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Sci. Adv., Mar 15 2024, 10 (11) eadi1863 | https://doi.org/10.1126/sciadv.adi1863 Brain hypothyroidism silences the immune response of microglia in Alzheimer's disease animal model

Dong Kyu Kim ^{1 2 †}, Hyunjung Choi ^{2 3 †}, Woochan Lee ¹, Hayoung Choi ^{1 2}, Seok Beom Hong ^{1 2}, June-Hyun Jeong ^{1 2}, Jihui Han^{1 2}, Jong Won Han ^{1 2}, Hoon Ryu ⁴, Jong-Il Kim ¹, Inhee Mook-Jung ^{1 2 3 *}

¹Department of Biomedical Science, College of Medicine, Seoul National University, Seoul, Korea.
²Convergence Dementia Research Center, College of Medicine, Seoul National University, Seoul, Korea.
³Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
⁴Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul, Korea.

^†These authors contributed equally
^*Corresponding author: correspondence to Inhee Mook-Jung

Abstract

Thyroid hormone (TH) imbalance is linked to the pathophysiology of reversible dementia and Alzheimer's disease (AD). It is unclear whether tissue hypothyroidism occurs in the AD brain and how it affects on AD pathology. We find that decreased iodothyronine deiodinase 2 is correlated with hippocampal hypothyroidism in early AD model mice before TH alterations in the blood. TH deficiency leads to spontaneous activation of microglia in wild-type mice under nonstimulated conditions, resulting in lowered innate immune responses of microglia in response to inflammatory stimuli or amyloid-β. In AD model mice, TH deficiency aggravates AD pathology by reducing the disease-associated microglia population and microglial phagocytosis. We find that TH deficiency reduces microglial ecto-5'-nucleotidase (CD73) and inhibition of CD73 leads to impaired innate immune responses in microglia. Our findings reveal that TH shapes microglial responses to inflammatory stimuli including amyloid-β, and brain hypothyroidism in early AD model mice aggravates AD pathology by microglial dysfunction.

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