Title : Neuroinflammation-autophagy crosstalk in neurodegenerative brain disorders: Mechanistic and therapeutic perspectives
Abstract:
Neurodegenerative brain disorders, such as Alzheimer’s disease, Parkinson’s disease, and associated dementias, are marked by a gradual loss of neurons, primarily driven by ongoing neuroinflammation and disrupted cellular homeostasis. Recent studies underscore an important reciprocal interaction between neuroinflammatory signaling and autophagy, which establishes this relationship as a key factor influencing neuronal survival and disease advancement. The activation of innate immune responses, especially through microglial inflammasomes and pro-inflammatory cytokine pathways, impairs autophagic processes, resulting in the build-up of misfolded proteins, damaged mitochondria, and oxidative stress. On the other hand, impaired autophagy exacerbates neuroinflammatory responses by facilitating mitochondrial dysfunction, generating reactive oxygen species, and releasing damage-associated molecular patterns. This harmful cycle speeds up synaptic impairment, increased neuronal susceptibility, and cognitive decline in various neurodegenerative diseases.
At the molecular level, significant regulators such as the NLRP3 inflammasome, mTOR, AMPK, NF-κB, and pathways related to mitophagy connect inflammatory and autophagic processes, providing mechanistic understanding of disease variability and progression. Preclinical investigations indicate that either pharmacological or genetic alterations in autophagy can mitigate neuroinflammation, restore cellular homeostasis, and offer neuroprotective effects. Importantly, natural bioactive substances and repurposed drugs that focus on redox balance, epigenetic modification, and mitochondrial quality control have shown potential in reshaping the neuroinflammation–autophagy axis.This abstract summarizes recent advancements in the understanding of the mechanistic relationship between neuroinflammation and autophagy in neurodegenerative brain disorders and explores new therapeutic strategies aimed at re-establishing their functional equilibrium. Focusing on this interplay presents a promising disease-modifying strategy with potential implications for slowing neurodegeneration and enhancing clinical outcomes.
