FSH blockade improves cognition in mice with Alzheimer’s disease

Jing Xiong, Seong Su Kang, Zhihao Wang, Xia Liu, Tan-Chun Kuo, Funda Korkmaz, Ashley Padilla, Sari Miyashita, Pokman Chan, Zhaohui Zhang, Pavel Katsel, Jocoll Burgess, Anisa Gumerova, Kseniia Ievleva, Damini Sant, Shan-Ping Yu, Valeriia Muradova, Tal Frolinger, Daria Lizneva, Jameel Iqbal, Ki A. Goosens, Sakshi Gera, Clifford J. Rosen, Vahram Haroutunian, Vitaly Ryu, Tony Yuen, Mone Zaidi () and Keqiang Ye ()
Additional contact information
Jing Xiong: Emory University School of Medicine
Seong Su Kang: Emory University School of Medicine
Zhihao Wang: Emory University School of Medicine
Xia Liu: Emory University School of Medicine
Tan-Chun Kuo: Icahn School of Medicine at Mount Sinai
Funda Korkmaz: Icahn School of Medicine at Mount Sinai
Ashley Padilla: Icahn School of Medicine at Mount Sinai
Sari Miyashita: Icahn School of Medicine at Mount Sinai
Pokman Chan: Alamak Biosciences
Zhaohui Zhang: Renmin Hospital of Wuhan University
Pavel Katsel: Icahn School of Medicine at Mount Sinai
Jocoll Burgess: Icahn School of Medicine at Mount Sinai
Anisa Gumerova: Icahn School of Medicine at Mount Sinai
Kseniia Ievleva: Icahn School of Medicine at Mount Sinai
Damini Sant: Icahn School of Medicine at Mount Sinai
Shan-Ping Yu: Emory University School of Medicine
Valeriia Muradova: Icahn School of Medicine at Mount Sinai
Tal Frolinger: Icahn School of Medicine at Mount Sinai
Daria Lizneva: Icahn School of Medicine at Mount Sinai
Jameel Iqbal: Icahn School of Medicine at Mount Sinai
Ki A. Goosens: Icahn School of Medicine at Mount Sinai
Sakshi Gera: Icahn School of Medicine at Mount Sinai
Clifford J. Rosen: Maine Medical Center Research Institute
Vahram Haroutunian: Icahn School of Medicine at Mount Sinai
Vitaly Ryu: Icahn School of Medicine at Mount Sinai
Tony Yuen: Icahn School of Medicine at Mount Sinai
Mone Zaidi: Icahn School of Medicine at Mount Sinai
Keqiang Ye: Emory University School of Medicine

Nature, 2022, vol. 603, issue 7901, 470-476

Abstract: Abstract Alzheimer’s disease has a higher incidence in older women, with a spike in cognitive decline that tracks with visceral adiposity, dysregulated energy homeostasis and bone loss during the menopausal transition1,2. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice3–7. Here we show that FSH acts directly on hippocampal and cortical neurons to accelerate amyloid-β and Tau deposition and impair cognition in mice displaying features of Alzheimer’s disease. Blocking FSH action in these mice abrogates the Alzheimer’s disease-like phenotype by inhibiting the neuronal C/EBPβ–δ-secretase pathway. These data not only suggest a causal role for rising serum FSH levels in the exaggerated Alzheimer’s disease pathophysiology during menopause, but also reveal an opportunity for treating Alzheimer’s disease, obesity, osteoporosis and dyslipidaemia with a single FSH-blocking agent.

Date: 2022
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DOI: 10.1038/s41586-022-04463-0

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