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CCR6: a biomarker for Alzheimer's-like disease in a triple transgenic mouse model
Sandhya Subramanian1, Patricia Ayala, Teri L Wadsworth
1Neuroimmunology Research, Veterans Affairs Medical Center, Portland, OR 97239, USA.
Abstract:
The inflammatory status of the brain in patients as well as animal models of Alzheimer's disease (AD) has been extensively studied. Accumulation of activated microglia producing tumor necrosis factor-α and monocyte chemotactic protein-1 contribute to the pathology of the disease. However, little is known about the changes in the spleen and associated peripheral immunity that might contribute to AD pathology. The goal of this study was to characterize phenotypic and functional changes in spleen, blood and brain cell populations that contribute to development of an AD-like disease in a triple transgenic (3xTg-AD) mouse model. The 3xTg-AD mice had increased percentages of brain Gr-1+ granulocytes, dendritic cells and macrophages, spleen and blood derived CD8+Ly6C+ memory T cells and CCR6+ B cells, as well as increased levels of secreted interleukin-6. Brain tissue from older 12 month old symptomatic 3xTg-AD female mice exhibited highly elevated mRNA expression of CCR6 compared to wild-type mice. Importantly, this pronounced increase in expression of CCR6 was also detected in brain and spleen tissue from pre-symptomatic 5--6 month old 3xTg-AD females and males. Our data demonstrate increased expression of CCR6 in the brain and peripheral immune organs of both pre-symptomatic and symptomatic 3xTg-AD mice, strongly suggesting an ongoing inflammatory process that precedes onset of clinical AD-like disease.
Insights
Alzheimer
Area of Science:
- Neuroimmunology
- Alzheimer's Disease Research
- Immunology
Background:
- Brain inflammation is a known factor in Alzheimer's disease (AD).
- The role of peripheral immune organs, like the spleen, in AD is less understood.
- Activated microglia contribute to AD pathology through inflammatory mediators.
Purpose of the Study:
- To investigate changes in spleen, blood, and brain immune cells in a triple transgenic mouse model of Alzheimer's disease (3xTg-AD).
- To characterize the early inflammatory processes preceding clinical symptoms in AD.
Main Methods:
- Analysis of immune cell populations in the brain, spleen, and blood of 3xTg-AD mice and wild-type controls.
- Quantification of inflammatory markers, including interleukin-6 and CCR6 expression.
- Comparison of pre-symptomatic and symptomatic AD mouse models.
Main Results:
- 3xTg-AD mice showed increased percentages of specific immune cells (granulocytes, dendritic cells, macrophages, CD8+Ly6C+ T cells, CCR6+ B cells) in the brain, spleen, and blood.
- Elevated levels of interleukin-6 were observed.
- Significantly increased CCR6 mRNA expression was found in the brain, spleen, and blood of both pre-symptomatic and symptomatic 3xTg-AD mice.
Conclusions:
- Increased CCR6 expression in immune cells is an early indicator of Alzheimer's disease pathology.
- Peripheral immune organs and their associated cells are involved in the inflammatory process of AD.
- These findings suggest an inflammatory process begins before the onset of clinical AD symptoms.
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