Synaptic function and memory performance are disrupted by soluble form of β-amyloid (Aβ). In the previous study, we found that early activation of microglia by toll-like receptor 2 (TLR2) attenuated Alzheimer’s disease-associated cognitive deficit. This study was designed to investigate whether pretreatment with the TLR2 receptor ligand can regulate microglia to produce interferon β (INFβ) in a rat model of Alzheimer’s disease. For this purpose, the BV-2 cell line was cultured in a 24-well plate, treated with Pam3Cys (1 μg/ml), and then incubated with oligomeric Aβ for 24 h. The expression of TRIF, IRF3, and INFβ was measured by western blot technique. For in-vivo study, bilateral guide cannulas were streotaxically implanted in the right and left lateral ventricles. Pam3Cys/vehicle was microinjected into the right ventricle every 3 days. Two weeks later, an osmotic pump was inserted into the left ventricle to microinfuse oligomeric Aβ/placebo over 14 days. In the meanwhile, treatment with Pam3Cys was continued every 3 days. Then, expression of TRIF, IRF3, and INFβ was measured in the hippocampus. The results showed that although oligomeric Aβ could not alter the expression of these proteins at the cell and tissue level, treatment with Pam3Cys resulted in enhanced expression of them at both cell culture and hippocampal tissue following treatment with oligomeric Aβ. It is concluded that stimulation of microglia through TLR2 pathway induces INFβ expression, which may in part mediate neuroprotection against oligomeric Aβ.