Emerging roles of brain tanycytes in regulating blood–hypothalamus barrier plasticity and energy homeostasis

Kannangara, Hasni; Cullen, Liam; Miyashita, Sari; Korkmaz, Funda; Macdonald, Anne; Gumerova, Anisa; Witztum, Ronit; Moldavski, Ofer; Sims, Steven; Burgess, Jocoll; Frolinger, Tal; Latif, Rauf; Ginzburg, Yelena; Lizneva, Daria; Goosens, Ki; Davies, Terry F.; Yuen, Tony; Zaidi, Mone; Ryu, Vitaly

doi:10.1111/nyas.15009

Cited by 11 publications

(4 citation statements)

References 80 publications

(206 reference statements)

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“…There is little information on circuitry through which glycoprotein hormones from the anterior pituitary regulate central functions 37 . We recently discovered that FSH, hitherto considered solely a fertility hormone but with a number of newly-discovered somatic functions [25][26][27] , acts on FSH receptors on neurons 29 .…”

Section: Discussionmentioning

confidence: 99%

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Korkmaz,

Sims,

Sen

et al. 2024

Preprint

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Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post–menopausal levels of the pituitary gonadotropin follicle–stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampalFshrto drive AD–like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female3xTg;Fshr+/+, 3xTg;Fshr+/–and3xTg;Fshr-/-mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham–operated3xTg;Fshr-/-mice were implanted with 17β-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects ofFshrdepletion.3xTg;Fshr+/+mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in3xTg;Fshr-/-mice and, to a lesser extent, in3xTg;Fshr+/-mice–– thus documenting a clear gene–dose–dependent prevention of hippocampal–dependent spatial memory impairment. At 5 and 10 months, sham–operated3xTg;Fshr-/-mice showed better memory performance during the acquisition and/or retrieval phases, suggesting thatFshrdeletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10–month–old3xTg;Fshr-/-mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized3xTg;Fshr-/-mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene–dose–dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels <8 ng/mL in 16–month–oldAPP/PS1mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH–blocking agent for the early prevention of cognitive decline in postmenopausal women.

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Section: Discussionmentioning

confidence: 99%

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Korkmaz,

Sims,

Sen

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

Section: Discussionmentioning

confidence: 99%

Gene–Dose–Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer’s Mice

Frolinger,

Korkmaz,

Sims

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Alzheimer’s disease (AD) is a major progressive neurodegenerative disorder of the aging population. High post–menopausal levels of the pituitary gonadotropin follicle–stimulating hormone (FSH) are strongly associated with the onset of AD, and we have shown recently that FSH directly activates the hippocampal Fshr to drive AD–like pathology and memory loss in mice. To establish a role for FSH in memory loss, we used female 3xTg;Fshr+/+, 3xTg;Fshr+/– and 3xTg;Fshr–/– mice that were either left unoperated or underwent sham surgery or ovariectomy at 8 weeks of age. Unoperated and sham–operated 3xTg;Fshr–/– mice were implanted with 17β-estradiol pellets to normalize estradiol levels. Morris Water Maze and Novel Object Recognition behavioral tests were performed to study deficits in spatial and recognition memory, respectively, and to examine the effects of Fshr depletion. 3xTg;Fshr+/+ mice displayed impaired spatial memory at 5 months of age; both the acquisition and retrieval of the memory were ameliorated in 3xTg;Fshr–/– mice and, to a lesser extent, in 3xTg;Fshr+/– mice––thus documenting a clear gene–dose–dependent prevention of hippocampal–dependent spatial memory impairment. At 5 and 10 months, sham–operated 3xTg;Fshr–/– mice showed better memory performance during the acquasition and/or retrieval phases, suggesting that Fshr deletion prevented the progression of spatial memory deficits with age. However, this prevention was not seen when mice were ovariectomized, except in the 10–month–old 3xTg;Fshr–/– mice. In the Novel Object Recognition test performed at 10 months, all groups of mice, except ovariectomized 3xTg;Fshr–/– mice showed a loss of recognition memory. Consistent with the neurobehavioral data, there was a gene–dose–dependent reduction mainly in the amyloid β40 isoform in whole brain extracts. Finally, serum FSH levels < 8 ng/mL in 16–month–old APP/PS1 mice were associated with better retrieval of spatial memory. Collectively, the data provide compelling genetic evidence for a protective effect of inhibiting FSH signaling on the progression of spatial and recognition memory deficits in mice, and lay a firm foundation for the use of an FSH–blocking agent for the early prevention of cognitive decline in postmenopausal women.

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“…Notably, pineal melatonin has heightened and prolonged effects in the third ventricle, versus circulating concentrations [ 121 ]. This has particular consequences for hypothalamic function, including in the differential regulation of hormones associated with modulating feeding, metabolism, aggression and reproduction [ 42 ], with effects strongly determined via tanycytes that line the third ventricle and hypothalamic astrocytes [ 122 ]. Many hypothalamus regulated hormones, such as testosterone, estrogen, luteinizing hormone and oxytocin as well as hypothalamus-regulated pituitary hormones and thyroid hormones, also have differential effects on different immune cells, cancer cells and their interactions.…”

Section: Hypothalamic Interactions Of Melatonin Gr and Trkb In Tumor ...mentioning

confidence: 99%

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

Anderson

2023

Exploration of Targeted Anti-Tumor Therapy

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A dysregulated circadian rhythm is significantly associated with cancer risk, as is aging. Both aging and circadian dysregulation show suppressed pineal melatonin, which is indicated in many studies to be linked to cancer risk and progression. Another independently investigated aspect of the circadian rhythm is the cortisol awakening response (CAR), which is linked to stress-associated hypothalamus-pituitary-adrenal (HPA) axis activation. CAR and HPA axis activity are primarily mediated via activation of the glucocorticoid receptor (GR), which drives patterned gene expression via binding to the promotors of glucocorticoid response element (GRE)-expressing genes. Recent data shows that the GR can be prevented from nuclear translocation by the B cell lymphoma-2 (Bcl-2)-associated athanogene 1 (BAG-1), which translocates the GR to mitochondria, where it can have diverse effects. Melatonin also suppresses GR nuclear translocation by maintaining the GR in a complex with heat shock protein 90 (Hsp90). Melatonin, directly and/or epigenetically, can upregulate BAG-1, suggesting that the dramatic 10-fold decrease in pineal melatonin from adolescence to the ninth decade of life will attenuate the capacity of night-time melatonin to modulate the effects of the early morning CAR. The interactions of pineal melatonin/BAG-1/Hsp90 with the CAR are proposed to underpin how aging and circadian dysregulation are associated with cancer risk. This may be mediated via differential effects of melatonin/BAG-1/Hsp90/GR in different cells of microenvironments across the body, from which tumors emerge. This provides a model of cancer pathogenesis that better integrates previously disparate bodies of data, including how immune cells are regulated by cancer cells in the tumor microenvironment, at least partly via the cancer cell regulation of the tryptophan-melatonin pathway. This has a number of future research and treatment implications.

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Emerging roles of brain tanycytes in regulating blood–hypothalamus barrier plasticity and energy homeostasis

Cited by 11 publications

References 80 publications

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Gene–Dose–Dependent ReductionFshrExpression Improves Spatial Memory Deficits in Alzheimer’s Mice

Gene–Dose–Dependent Reduction Fshr Expression Improves Spatial Memory Deficits in Alzheimer’s Mice

Melatonin, BAG-1 and cortisol circadian interactions in tumor pathogenesis and patterned immune responses

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