FSH blockade improves cognition in mice with Alzheimer's disease

Jing Xiong, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Seong Su Kang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Zhihao Wang, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Xia Liu, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Tan-Chun Kuo, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Funda Korkmaz, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ashley Padilla, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sari Miyashita, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Pokman Chan, Alamak Biosciences, Beverly, MA, USA.
Zhaohui Zhang, Department of Neurology, Renmin Hospital of Wuhan University, Wuhan, China.
Pavel Katsel, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jocoll Burgess, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Anisa Gumerova, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Kseniia Ievleva, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Damini Sant, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Shan-Ping Yu, Department of Anesthesiology, Emory University School of Medicine, Atlanta, GA, USA.
Valeriia Muradova, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Tal Frolinger, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Daria Lizneva, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Jameel Iqbal, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Ki A. Goosens, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Sakshi Gera, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Clifford J. Rosen, Maine Medical Center Research Institute, Scarborough, ME, USA.Follow
Vahram Haroutunian, Department of Psychiatry and Friedman Brain Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Vitaly Ryu, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Tony Yuen, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Mone Zaidi, Center for Translational Medicine and Pharmacology and Departments of Pharmacological Sciences and Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. mone.zaidi@mssm.edu.

Document Type

Article

Publication Date

3-1-2022

Journal Title

Nature

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 transition. Inhibiting the action of follicle-stimulating hormone (FSH) reduces body fat, enhances thermogenesis, increases bone mass and lowers serum cholesterol in mice. 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.

First Page

470

Last Page

476

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