Although the prevailing view remains that β-amyloid (Aβ) is key in the pathogenesis of AD, and there is considerable research evidence to support this, the progression of AD brain atrophy is associated with the accumulation of only one other pathological marker, tau protein.
Recently, a study published in the journal Nature made a surprising discovery. David Holtzman's team at the University of Washington's AD powerhouse found that tau pathology leads to a unique immune response in which microglia and T cells "collaborate" to drive neurodegeneration in AD.
Depletion of T cells, inhibition of interferon gamma, and inhibition of PD-1 all significantly improved brain atrophy and improved cognitive behavior in mice. Could T cells be the next new hot spot for treating AD?
In this study, the researchers used a total of three AD model mice, APP/PS1-21 (A/PE4), 5xFAD (5xE4), and tauopathy (TE4), the first two with predominantly Aβ pathology and the latter able to observe significant tau pathology and neurodegenerative lesions. Both they and the control mice (E4) expressed human APOE4. APOE4-carrying mice did not vary from APOE3-carrying mice in the follow-up investigation, therefore the researchers concluded that the APOE subtype did not influence the experimental outcomes.
Both A/PE4 and 5xE4 mice already had high levels of Aβ deposition at 9.5 months of age, but no brain atrophy. In contrast, TE4 showed significant brain atrophy at 9.5 months of age visible at the hippocampus, internal olfactory cortex, and amygdala where tau pathology is most severe.
Experimentally, the level of brain atrophy was more severe in male mice, so all subsequent studies focused on male mice.
To determine what is going on in the brain, the researchers used immune single-cell RNA sequencing (scRNA-seq) technology to investigate immune cells in the brain and discovered a total of 12 immune cell subpopulations in the brain parenchyma.
As a novel discipline in biology, scRNA-seq offers the sequencing information of individual cells and uncovers the individuality of each cell. By knowing the function of each individual cell, scRNA-seq can answer problems that cannot be answered by bulk analysis. The procedure of scRNA-seq is comparable to that of bulk RNA-seq and consists of reverse transcription (RT), amplification, library construction, and sequencing.
Interestingly, the proportion of T cells in TE4 mice aged 9.5 months was much higher than in younger mice or other mouse strains. A/PE4 and 5xE4 mice, in comparison, did not have as many T cells until they were 19 months old. The number of these T cells was positively linked with the number of microglia and negatively correlated with the thickness of the dentate gyrus. The researchers also analyzed brain samples from human AD patients with brain atrophy at different Braak classifications and again found more T cells in brain regions with more severe tau pathology. This confirms the presence of increased numbers of T cells in the brain parenchyma of tau pathology, independent of Aβ deposition.
During tau pathology, brain parenchymal microglia shifts to a disease-associated activation pattern, accompanied by an increase in inflammatory chemokines and cytokines that attract and activate T cells in the brain. In turn, IFN released by CD8+ T lymphocytes exacerbates tau pathology and neurodegeneration via microglial proinflammation and antigen presentation.
Lowering of T cells with neutralizing antibodies altered microglia in the mouse brain from an active to a stable state, accompanied by a substantial decrease in phosphorylated tau protein levels in the hippocampus and neurofilament light chain concentrations. In addition, several behavioral symptoms in mice were improved.
Several strategies for modulating T-cell activity have also been investigated by researchers. In a previous study, PD-1 inhibition was found to be effective in enhancing cognitive function in AD mice, and the researchers discovered that anti-PD-1 treatment was initiated in mice during a window of brain atrophy (8-9.5 months of age) and discovered a significant increase in the proportion of Treg in the mouse brain, without significant changes in effector T cells. The enhanced immunosuppressive action of Treg therefore lowered neurodegeneration and tau protein phosphorylation caused by tau.
Nevertheless, the researchers did not study how anti-PD-1 impacts brain pathology, and it remains unclear why anti-PD-1 therapy has the opposite effect in the brain compared to its antitumor effect.
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