Dendrimer-tesaglitazar conjugate induces a phenotype shift of microglia and enhances β-amyloid phagocytosis

Switching microglia from a disease exacerbating, 'pro-inflammatory' state into a neuroprotective, 'anti-inflammatory' phenotype is a promising strategy for addressing multiple neurodegenerative diseases. Pro-inflammatory microglia contribute to disease progression by releasing neurotoxic substances and accelerating pathogenic protein accumulation. PPAR alpha and PPAR gamma agonists have both been shown to shift microglia from a pro-inflammatory ('M1-like') to an alternatively activated ('M2-like') phenotype. Such strategies have been explored in clinical trials for neurological diseases, such as Alzheimer's and Parkinson's disease, but have likely failed due to their poor blood-brain barrier (BBB) penetration. Hydroxyl-terminated polyamidoamine dendrimers (without the attachment of any targeting ligands) have been shown to cross the impaired BBB at the site of neuroinflammation and accumulate in activated microglia. Therefore, dendrimer conjugation of a PPAR alpha/gamma dual agonist may enable targeted phenotype switching of activated microglia. Here we present the synthesis and characterization of a novel dendrimer-PPAR alpha/gamma dual agonist conjugate (D-tesaglitazar). In vitro, D-tesaglitazar induces an 'M1 to M2' phenotype shift, decreases secretion of reactive oxygen species, increases expression of genes for phagocytosis and enzymatic degradation of pathogenic proteins (e.g. beta-amyloid, alpha-synuclein), and increases beta-amyloid phagocytosis. These results support further development of D-tesaglitazar towards translation for multiple neurodegenerative diseases, especially Alzheimer's and Parkinson's Disease.

Automated summary

Switching microglia from a pro-inflammatory to an anti-inflammatory phenotype could be a promising strategy for treating neurodegenerative diseases. Using PPAR alpha/gamma agonists may help achieve this switch, but overcoming the challenges of the blood-brain barrier is essential for successful treatment outcomes.