Background: Alzheimer's disease (AD) is an age-related neurodegenerative disorder associated with brain innate immune activation mainly mediated by microglia. These cells are known to be activated in the brain of AD patients and to produce inflammatory cytokines and neurotoxic molecules in response to Amyloid beta (Aβ). Activation of microglia can also promote Aβ clearance via Toll-like receptors (TLRs). Myeloid differentiation factor 88 (MyD88) is the adaptor molecule for most of these innate immune receptors, transducing the intracellular signal from TLRs to nucleus.
Results: Here, we report that more than 50% reduction in MyD88 expression in a mouse model of AD accelerated spatial learning and memory deficits. Brain of APPswe/PS1-MyD88+/- mice was characterized by a delay in accumulation of Aβ plaques and increased soluble levels of Aβ oligomers. Furthermore, inflammatory monocyte subset and brain IL-1β gene expression were significantly reduced in APPswe/PS1 mice with impaired MyD88 signaling.
Conclusions: These data indicate that activation of MyD88 intracellular signaling pathway, likely by TLRs, acts as a natural innate immune mechanism to restrict disease progression of APPswe/PS1 mice.