Microglia are the resident immune cells of the brain, and they are critical in maintaining homeostasis during health, but significantly contribute to pathology in the diseased brain. For example, microglial constantly remove beta-amyloid peptides as they are created in the healthy brain, but in Alzheimer's disease microglia enter a pro-inflammatory state that both leads to decreased removal of beta-amyloid as well as to release of reactive oxygen species and other molecules that directly contribute to damage to the brain tissue. Microglia play a similar role in multiple additional neurological diseases. Thus, drugs that can convert microglia from a pro-inflammatory disease phenotype to a healthy phenotype may be beneficial for the treatment of multiple neurological diseases. However, the blood-brain-barrier (BBB) prevents many drugs from reaching the brain, preventing the treatment of multiple neurological diseases. Hydroxy-terminated poly(amidoamine) dendrimers (PAMAM dendrimers) have been shown to bypass the BBB and reach microglial after intravenous injection in multiple different neurological disease models. Herein, we present D-Tesaglitazar (D-Tesa), which is a dendrimer-drug conjugate with the PPAR alpha/gamma dual agonist Tesaglitazar. We demonstrate D-Tesa is capable of reducing the amount of nitric oxide that microglia secrete, increasing the amount of beta-amyloid taken up by phagocytosis, and changing the gene expression from a 'M1-like' towards a mixed 'M2-like' phenotype. D-Tesa thus has the potential to help treat multiple neurological disease given the shared role of microglia in multiple different diseases states, including Alzheimer's disease, Parkinson's disease and multiple additional neurological diseases.
