therapeutics for AD is hindered by the lack of preclinical models that prevent immune rejection of human cells.
- The 5xFAD transgenic mouse model exhibits key AD pathologies, including amyloid-beta plaques and neuroinflammation.
Purpose of the Study:
- To develop a novel mouse model for Alzheimer's disease (AD) that permits the transplantation of human cells without immune rejection.
- To establish a 5xFAD-NSG mouse model that accurately recapitulates AD-like pathology and allows for *in vivo* testing of human cell-based therapies.
Main Methods:
- Crossed 5xFAD transgenic mice with NOD-SCID-IL-2Rγ-deficient (NSG) mice to create 5xFAD-NSG mice.
- Characterized the 5xFAD-NSG model for AD-specific pathologies, including amyloid plaques, microgliosis, neuroinflammation, and age-dependent behavioral changes.
- Administered CAR engineered human T regulatory cells and tracked their presence in the brain and spleen.
Main Results:
- 5xFAD-NSG mice developed progressive amyloid-beta plaques, microgliosis, and neuroinflammation, mirroring human AD.
- Age-dependent behavioral deficits were observed in the 5xFAD-NSG mice.
- Transplanted human T regulatory cells were detected in the cerebral cortex and spleen eight days post-injection, indicating successful engraftment.
Conclusions:
- The 5xFAD-NSG mouse model is a viable preclinical tool for studying Alzheimer's disease (AD).
- This model facilitates the evaluation of human cell-based therapies for AD by overcoming immune rejection barriers.
- The 5xFAD-NSG mouse provides a platform for advancing the development of novel therapeutic strategies for Alzheimer's disease.
