Microglial immune memory in Parkinson's and Huntington's diseases: epigenetics, triggers, and therapies

Neurodegenerative disorders, like Parkinson's and Huntington's disease, have a profound global impact but currently lack effective treatments. Accumulations of misfolded proteins of α-synuclein and huntingtin are a common pathological hallmark in these diseases, respectiveley. Recently, the role of microglia and innate immune memory in modulating neurodegenerative diseases has been studied in more detail. This review explores the mechanisms of microglial activation in Parkinson's and Huntington's, emphasizing innate immune memory, epigenetic reprogramming, and the influence of external triggers such as lipopolysaccharides (LPS) and high-fat diets (HFD). The review also examines therapeutic strategies targeting microglia to mitigate neurodegeneration, including shifting microglial phenotypes from pro-inflammatory to anti-inflammatory states using epigenetic interventions. To support this review, a structured literature search was conducted using PubMed, Scopus, and Web of Science. Keywords included microglia, innate immune memory, epigenetics, neuroinflammation, and disease-specific terms. Future research should focus on improving animal models, investigating environmental stressors, and developing reliable biomarkers to strengthen translational approaches for neuroinflammatory-driven neurodegenerative diseases.