Inflammation in the Brain Drives Neurodegeneration in Tauopathy
Post by Elisa Guma
The takeaway
Neurodegeneration and tauopathy, but not amyloid deposition, are associated with increased immune markers in the brain of humans and mouse models. Importantly, reducing inflammation in mouse models is associated with a decrease in disease progression.
What's the science?
Alzheimer’s disease is characterized by the deposition of amyloid-B plaques and intracellular tau neurofibrillary tangles in the brain, together with brain atrophy. Interestingly, regional patterns of brain atrophy mirror regional patterns of tau accumulation, but not amyloid deposition in the brain. While the pathology of Alzheimer’s disease remains to be fully elucidated, evidence suggests that the immune system may play an important role in disease pathology. This week in Nature, Chen and colleagues investigate the relationship between the immune system and neurodegeneration in two different mouse models of Alzheimer’s disease, one with amyloid-B deposition and the other with tauopathy, to better understand the contribution of the immune system to each of these hallmark features of the disease.
How did they do it?
The authors compared the immune system function in the brains of two transgenic mouse models, one with amyloid-B-deposition and the other with tauopathy, both created by crossing transgenic mice with human-APOE-knock-in mice. The authors performed single-cell RNA sequencing of immune cells from the meningeal and parenchymal lining surrounding the brains of male mice. They also performed immunohistochemical analyses of the parenchyma to characterize further the presence of T cells, microglia, and antibodies in both mouse models. To compare the findings in the mouse models to human Alzheimer’s disease, they performed the same immunohistochemistry experiments on brain samples of patients with Alzheimer’s disease at different levels of disease severity.
Next, the authors wanted to understand the specific role of several immune modulators in the immune response to tauopathy. They tested each of these by administering a neutralizing antibody to the mice. The first one they tested was IFN-gamma, a cytokine that can augment the immune response. The second one was T cells, and the third was the programmed cell death protein 1 (PDCD1), an immune checkpoint for T cells. They then evaluated the immune profile, accumulation of phosphorylated tau in the brain, and behavior.
What did they find?
First, the authors found that only mice with tau pathology showed brain atrophy at 9.5 months of age, with regional patterns mirroring human disease. The authors found that 9.5-month-old tau mice had an increased presence of adaptive immune cells, including T cells, dendritic cells, and macrophages in their parenchyma and meninges compared to amyloid mice. Immunohistochemistry of the parenchyma confirmed that tau mice had elevated levels of T cells, enriched for INF-gamma transcripts, and microglia compared to amyloid mice. Importantly, similar elevations in T cell number were observed in the brain of humans with Alzheimer’s disease, particularly in regions with more tauopathy.
Next, the authors found that anti-IFN-gamma treatment resulted in attenuated brain atrophy in tau mice. Similarly, the T cell depletion treatment resulted in decreased brain atrophy, and a reduction in the overall number of microglia, suggesting that T cells in the brain of tau mice can indeed augment the number of microglia. Furthermore, T cell depletion improved performance on several memory tasks (short-term, hippocampal- and amygdala-dependent), and resulted in a decrease of phosphorylated tau (the conformation that allows it to accumulate into fibrils), resembling that of earlier disease stages. Blockade of PCDC1 also led to a decrease in tau-mediated neurodegeneration and p-tau staining. These data suggest that a reduction in immune mediators in the brain can attenuate some of the key features associated with disease progression in Alzheimer’s disease.
What's the impact?
This study suggests that tauopathy and neurodegeneration are linked to an immune system signature of activated microglia and T cells and that a reduction in the presence of these immune markers can delay disease progression. These mechanistic insights may aid in identifying therapeutic targets for preventing or slowing down neurodegeneration in Alzheimer’s disease. While these findings are compelling, the experiments were mostly performed in male mice - the need to replicate these findings in female mice is of paramount importance.
