Nature: Can PD-1 inhibitors treat Alzheimer’s disease?

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Nature: Can PD-1 inhibitors treat Alzheimer’s disease?

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“Nature”: Can PD-1 inhibitors treat Alzheimer’s disease? 

Scientists discover for the first time that tau pathology interacts with microglia and T cells to drive neurodegeneration in Alzheimer’s disease.

Although the mainstream view still believes that β-amyloid (Aβ) is the key to the pathological mechanism of AD, and there is also a lot of research evidence to support it, the progression of AD brain atrophy is only related to the accumulation of another pathological marker- tau protein .

How exactly does tau mediate neurodegeneration? Suffice it to say, we don’t know yet.

On March 09, a study published in the journal Nature has made a surprising discovery.

The team of David Holtzman, an AD guru at the University of Washington, found that tau pathology leads to a unique immune response in which microglia and T cells “cooperate” with each other to drive neurodegeneration in AD .

Depletion of T cells, inhibition of interferon gamma, or inhibition of PD-1 all significantly ameliorated brain atrophy and improved cognitive behavior in mice . Will T cells be the next new hotspot in the treatment of AD?

Mechanism diagram

Why is brain atrophy only related to tau protein but not Aβ? The researchers decided to do a thorough search of what’s going on in the brain.

In this study, the researchers used a total of three AD model mice, APP/PS1-21 (A/PE4), 5xFAD (5xE4), and tauopathy (TE4) . One can observe obvious tau pathology and neurodegeneration . They and control mice (E4) both express human APOE4.

However, in the results of follow-up studies, there was no difference between mice carrying APOE4 and APOE3, so the researchers believed that the APOE subtype did not affect the experimental results.

Both A/PE4 and 5xE4 mice had high levels of Aβ deposition at 9.5 months of age, but no brain atrophy; while TE4 had the most severe tau pathology in the hippocampus and entorhinal cortex at 9.5 months of age Significant brain atrophy occurred in the amygdala and amygdala .

Significant brain atrophy in tau pathological mice (TE4)

In the experiment, the level of brain atrophy in male mice was more severe, so subsequent studies focused on male mice.

In order to understand what is going on in the brain, the researchers analyzed immune cells in the brain using immune single-cell RNA sequencing (scRNA-seq) technology, and identified 12 immune cell subsets in the brain parenchyma.

Unexpectedly, the percentage of T cells was significantly increased in 9.5-month-old TE4 mice compared with young mice or other groups of mice . The A/PE4 and 5xE4 mice did not even have as many T cells by 19 months of age.

Significantly higher proportion of T cells in TE4

The number of these T cells correlated positively with the number of microglia and negatively with the thickness of the dentate gyrus.

The researchers also analyzed brain samples from human AD patients with different Braak grades of brain atrophy, and also found more T cells in brain regions with more severe tau pathology.

This confirms that there is an increase in the number of brain parenchymal T cells in the tau pathological brain region, which is not related to Aβ deposition.

More T cells (green) and microglia (purple) are present in high Braak grade samples

So what’s going on?

After further analyzing the cell phenotype, the researchers found that this was actually a “two-way rush” between microglia and T cells under the coordination of tau pathology.

Under tau pathology, the phenotype of brain parenchymal microglia will shift to a disease-associated activation state, accompanied by an increase in the number of inflammatory chemokines and cytokines, recruiting and activating T cells into the brain; while CD8 + T cells Secreted IFNγ enhances tau pathology and neurodegeneration at least in part through microglial pro-inflammatory and antigen presentation.

Using neutralizing antibodies to reduce T cells, microglia in the mouse brain switched from an activated state to a more stable state, and the level of phosphorylated tau protein was significantly reduced in the hippocampus, as was the concentration of neurofilament light chains.

In addition, the mice showed improvements in a variety of behaviors.

Depletion of T cells significantly reduces brain atrophy in TE4 mice

The researchers also tried other ways to modulate T cell function. Previous studies have found that inhibiting PD-1 can effectively improve the cognitive function of AD mice.

Researchers started anti-PD-1 treatment in the mouse brain atrophy window (8-9.5 months old) and found that the proportion of Treg in the mouse brain was significantly However, effector T cells did not change significantly.

As a result, the immunosuppressive function of Treg was enhanced, and tau-mediated neurodegeneration and tau protein phosphorylation were significantly reduced.

However, the researchers did not further study how anti-PD-1 affects brain pathology. Why anti-PD-1 treatment in the brain shows the opposite effect to anti-tumor requires follow-up studies to clarify.

The researchers believe that the tau pathological microenvironment in the brain parenchyma plays an important role in the recruitment and transformation of T cells.

Which factors lead to T cell activation in this process, such as various modified tau proteins, or other proteins or myelin fragments released by damaged neurons, etc., will also be a question worth discussing.

This would provide a valuable intervention to prevent or reverse brain atrophy and neurodegeneration in tauopathies.

References:

[1]Chen, X., Firulyova, M., Manis, M. et al. Microglia-mediated T cell infiltration drives neurodegeneration in tauopathy. Nature (2023). https://doi.org/10.1038/s41586-023- 05788-0

Nature: Can PD-1 inhibitors treat Alzheimer’s disease?

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