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Quantitative 3D In Silico Modeling q3DISM of Cerebral Amyloid-beta Phagocytosis in Rodent Models of Alzheimer's Disease
Published on: December 26, 2016
Gene therapy for Alzheimer's disease targeting CD33 reduces amyloid beta accumulation and neuroinflammation
Ana Griciuc1, Anthony N Federico1, Jeyashree Natasan2
1Genetics and Aging Research Unit, McCance Center for Brain Health, MassGeneral Institute for Neurodegenerative Disease, Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
Abstract:
Neuroinflammation is a key contributor to the pathology of Alzheimer's disease (AD). CD33 (Siglec-3) is a transmembrane sialic acid-binding receptor on the surface of microglial cells. CD33 is upregulated on microglial cells from post-mortem AD patient brains, and high levels of CD33 inhibit uptake and clearance of amyloid beta (Aβ) in microglial cell cultures. Furthermore, knockout of CD33 reduces amyloid plaque burden in mouse models of AD. Here, we tested whether a gene therapy strategy to reduce CD33 on microglia in AD could decrease Aβ plaque load. Intracerebroventricular injection of an adeno-associated virus (AAV) vector-based system encoding an artificial microRNA targeting CD33 (miRCD33) into APP/PS1 mice reduced CD33 mRNA and TBS-soluble Aβ40 and Aβ42 levels in brain extracts. Treatment of APP/PS1 mice with miRCD33 vector at an early age (2 months) was more effective at reducing Aβ plaque burden than intervening at later times (8 months). Furthermore, early intervention downregulated several microglial receptor transcripts (e.g. CD11c, CD47 and CD36) and pro-inflammatory activation genes (e.g. Tlr4 and Il1b). Marked reductions in the chemokine Ccl2 and the pro-inflammatory cytokine Tnfα were observed at the protein level in the brain of APP/PS1 mice treated with miRCD33 vector. Overall, our data indicate that CD33 is a viable target for AAV-based knockdown strategies to reduce AD pathology. One Sentence Summary: A gene therapy approach for Alzheimer's disease using adeno-associated virus vector-based knockdown of CD33 reduced amyloid beta accumulation and neuroinflammation.
Insights
Gene therapy using adeno-associated virus vector to reduce CD33 on microglia effectively lowered amyloid beta plaque accumulation in Alzheimer's disease mouse models. Early intervention proved most effective in reducing pathology and neuroinflammation.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Neuroinflammation is a critical factor in Alzheimer's disease (AD) pathology.
- CD33, a receptor on microglial cells, is upregulated in AD brains and impairs amyloid beta (Aβ) clearance.
- Reducing CD33 has shown promise in decreasing amyloid plaque burden in AD mouse models.
Purpose of the Study:
- To investigate the efficacy of a gene therapy strategy using an adeno-associated virus (AAV) vector to reduce CD33 expression on microglia in AD mouse models.
- To determine if targeting CD33 can decrease amyloid beta plaque load and associated neuroinflammation.
Main Methods:
- APP/PS1 mice were treated with an AAV vector encoding an artificial microRNA targeting CD33 (miRCD33) via intracerebroventricular injection.
- Intervention timing was varied (2 months vs. 8 months of age) to assess the impact of early versus late treatment.
- Levels of CD33 mRNA, soluble Aβ, amyloid plaque burden, microglial receptor transcripts, and inflammatory markers were measured.
Main Results:
- miRCD33 treatment significantly reduced CD33 mRNA and soluble Aβ40/Aβ42 levels in the brain.
- Early intervention (at 2 months) was more effective in reducing amyloid plaque burden compared to later intervention (at 8 months).
- Early treatment downregulated microglial receptors (e.g., CD11c, CD47, CD36) and inflammatory genes (e.g., Tlr4, Il1b), and reduced protein levels of Ccl2 and Tnfα.
Conclusions:
- CD33 is a viable therapeutic target for Alzheimer's disease.
- AAV-based gene therapy for CD33 knockdown is a promising strategy to reduce amyloid beta accumulation and neuroinflammation in AD.
- Early therapeutic intervention is crucial for maximizing the benefits of CD33-targeted gene therapy.
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