TLR2 and TLR4-mediated inflammation in Alzheimer’s disease: self-defense or sabotage?

Alzheimer’s disease (AD) is an irreversible that leads to neurodegeneration. The underpinning mechanisms of neuronal cell death are a matter ongoing debate regarding the impact accumulation amyloid beta (Aβ) peptide and post-translation modifications tau protein. However, growing area research one may provide more rigorous account early changes seen in brains inflammation. Brain inflammation coordinated immune response subtle brain’s microenvironment indicative injury disease. Neuroinflammation can be either short lived or chronic lead brain structure its neurochemistry. In AD, ability self-regulate inflammatory signals compromised deleterious response. Understanding molecular entities involved neuroinflammation AD will open door much needed novel therapeutic strategies. this cautionary tale with respect timing exact nature proposed strategy. perspective article, we briefly introduce current view dual Toll-like receptor (TLR) 2 TLR4-driven highlight why believe modulating status within defined time window might better concept than globally supressing it for prolonged time. Molecular studies as well neuropathological mouse tissue post-mortem patient have provided striking evidence correlation between AD. addition, clinical individuals high levels markers increased risk developing dementia (Dziedzic, 2006). relationship still not understood. While some claim contributes development progression, others suggest merely result This controversy has relevance given increase anti-inflammatory drugs being managing complex neurological disorders, such context non-steroidal (NSAIDs) been trialed potential treatment option. despite promising initial epidemiological data, meta-analyses trials showed little no benefits frequency adverse health effects. We postulate lack robust effects likely caused by inappropriate intervention. Notably, most investigated NSAIDS on elderly when targeted approach finite proven successful. should administered before phase diagnosis through presentation (Figure 1A). could achieved using advanced neuroimaging technology direct measurement (e.g., ultra-high field imaging coupled iron oxide nanoparticle injection), indirect via blood-brain barrier permeability.Figure 1: Proposed atrophy proinflammatory signaling induced TLR2 TLR4.(A) A temporal schematic progression (AD). profile indicates progressive degeneration age indicated (orange line, right axis), highlights presentation. Alongside atrophy, mapped (blue left axis). Here, observed counteract related damage. curtailed system represents ‘good’ (green shaded area). patients, secondary observed. escalates unchecked subsequently degenerative processes. ‘bad’ pink area. leaves discrete window, which targeting beneficial neurodegenerative diseases (B) Proinflammatory feed forward loops mediated TLR4. Aβ DAMPs bind activate Membrane-bound TLR4 recruit MyD88 TRAF6 into complex. activation TAK1 turn IKK composed IKKα, IKKβ NEMO. Once activated upstream signals, phosphorylates inhibitory IκB proteins thereby mediating their proteasomal degradation. Degradation liberates nuclear localisation DNA binding NF-κB subunits leading translocation transcription pro-inflammatory target genes including TNF-α, IL-1β IL-8. secreted, these respective receptors further increasing activity. loop also involves TAK1-mediated kinases JNK, ERK1/2, p38. results activity factor AP1 additional targets IL-2, IL-5.From neurobiochemical point view, acute often attributed TLRs. TLRs type I integral membrane extracellular domain, transmembrane cytoplasmic domain where N-terminal end contains leucine-rich ligands. TLR family innate responses oversees recognition broad range pathogen-derived molecules (pathogen associated patterns). respond variety other indicate damage (danger-associated patterns) serum Aβ. Activation both danger-associated patterns pathogen culminates prototypic, factor-κB (NF-κB) induces local many tumour necrosis alpha, interleukin 1 (IL-1β) IL-8 mediators generating 1B). TLR-signaling c-Jun (JNK), signal-regulated 1/2 (ERK1/2), p38 activator protein (AP1) but limited IL-2 IL-5. Expression immune-competent cells expressed neurons, microglia, astrocytes, oligodendrocytes (Bsibsi et al., 2002). Importantly, microglia reported express wide repertoire constitutively at levels. pertinent study pivotal role initiation, maintenance (Landreth Reed-Geaghan, 2009). microglia-mediated, NF-κB-dependent regulation homeostasis least partly (Kielian, homeostasis, physiological induce contribute neuroprotection (Kaltschmidt 2005). neurodegeneration Thus, strength contribution individual cellular players evidently plays important death. Biochemical genetic vivo approaches alongside multitude vitro strong drive dependent manner (Song 2011; Liu 2012). It mRNA animal models human samples, although observations contested. These discrepancies timeline expression from initiation symptomatic Functional demonstrated increases microglial uptake exogenous contrasts reports indicating inhibition suppresses pathology. datasets, suggestive contribution, arise work mice overexpress precursor presenilin (APP/PS1). data 7-month intervention anti-TLR2 antibody prior cognitive impairment model. Follow up same model TLR2–/– revealed decline accelerated TLR2–/–/APP-PS1 compared APP/PS-1 mice. deficits restored viral induction (circa 3 months). Interestingly, TLR2-dependent JNK/NF-κB linked singling out main protagonist would wrong all complementary manner. Animal transgenic modulation outcomes. ablation manipulation led enhanced deposition worsening outcomes control animals. Conversely, long-term mild stimulation lipopolysaccharide administration weeks onset deficits, improved performance reduced clearance CD36 patients. Collectively, roles TLR2/TLR4 dynamically regulated considerable (both positive negative) respect, favourable contrast situation (Huang 2017). known subject crosstalk (Tan 2014) cross-coupling similar strategy applied signaling. Briefly, involve activating whilst suppressing phase. As surface receptors, represent easily accessible drug targets. explored preclinical Repeated systemic injections biased agonist monophosphorylic lipid APPswe/PS1 resulted significant reduction load function. TAK-242, specific inhibitor signaling, addition characterized candidates, several compounds believed inhibit α-mangostin, geraniin, osmotin, berberine mode action clarified. TLR4, there chemical Nevertheless, intranasal blocking TLR2-interacting memory learning 5XFAD Overall, emerging precedes symptoms. For phase, our knowledge largely comes studies. begun reveal insights Late stage predominantly plaque deposition, whereby hallmark plaques sites recurrent array phenotypes constitutive NF-κB. Summary conclusions: summary, rapidly expanding diseases. presents snapshots production biomarkers. underestimation complexities processes disorders failure NSAID based prevention strategies intrinsically TLR4-mediated self-defence mechanism affords protection. Therefore, global preventive measure during only ineffective even regenerative contrast, uncontrolled continuous resulting feed-forward causative progression. Together creates aiming prevent switch slow down challenge community now accurately identify clinically relevant population.