Intracortical injection of immune checkpoint inhibitor promotes monocyte/macrophage infiltration and restores microglial function and neuronal activity in an AD mouse model

Understanding the intricate interplay among immune responses and homeostatic cell function in Alzheimer's disease (AD) remains challenging. Here, we present a novel strategy to mitigate AD pathology by directly modulating the immune checkpoint PD-1/PD-L1 signaling pathway in the brain, where elevated levels of microglial PD-1 and astrocytic PD-L1 have been observed. We found that a single intracortical injection of anti-PD-L1 antibody facilitates the infiltration of peripheral immune cells into the brain, including IL-10-secreting Ly6C+ monocytes. Subsequently, this leads to the restoration of microglial homeostatic functions including an increase in P2RY12 expression, which enhances microglial process extension. This cascade of events following anti-PD-L1 injection is crucial for regulating abnormally hyperactive neurons and reducing amyloid-beta plaques. These findings suggest that the direct application of immune checkpoint blockade in the brain could offer a new approach to managing the delicate cell-cell interactions among neurons, glial cells, and peripheral immune cells in the AD brain.