Unraveling cerebral ultrastructural alterations in TLR4-mediated neuroinflammation via transmission electron microscopy: a systematic preclinical review.

Ultrastructural alterations in the central nervous system-such as synaptic dysfunction, axonal injury, and demyelination-contribute to the cognitive and sensorimotor deficits observed in neurological damage, in which TLR4-mediated neuroinflammation is a key pathological feature. This systematic review synthesizes evidence from 20 rodent studies employing transmission electron microscopy (TEM) to investigate central ultrastructural alterations induced by neuroinflammation, with a focus on the brain. A search was performed on Embase, PubMed, Scopus, and Web of Science databases. Study quality was assessed using the SYRCLE Risk of Bias tool for in vivo/ex vivo studies and an adapted QUIN tool for in vitro studies. Most studies have modeled neuroinflammation through LPS-infection or toxic insults, which have been implicated in disorders ranging from early brain injury to late-onset neurodegeneration, such as Alzheimer's disease. We observed that ultrastructural alterations originate from changes in glial morphology and function, subsequently affecting intracellular organelles and the extracellular space, thereby compromising cellular metabolism and neural integrity. TEM results show vascularized regions and protective barriers, enriched in glial cells, are particularly susceptible to early ultrastructural impairment. The damage extends to myelin architecture and axonal structure, which exhibit aberrant characteristics. Although the molecular mechanisms of neuroinflammation are well characterized, its ultrastructural consequences remain poorly explored. Elucidating these alterations through TEM studies provides a basis for targeted therapeutic strategies in neuroinflammation-related conditions.