Toll-like receptor-2 (TLR2), a member of the TLR family, plays an important role in the initiation and regulation of immune/inflammation response, which is a critical mechanism underlying Alzheimer's disease (AD). To clarify the role of TLR2 in the pathological process of AD, in the present study, TLR2 knockout plus APPswe/PSEN1dE9 transgenic mice (AD-TLR2KO) were generated. Neurobehavioral tests and brain MRI scan were conducted on mice at the age of 12 months. Additionally, neuron loss was evaluated using NeuN staining. Amyloid β protein (Aβ), glial fibrillary acidic protein (GFAP), endogenous ligands for TLR2, and the activation of downstream signaling of TLR2 in mouse brains were detected by immunohistochemistry and Western blots. The results demonstrated that TLR2 deficit induced learning disabilities, decreased spontaneous activity, increased anxiety and depression, and led to white matter damage (WMD), brain atrophy, loss of neurons, and glial activation. Moreover, TLR2 deficit aggravated impaired neurobehavioral functions and WMD in AD mice, but did not affect the Aβ deposition in mouse brains. Our data indicate that the genomic deletion of TLR2 impairs neurobehavioral functions, induces WMD and brain atrophy, and increases the activation of astrocytes, which in turn aggravate the symptoms of AD through a non-Aβ mechanism.

Myeloid differentiation primary-response protein-88 (MyD88) is one of adaptor proteins mediating Toll-like receptors (TLRs) signaling. Activation of MyD88 results in the activation of nuclear factor kappa B (NFκB) and the increase of inflammatory responses. Evidences have demonstrated that TLRs signaling contributes to cerebral ischemia/reperfusion (I/R) injury. However, the role of MyD88 in this mechanism of action is disputed and needs to be clarified. In the present study, in a mouse model of cerebral I/R, we examined the activities of NFκB and interferon factor-3 (IRF3), and the inflammatory responses in ischemic brain tissue using ELISA, Western blots, and real-time PCR. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. Our results showed that NFκB activity increased in ischemic brains, but IRF3 was not activated after cerebral I/R, in wild-type (WT) mice. MyD88 deficit inhibited the activation of NFκB, and the expression of interleukin-1β (IL-1β), IL-6, Beclin-1 (BECN1), pellino-1, and cyclooxygenase-2 (COX-2) increased by cerebral I/R compared with WT mice. Interestingly, the expression of interferon Beta 1 (INFB1) and vascular endothelial growth factor (VEGF) increased in MyD88 KO mice. Unexpectedly, although the neurological function improved in the MyD88 knockout (KO) mice, the deficit of MyD88 failed to reduce cerebral infarct size compared to WT mice. We concluded that MyD88-dependent signaling contributes to the inflammatory responses induced by cerebral I/R. MyD88 deficit may inhibit the increased inflammatory response and increase neuroprotective signaling.