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TLR2 forms heterodimers with TLR1 and TLR6 and amyloid β (Aβ) plaques in post-mortem brain sections
mediates the host response to Gram-positive bacteria and in an AD mouse model, raising the question
and yeast infections via stimulation of NF-κB signaling whether and how TLR2 might be involved in AD
[71]
pathway. Recently, it has been demonstrated that pathology. [47,79] Injecting Aβ in the hippocampus of
TLR2 can also form a heterodimer with TLR10 acting wild type (WT) mice increases TLR2 expression
as an inhibitory receptor with immune suppressing in microglia; Aβ protein was unable to induce a
effects. [72] microglia-dependent inflammatory response in the
cortex of TLR2 deficient mice. [80,81] The interaction
PD between Aβ and TLR2 also affects behavior; TLR2
Clinical studies have shown that TLR2 expression deficient mice showed more pronounced cognitive
is increased in PD. In particular, one study revealed impairments, which correlated with increased
specific increase in microglial TLR2 in the substantia levels of Aβ protein. It remains to be demonstrated
[81]
nigra and the hippocampus in the early stages of whether there is a direct binding between TLR2 and
the disease, but not during the late stages, while the Aβ protein.
[73]
another study showed an increase in TLR2 in the
striatum of advanced PD patients. These results AD-related damage to neurons is at least partially
[74]
indicate that expression of TLR2 in either early or dependent on microglial TLR2, since the effects of
advanced PD could be region-specific, and that TLR2 Aβ protein and TLR1/2 ligand on neuronal viability
is not necessarily expressed in all regions at the are additive and dependent on microglia, and the
same time. The involvement of TLR2 in PD might be microglial inflammatory and phagocytic response
two-dimensional: microglial activation of TLR2 can to Aβ protein is TLR2-dependent. [80,82,83] Aβ protein-
induce neurotoxicity or TLR2 can be important for the and TLR1/2 ligand-induced microglial-mediated
clearance of α-synuclein, thus being neuroprotective. neuronal death is likely conferred through the release
of inflammatory mediators. There is also indication
[84]
In support of this function is the evidence that for the involvement of neuronal TLR2 in AD. Neuronal
TLR2 polymorphism tends to be associated with an TLR2 was upregulated when neuronal cultures were
increased risk of PD. This polymorphism results in exposed to hydroxynonenal (HNE), an AD-related
altered TLR2 promoter transcriptional activity leading lipid peroxidation product, but not when exposed to Aβ
to lower expression of TLR2. [75,76] Taken together, these [40]
findings are indirect indications of a possible role of protein. HNE exposure also resulted in an increase
TLR2 in the pathology of PD. in both phosphorylated JNK and cleaved caspase 3;
however these effects were abolished by TLR4 knock-
Overexpression of human α-synuclein in mice out. Therefore, the functional consequence of TLR2
resulted in microglial activation and an increase upregulation in neurons by HNE is not yet known.
in TLR2 expression. Microglia seem to form a
[74]
crucial link between TLR2 and PD pathology; an In summary, microglial TLR2 is key in the
idea that is supported by results from cell culture neuroinflammatory response of AD pathology, but
studies: exposure to α-synuclein activates cultured is also responsible for the clearance of Aβ protein,
microglia and increases their TLR2 expression; [49,77] while neuronal TLR2 might also play a part in this
it also changes the response of microglial cells to neuroinflammatory environment. So TLR2 can have
TLR1/2 stimulation by increasing their inflammatory either a beneficial or detrimental role in AD.
response. [78]
Stroke
It can be speculated that α-synuclein triggers Neuronal TLR2 was studied in the cerebral ischemia/
neuroinflammation through microglial TLR2, reperfusion (I/R) animal model of stroke. Cortical and
initiating a positive feedback loop by increasing hippocampal neurons of WT mice subjected to I/R
TLR2 expression on the microglia, resulting in injury showed transient TLR2 protein upregulation,
neurodegeneration and disease progression. However, although upregulation in the cortex may not have been
-/-
it is not yet clear why this process would be limited exclusively neuronal. [29,37,39] TLR2 mice exposed to I/R
to the early disease stage in the substantia nigra showed less brain damage, smaller infarct volumes
-/-
and the hippocampus, while only occurring later in and less neurological deficits than WT mice, and TLR2
the striatum, or whether and how neuronal TLR2 mice and mice treated with TLR2 antibody showed less
participates in this process. inflammatory cell accumulation and reduced neuronal
loss. [29,39,42] From a treatment perspective it is interesting
AD that the anti-inflammatory agent baicalin, used for
TLR2 expression was found on microglia surrounding the treatment of stroke, reduced TLR2 expression in

30 Neuroimmunol Neuroinflammation | Volume 3 | Issue 2 | February 15, 2016