The TLR2-MyD88 Pathway in Alzheimer’s Disease: Linking Innate Immunity to Neurodegeneration

Image Credit: [1]

Writer: Ivan Yu ‘29

Editor: Elise Park ‘28

Alzheimer’s Disease (AD) is a neurodegenerative disorder that is characterized by cognitive decline and memory loss, impacting portions of the elderly and of middle-aged adults. While classical models of AD pathogenesis have centered around amyloid-beta (Aβ) accumulation and tau pathology, increasing studies have highlighted the central role of neuroinflammation within disease progression. More specifically, microglial activation in response to Aβ aggregation triggers innate immune cascades which further neuronal injury. Among these, toll-like receptors, specifically toll-like receptor 2 (TLR2) and its adaptor protein MyD88, have risen as key mediators which link innate immune recognition to inflammation. Better understanding the involvement of the TLR2-MyD88 pathway within AD is important to not only provide insight into disease mechanisms but also to discover potential avenues for therapeutic intervention strategies.

Recent studies have highlighted the upregulation levels of TLR2 and MyD88 protein levels in individuals with AD dementia compared to those with mild cognitive impairment (MCI) or no cognitive impairment (NCI) [2]. These levels of proteins show a positive correlation with Braak staging, a measurement of neurofibrillary tangle pathology, overlapping to establish a link between TLR2-MyD88 axis and disease severity. The mechanisms involved within pathways contribute to pro-inflammatory signaling. Fibrillar Aβ has been recognized as a binding molecule for TLR2, a process which leads to the recruitment of intracellular adaptor protein MyD88, initiating a cascade sequence that activates nuclear factor kappa B (NF-kB) and mitogen-activated protein kinase (MAPK) pathways [3]. This activation drives transcription of pro-inflammatory cytokines like TNF-α and IL-1β and inducible nitric oxide synthase (iNOS) [4]. The enzyme iNOS is critical in catalyzing production of high, sustained levels of nitric oxide (NO); however its overproduction of NO may result in oxidative stress where NO builds and reacts with radicals, causing extensive damage to cellular components [5]. Thus, this initially protective inflammatory response contributes to a highly toxic environment, leading to synaptic dysfunction and ultimately neuronal death. 

It is important to note that the influence of TLR2-MyD88 signaling extends beyond amyloid pathology and can even have a direct impact within tau hyperphosphorylation, a driver in AD pathology. While tau protein, under normal conditions, stabilizes microtubules which are structural components within neurons that facilitate transport, its hyperphosphoralization causes tau to detach and misfold developing neurofibrillary tangles (NFTs). These NFTs are insoluble aggregates that may disrupt neuronal function and lead to cellular death. Critically, neuroinflammation driven by the TLR2-MyD88 axis activates kinases like glycogen synthase kinase-3β (GSK-3β) and p38 MAPK, which are known to directly phosphorylate tau [6]. These observed correlations between the TLR2, MyD88 levels with Braak staging collectively suggest this inflammatory pathway may accelerate tau pathology, connecting the two hallmarks of AD and prompting a damaging cycle. 

This aspect of understanding inflammatory characteristics and its involvement with AD’s pathogenesis is essential for therapeutic targeted immunomodulation. Rather than completely suppressing immunological responses, a precise inhibition of TLR2, MyD88 signaling that drives neurodegeneration may be further explored. Existing studies posit that TLR signaling may be a new therapeutic target for AD, and thus create new approaches involving small-molecular inhibitors to selectively disrupt interaction, or gene silence to downregulate TLR2 expression [7]. These new avenues of research hold potential to disrupt the self-perpetuating cycle of inflammation and neurodegeneration, with potential to slow or halt AD progression. 

References

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