FSH blockade improves cognition in mice with Alzheimer’s disease

Xiong, Jing; Kang, Seong Su; Wang, Wenwen; Liu, Xia; Kuo, Tan-Chun; Korkmaz, Funda; Padilla, Ashley; Miyashita, Sari; Chan, P.; Zhao-hui, Zhang; Katsel, Pavel; Burgess, Jocoll; Гумерова, А. А.; Ievleva, Kseniia; Sant, Damini; Yu, Shan-Ping; Muradova, Valeriia; Frolinger, Tal; Lizneva, Daria; Iqbal, Jameel; Goosens, Ki A.; Gera, Sakshi; Rosen, Clifford J.; Haroutunian, Vahram; Ryu, Vitaly; Yuen, Tony; Zaidi, Mone; Ye, Keqiang

doi:10.1038/s41586-022-04463-0

Cited by 190 publications

(199 citation statements)

References 62 publications

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“…We recently reported the expression of FSHRs in mouse, rat and human brains, particularly in AD–vulnerable regions, including hippocampus and cortex (30). We also found that FSH exacerbated AD–like neuropathology and cognitive decline in 3xTg, APP/PS1 and APP -KI mice, while the inhibition of FSH action rescued this phenotype.…”

Section: Resultsmentioning

confidence: 99%

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

Ryu

Гумерова

Korkmaz

et al. 2022

Preprint

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There is increasing evidence that anterior pituitary hormones, traditionally thought to have unitary functions in regulating single endocrine targets, act on multiple somatic tissues, such as bone, fat, and liver. There is also emerging evidence for anterior pituitary hormone action on brain receptors in mediating central neural and peripheral somatic functions. Here, we have created the most comprehensive neuroanatomical atlas on the expression of TSHRs, LHCGRs and FSHRs. We have used RNAscope, a technology that allows the detection of mRNA at single-transcript level, together with protein level validation, to document Tshr expression in 173 and Fshr expression in 353 brain regions, nuclei and sub–nuclei identified using the Atlas for the Mouse Brain in Stereotaxic Coordinates. We also identified Lhcgr transcripts in 401 brain regions, nuclei and sub–nuclei. Complementarily, we used ViewRNA, another single-transcript detection technology, to establish the expression of FSHRs in human brain samples, where transcripts were co–localized in MALAT1–positive neurons. In addition, we show high expression for all three receptors in the ventricular region—with yet unknown functions. Intriguingly, Tshr and Fshr expression in the ependymal layer of the third ventricle was similar to that of the thyroid follicular cells and testicular Sertoli cells, respectively. TSHRs were expressed specifically in tanycytes. In contrast, Fshrs were localized to NeuN–positive neurons in the granular layer of the dentate gyrus in murine and human brain—both are Alzheimer's disease vulnerable regions. Our atlas thus provides a vital resource for scientists to explore the link between the stimulation or inactivation of brain glycoprotein hormone receptors on somatic function. New actionable pathways for human disease may be unmasked through further studies.

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Section: Resultsmentioning

confidence: 99%

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

Ryu

Гумерова

Korkmaz

et al. 2022

Preprint

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“…We have recently documented exaggerated AD pathology and cognitive decline upon ovariectomy or exogenous FSH injection in three murine models of AD, even in the face of estrogen levels clamped in the normal range (41). This phenotype arises from the action of FSH on hippocampal and cortical neuronal receptors using a pathway involving CEBP/β and the δ– secretase asparagine endopeptidase (41). Most notably, however, we found that our polyclonal FSH–blocking antibody, which shares the target epitope with MS-Hu6 (17, 26), prevented the AD–like phenotype induced upon ovariectomy (41)—providing a clear avenue for further exploration of the effects of MS–Hu6 in models of AD.…”

Section: Discussionmentioning

confidence: 99%

“…During this period, women also show a sharp decline in memory function and increased risk of mild cognitive impairment and dementia (11, 52, 53). We have recently documented exaggerated AD pathology and cognitive decline upon ovariectomy or exogenous FSH injection in three murine models of AD, even in the face of estrogen levels clamped in the normal range (41). This phenotype arises from the action of FSH on hippocampal and cortical neuronal receptors using a pathway involving CEBP/β and the δ– secretase asparagine endopeptidase (41).…”

Section: Discussionmentioning

confidence: 99%

“…Our comprehensive analysis of the biology and physicochemistry of a first-in-class, humanized FSHblocking antibody, MS-Hu6, establishing it as efficacious, safe and manufactureable may arguably be amongst the first attempts at an extensive in-house effort. In 2003, we conceived the idea that pituitary hormones, including FSH, have direct actions on bone (13,(38)(39)(40); shifted this new paradigm to establish novel actions of FSH on fat, and more recently, on brain (16,41); created the first polyclonal FSH-blocking antibody targeted to a 13-amino-acid-long receptor-binding epitope of FSHβ (17,18); and finally developed a humanized multipurpose therapeutic (26) for future use in osteoporosis and obesity, and perhaps even in hyperlipidemia and Alzheimer's disease. Notably, the in-house studies described here have been carried out using our own platform that complies with Good Laboratory Practice, as mandated by the Food and Drug It is now well recognized that targeting the receptor-binding epitope of FSHβ to block its interaction with the FSHR inhibits bone resorption, increases bone formation and bone mass, reduces body fat, and enhances thermogenesis (15)(16)(17)(18)(19)22).…”

Section: Discussionmentioning

confidence: 99%

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A Single Multipurpose FSH–Blocking Therapeutic for Osteoporosis and Obesity

Gera

Kuo

Korkmaz

et al. 2022

Preprint

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Pharmacological and genetic studies over the past decade have established FSH as an actionable target for diseases affecting millions, notably osteoporosis, obesity and Alzheimer’s disease (AD). Blocking FSH action prevents bone loss, fat gain and AD–like features in mice. We recently developed a first–in–class, humanized, epitope–specific FSH blocking antibody, MSHu6, with a KD of 7.52 nM. Using a GLP–compliant platform, we now report the efficacy of MSHu6 in preventing obesity and osteoporosis in mice, and parameters of acute safety in monkeys. Biodistribution studies using 89Zr–labelled, biotinylated or unconjugated MS-Hu6 in mice and monkeys showed localization to bone, bone marrow and fat depots. MS-Hu6 displayed a β phase t½ of 13 days (316 hours) in humanized Tg32 mice, and bound endogenous FSH. We tested 215 variations of excipients using the protein thermal shift assay to generate a final formulation that rendered MS-Hu6 stable in solution upon freeze–thaw and at different temperatures, with minimal aggregation, and without self–, cross–, or hydrophobic interactions or appreciable binding to relevant human antigens. MS-Hu6 showed the same level of “humanness” as human IgG1 in silico, and was non–immunogenic in ELISPOT assays for IL-2 and IFNγ in human peripheral blood mononuclear cell cultures. We conclude that MS-Hu6 is efficacious, durable and manufacturable, and is therefore poised for future human testing as a multipurpose therapeutic.

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“…The experiments were approved by the Ethics Committee for Animal Care and Research of Zhujiang Hospital of Southern Medical University (Guangdong, China) and were performed according to the ARRIVE guidelines. As female hormone such as estrogen and follicle-stimulating hormone can significantly affect cognition [ 26 , 27 ], to exclude possible influence of female hormone, male mice were used in this study. Adult male C57BL/6J mice (8–10 weeks, 22–25 g) were purchased from Guangdong Medical Laboratory Animal Center (Guangzhou, China).…”

Section: Methodsmentioning

confidence: 99%

Gut microbiota is causally associated with poststroke cognitive impairment through lipopolysaccharide and butyrate

Wang

Zhang

et al. 2022

J Neuroinflammation

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Background Poststroke cognitive impairment (PSCI) is prevalent in stroke patients. The etiology of PSCI remains largely unknown. We previously found that stroke induces gut microbiota dysbiosis which affects brain injury. Hereby, we aimed to investigate whether the gut microbiota contributes to the pathogenesis of PSCI. Methods 83 stroke patients were recruited and their cognitive function were measured by Montreal Cognitive Assessment (MoCA) scores 3 months after stroke onset. The peripheral inflammatory factor levels and gut microbiota compositions of the patients were analyzed. Fecal microbiota transplantation from patients to stroke mice was performed to examine the causal relationship between the gut microbiota and PSCI. The cognitive function of mice was evaluated by Morris water maze test. Results 34 and 49 stroke patients were classified as PSCI and non-PSCI, respectively. Compared with non-PSCI patients, PSCI patients showed significantly higher levels of gut Enterobacteriaceae, lipopolysaccharide (LPS) and peripheral inflammation markers. Consistently, stroke mice that received microbiota from PSCI patients (PSCI mice) presented a higher level of Enterobacteriaceae, intestinal Toll-like receptor-4 (TLR4) expression, circulating LPS, LPS-binding protein (LBP) and inflammatory cytokines, and a lower level of fecal butyrate, severer intestine destruction and cognitive impairment than mice that received microbiota from nPSCI patients (nPSCI mice). In addition, we observed exacerbations in blood–brain barrier (BBB) integrity, microglial activation, neuronal apoptosis in the CA1 region of the hippocampus, and Aβ deposition in the thalamus of PSCI mice in comparison with nPSCI mice. Intraperitoneal injection of LPS after stroke caused similar pathology to those seen in PSCI mice. Supplementation with sodium butyrate (NaB) via drinking water rescued these detrimental changes in PSCI mice. Conclusions Our data indicate a cause–effect relationship between gut microbiota and PSCI for the first time, which is likely mediated by inflammation-regulating metabolites including LPS and butyrate.

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FSH blockade improves cognition in mice with Alzheimer’s disease

Cited by 190 publications

References 62 publications

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

Brain Atlas for Glycoprotein Hormone Receptors at Single-Transcript Level

A Single Multipurpose FSH–Blocking Therapeutic for Osteoporosis and Obesity

Gut microbiota is causally associated with poststroke cognitive impairment through lipopolysaccharide and butyrate

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