PD-L1 Blockade in the Brain Restores Measures of Glial Cell Function
PD-L1 found on the surface of cells is a well known immune checkpoint protein. When it binds to the receptor PD-1 found on the surface of T cells and B cells, it acts to suppress immune activity. This is a necessary brake to avoid runaway immune reactions, but because it is also abused by cancer cells to shield them from the immune system, the cancer research community has given a great deal of attention to this and other forms of immune checkpoint. Checkpoint inhibitors such as antibodies for PD-L1 are a well established class of drug intended to enable the immune system to better attack cancerous cells.
In today's open access paper, researchers report on the results of delivering a PD-L1 antibody directly into the brains of Alzheimer's disease model mice. Past research has suggested that the more usual intravenous delivery outside the brain can help improve clearance of protein aggregates in the brain by immune cells, but the mechanism would have to be fairly indirect. The immune systems of body and brain are quite distinct from one another, separated by the blood-brain barrier, and in normal circumstances only small numbers of immune cells from the body can enter the brain. Would a more direct targeting of brain cells produce a larger effect?
While the authors of today's paper view checkpoint inhibition in terms of enabling greater clearance of protein aggregates by a more active population of immune cells, it seems plausible that clearance of senescent cells in the brain is equally important. Like cancerous cells, senescent cells in aged tissues have been found to employ immune checkpoint activation to preserve themselves from clearance by the immune system. Senescent cells are clearly detrimental to the aging brain, a major contribution to disruptive chronic inflammation. It is plausible that checkpoint inhibition could reduce the burden of senescent cells in an aging brain. Alas, the researchers here restrict themselves to measuring only some functional aspects of brain cell populations, so whether or not this is the case in the present study is unclear.
Immunotherapy targeting the immune checkpoint pathway, particularly the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis, has emerged as a promising strategy for treating Alzheimer's disease (AD). Previous studies have suggested that the systemic administration of anti-PD-L1 antibody reduces amyloid-β burden and improves cognitive outcomes in AD mouse models, primarily by activating peripheral immune responses and promoting the recruitment of monocyte-derived macrophages (MDMs) into the brain. However, these studies have primarily focused on peripheral immune cells.
Unlike the systemic approaches, our study emphasizes the direct modulation of PD-1/PD-L1 signaling within the brain and its implications for glial and neuronal functions. Microglia, the brain's intrinsic immune cells, are central to maintaining neuronal homeostasis; they monitor neuronal activities and modulate synaptic functions. In AD, microglia often exhibit a dysfunctional state characterized by impaired phagocytosis, reduced motility, and altered gene expression. Astrocytes also play a vital role in maintaining brain homeostasis by modulating neuronal activities, thereby regulating synaptic transmission and supporting microglial function. PD-L1 expressed on astrocytes has been implicated in neuroimmune interactions, but its specific role in AD has not been fully investigated.
Increased PD-1 and PD-L1 levels in microglia and astrocytes show features analogous to their sustained expression in exhausted peripheral immune cells during chronic infections and tumors, in which they help suppress heightened immune responses. In AD, such upregulation of PD-1/PD-L1 may contribute to glial dysfunction, with potential consequences for immune surveillance and neuronal modulation. Consequently, targeting glial PD-1/PD-L1 signaling directly within the brain could provide a promising strategy to restore glial and neuronal function.
In this study, we investigated the effects of direct intracortical anti-PD-L1 administration on microglial function, neuronal activity, and amyloid-β pathology in a 5xFAD mouse model using real-time in vivo two-photon microscopy. Seven days after the intracortical injection, the anti-PD-L1 treatment effectively rescued microglial process motility and restored spontaneous neuronal calcium activity, while reducing amyloid-β plaque burden and increasing plaque-associated microglia. Furthermore, astrocyte-specific PD-L1 knockdown showed effects similar to those resulting from the inhibition of the glial PD-1/PD-L1 pathway. Collectively, our findings suggest that brain-intrinsic glial PD-1/PD-L1 modulation reduces amyloid-β pathology along with restoring functional interactions among microglia, astrocytes, and neurons.