Role of Testosterone Signaling in Microglia: A Potential Role for Sex‐Related Differences in Alzheimer's Disease

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  • Haiyan Du
    Department of Cell Biology, Aging Science, and Pharmacology Division of Oral Biological Sciences Faculty of Dental Science Kyushu University 3‐1‐1 Maidashi, Higashi‐ku Fukuoka 812‐8582 Japan
  • Akiko Mizokami
    OBT Research Center Faculty of Dental Science Kyushu University 3‐1‐1 Maidashi, Higashi‐ku Fukuoka 812‐8582 Japan
  • Junjun Ni
    Key Laboratory of Molecular Medicine and Biotherapy Department of Biology School of Life Science Beijing Institute of Technology Beijing 100081 China
  • Simeng Zhang
    Key Laboratory of Molecular Medicine and Biotherapy Department of Biology School of Life Science Beijing Institute of Technology Beijing 100081 China
  • Yosuke Yamawaki
    Department of Advanced Pharmacology Daiichi University of Pharmacy 22‐1 Tamagawa‐cho, Minami‐ku Fukuoka 815‐8511 Japan
  • Tomomi Sano
    Department of Cell Biology, Aging Science, and Pharmacology Division of Oral Biological Sciences Faculty of Dental Science Kyushu University 3‐1‐1 Maidashi, Higashi‐ku Fukuoka 812‐8582 Japan
  • Eijiro Jimi
    OBT Research Center Faculty of Dental Science Kyushu University 3‐1‐1 Maidashi, Higashi‐ku Fukuoka 812‐8582 Japan
  • Isei Tanida
    Department of Cellular and Molecular Neuropathology Juntendo University Graduate School of Medicine Tokyo 113‐8421 Japan
  • Takashi Kanematsu
    Department of Cell Biology, Aging Science, and Pharmacology Division of Oral Biological Sciences Faculty of Dental Science Kyushu University 3‐1‐1 Maidashi, Higashi‐ku Fukuoka 812‐8582 Japan

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<jats:title>Abstract</jats:title><jats:p>Alzheimer's disease (AD) is less prevalent in men than in women, although mechanisms remain unclear. Microglia degrade aggregated amyloid β (Aβ) through the lysosomal system, including autophagy. G protein‐coupled receptor family C group 6 member A (GPRC6A), predominantly expressed in mouse microglial MG6 cells, is a primary mediator of testosterone signaling. This study examines testosterone's role in modulating Aβ‐induced autophagy in microglia. Testosterone promotes Aβ‐induced autophagy leading to Aβ clearance in MG6 cells by suppressing extracellular signal‐regulated kinase (ERK) phosphorylation and subsequently inhibiting mammalian target of rapamycin (mTOR) activation, which is abrogated by shRNA knockdown of GPRC6A. In in vivo experiments with male 5xFAD AD model mice, Aβ clearance activity is associated with autophagy in microglia and is reduced by orchiectomy, but restored by testosterone supplementation. ERK phosphorylation in the brains of male AD model mice is upregulated by orchiectomy. Therefore, testosterone is involved in autophagy‐mediated Aβ clearance in microglia. Aβ accumulation in human brain samples from patients with AD is significantly lower in men than in women, with less pronounced colocalization of Aβ with p62 aggregates, suggesting enhanced autophagic activity in men. In conclusion, testosterone enhances Aβ‐induced autophagy in microglia, possibly contributing to lower susceptibility to AD in men.</jats:p>

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