Focusing on TLR4 and TLR2
Among the 10 known human TLRs, TLR4 and TLR2 have emerged as the primary culprits in neurodegenerative pathology. TLR4 is the receptor famous for detecting lipopolysaccharide (LPS) from bacteria, but in the brain, it has a sinister alter ego: it binds to amyloid-beta (Aβ) aggregates. This interaction triggers microglial phagocytosis (which is good) but also launches a massive inflammatory response (which is bad). Over time, the inflammatory signal dominates, leading to a toxic environment that actively harms neurons.
TLR2 and Synaptic Pruning
TLR2 plays a similarly dualistic role. While essential for sensing Gram-positive bacteria, in the nervous system, it helps regulate the formation and plasticity of synapses. However, in disease states, specific forms of Aβ and alpha-synuclein (the protein implicated in Parkinson's) can hijack TLR2 signaling. This not only fuels inflammation but can also directly interfere with synaptic integrity, leading to the early memory loss seen in Alzheimer's patients.
The Autism Connection
In Autism Spectrum Disorder, the story is one of systemic dysregulation. Post-mortem studies of autistic brains often reveal a state of chronic neuroinflammation, characterized by activated microglia and elevated cytokine levels. Both TLR2 and TLR4 have been found to be upregulated in peripheral blood cells of children with ASD. This "primed" immune state means that even minor infections or environmental stressors can trigger a disproportionate inflammatory response in the brain, potentially disrupting neural connectivity and exacerbating behavioral symptoms.
The Case for Specificity
The involvement of these specific receptors highlights the need for targeted intervention. Broad-spectrum anti-inflammatories like NSAIDs have largely failed in clinical trials for neurodegeneration, likely because they are too non-specific and do not address the upstream drivers of the inflammatory cascade. By specifically targeting TLR4 or TLR2, we can theoretically block the pathological signal at its source while leaving the rest of the immune system intact.
Excerpt from: Targeting Toll-like Receptors in Neurodegeneration: The Potential of Engineered Decoy Receptors as Therapeutic Innovations by Peter De Ceuster
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