PD-1/PD-L1 Inhibitors for Alzheimer’s Pathology: A Literature Review

Abstract

Alzheimer’s Disease (AD) is a neurodegenerative disease where the buildup of insoluble amyloid-beta plaques causes synaptic dysfunction, tau pathology, and loss of neurons, which leads to mood disorders, mental decline, and dementia. PD-1/PD-L1 is an immune checkpoint which involves the binding of PD-L1 (Programmed Death Ligand 1) on a target cell to the PD-1 receptor (Programmed Cell Death Protein 1) on an immune cell. This immune checkpoint allows for the suppression and regulation of the immune system. Previous studies have shown that the blockade of PD-1/PD-L1 allows for the activation of the immune cell and pro-inflammatory responses. However, in AD, chronic neuroinflammation has been strongly linked with the pathogenesis of the disease. The use of PD-1 inhibitors in AD is unorthodox, but not unfounded, since the blockade of PD-1/PD-L1 can reduce local brain inflammation by the recruitment of immune cells for Aβ clearance, even if the immune cells are pro-inflammatory. Furthermore, PD-1 inhibitors have been found to inhibit tauopathy and there is even potential in efficient combination therapies with NOD2. The PD-1/PD-L1 axis in neuroinflammation and AD is highly complex, and through this review, we aim to provide some insight into this relationship and explore the potential of it as an AD treatment.