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Intracerebroventricular Injection of Amyloid-β Peptides in Normal Mice to Acutely Induce Alzheimer-like Cognitive Deficits
Published on: March 16, 2016
Beneficial Effect of ACI-24 Vaccination on Aβ Plaque Pathology and Microglial Phenotypes in an Amyloidosis Mouse
Jasenka Rudan Njavro1, Marija Vukicevic2, Emma Fiorini2
1German Center for Neurodegenerative Diseases (DZNE), 81377 Munich, Germany.
Abstract:
Amyloid-β (Aβ) deposition is an initiating factor in Alzheimer's disease (AD). Microglia are the brain immune cells that surround and phagocytose Aβ plaques, but their phagocytic capacity declines in AD. This is in agreement with studies that associate AD risk loci with genes regulating the phagocytic function of immune cells. Immunotherapies are currently pursued as strategies against AD and there are increased efforts to understand the role of the immune system in ameliorating AD pathology. Here, we evaluated the effect of the Aβ targeting ACI-24 vaccine in reducing AD pathology in an amyloidosis mouse model. ACI-24 vaccination elicited a robust and sustained antibody response in APPPS1 mice with an accompanying reduction of Aβ plaque load, Aβ plaque-associated ApoE and dystrophic neurites as compared to non-vaccinated controls. Furthermore, an increased number of NLRP3-positive plaque-associated microglia was observed following ACI-24 vaccination. In contrast to this local microglial activation at Aβ plaques, we observed a more ramified morphology of Aβ plaque-distant microglia compared to non-vaccinated controls. Accordingly, bulk transcriptomic analysis revealed a trend towards the reduced expression of several disease-associated microglia (DAM) signatures that is in line with the reduced Aβ plaque load triggered by ACI-24 vaccination. Our study demonstrates that administration of the Aβ targeting vaccine ACI-24 reduces AD pathology, suggesting its use as a safe and cost-effective AD therapeutic intervention.
Insights
The ACI-24 vaccine effectively reduced amyloid-beta plaque buildup in a mouse model of Alzheimer's disease (AD). This immunotherapy shows promise as a safe and cost-effective treatment for AD pathology.
Area of Science:
- Neuroscience
- Immunology
- Pathology
Background:
- Amyloid-beta (Aβ) deposition initiates Alzheimer's disease (AD) pathology.
- Microglia, the brain's immune cells, phagocytose Aβ but show reduced capacity in AD.
- Immune system modulation is a key strategy for AD therapeutic development.
Purpose of the Study:
- To evaluate the efficacy of the Aβ-targeting ACI-24 vaccine in reducing AD pathology.
- To investigate the impact of ACI-24 vaccination on microglial activation and Aβ plaque load in a mouse model.
Main Methods:
- Utilized an amyloidosis mouse model (APPPS1) for ACI-24 vaccine administration.
- Assessed Aβ plaque load, associated markers (ApoE, dystrophic neurites), and microglial activation (NLRP3).
- Analyzed microglial morphology and performed bulk transcriptomic analysis of microglia.
Main Results:
- ACI-24 vaccination induced a strong antibody response and significantly reduced Aβ plaque load.
- Vaccination increased NLRP3-positive microglia at plaques and promoted ramified morphology in distant microglia.
- Transcriptomic analysis indicated a trend towards reduced disease-associated microglia (DAM) signatures.
Conclusions:
- The Aβ-targeting vaccine ACI-24 effectively reduces Alzheimer's disease pathology in a preclinical model.
- ACI-24 demonstrates potential as a safe, cost-effective therapeutic intervention for AD.
- Modulating the immune response via vaccination is a viable strategy for combating AD.
