Alzheimer’s disease (AD) is a complicated thing. Although amyloid-β (Aβ) is still considered to be the key to the pathogenesis of AD, which is supported by considerable evidence, the progression of AD brain atrophy is only associated with the accumulation of another pathological marker, tau protein.
How does tau protein mediate neurodegeneration?
Recently, a study published in Nature made a surprising discovery. David Holtzman’s team at the University of Washington finds that tau pathology leads to a distinct immune response in which microglia and T cells “cooperate” with each other to drive neurodegeneration in Alzheimer’s disease (AD). Depletion of T cells, inhibition of interferon-gamma, or inhibition of PD-1 significantly improve brain atrophy and cognitive behavior in mice. T cells are likely to become the next hot spot in AD treatment.
Why is brain atrophy only associated with tau protein but not with Aβ?
The researchers decide to take a thorough look at what is going on inside the brain. In this study, researchers use a total of three mouse models of AD: APP/PS1-21 (A/PE4), 5xFAD (5xE4), and tauopathy (TE4). The first two are characterized by Aβ pathology while the latter shows significant tau pathology and neurodegeneration. They express human APOE4 the same as control mice (E4). However, there is no difference between mice carrying APOE4 and APOE3 in subsequent studies, so the researchers believe that the APOE subtype does not affect experimental results.
Both A/PE4 and 5xE4 mice have high levels of Aβ deposition at 9.5 months, but no brain atrophy. At 9.5 months of age, TE4 shows obvious brain atrophy in the hippocampus, entorhinal cortex, and amygdala where tau pathology is most severe.
In the experiment, male mice show greater levels of brain atrophy, so subsequent studies have focused on them.
To figure out what’s going on in the brain, the researchers use single-cell RNA sequencing (scRNA-seq) to analyze immune cells and identify 12 subgroups of immune cells in the brain parenchyma. Surprisingly, the 9.5-month-old TE4 mice have a significantly increased percentage of T cells compared to younger mice or other groups of mice. The A/PE4 and 5xE4 mice do not have as many T cells even at 19 months of age. The number of T cells is positively correlated with the number of microglia and negatively correlated with the dentate gyrus thickness.
Researchers also analyze the brain samples from human AD patients with brain atrophy at different Braak levels and also find more T cells in brain regions with more severe tau pathology. This confirms an increase in the number of parenchymal T cells in the tau pathological brain area, independent of Aβ deposition.
What’s going on between microglia and T cells?
After further analysis of the cell phenotype, researchers find that it is a “two-way rush” between microglia and T cells mediated by tau pathology. Under tau pathology, brain parenchymal microglia will change into a state of disease-related activation, and T cells will be recruited into the brain and activated with the increase in the number of inflammatory chemokines and cytokines. IFNγ secreted by CD8+ T cells enhances tau pathology and neurodegeneration at least in part through microglia proinflammatory and antigen presentation. When neutralizing antibodies are used to reduce T cells, microglia in the mouse brain shift from an activated state to a more stable state. In addition, the level of phosphorylated tau protein in the hippocampus is significantly reduced, as is the concentration of the neurofilament light chain. And the mice show improvements in behaviors as well.
Researchers have also tried other ways to regulate T-cell function. Previous studies have found that PD-1 inhibition can effectively improve the cognitive function of AD mice. Researchers start anti-PD-1 treatment at the window of brain atrophy of mice (8-9.5 months of age), and find that the proportion of Treg in the brain of mice increases significantly, while the effector T cells do not change significantly. The immunosuppressive function of Treg is enhanced and tau-mediated neurodegeneration and tau phosphorylation are significantly reduced. However, researchers haven’t investigated how anti-PD-1 affects brain pathology, and further studies are required to clarify why anti-PD-1 therapy has the opposite effect on the brain as an anti-tumor therapy.
What’s to be explored further?
It is believed that the tau pathologic microenvironment in brain parenchyma plays an important role in T cell recruitment and transformation. What factors in this process cause T cell activation, such as modified tau proteins, other proteins, or myelin fragments released by damaged neurons, are also open to discussion. This will provide valuable interventions for preventing or reversing brain atrophy and neurodegeneration in tau disease.