Title:
The regulation of microglia to confer neuroprotective effect on Alzheimer’s disease

Tetsuya Mizuno, MD, Associate Professor
Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University

Abstract:
Microglia, macrophage-like resident immune cells in the brain, have both neurotoxic and neuroprotective properties, and play pivotal roles in the development of neurodegenerative diseases such as Alzheimer’s disease (AD), amyotrophic lateral sclerosis, and Parkinson disease. The senile plaque is a pathological hallmark of AD. Amyloid b (Aβ ) protein, a major component of senile plaques, induces tau hyperphosphorylation and neuronal dystrophy. Soluble oligomeric Aβ (oAβ ) exhibits higher neurotoxicity than fibrillar Aβ , because oAβ inhibits hippocampal long-term potentiation and disrupts synaptic plasticity. We found that Toll-like receptor 9 ligand CpG or IL-34 enhanced microglial neuroprotective effects against oAβ 1-42 toxicity, and that intracerebroventricular administration of CpG or IL-34 ameliorated the cognitive impairment of associative learning in mouse model of AD. The neuroprotective effect is mainly mediated by the clearance of oAβ such as phagocytosis and degradation, and the induction of anti-oxidant enzyme heme oxygenase-1 in microglia to reduce oxidative stress, without producing neurotoxic molecules. The enhancement of the neuroprotective property of microglia may be an effective approach against oA b neurotoxicity in AD.