Thyroid hormone levels in the cerebrospinal fluid correlate with disease severity in euthyroid patients with Alzheimer’s disease

Accorroni, Alice; Giorgi, Filippo Sean; Donzelli, Riccardo; Lorenzini, Leonardo; Prontera, Concetta; Vergallo, Andrea; Tognoni, Gloria; Siciliano, Gabriele; Baldacci, Filippo; Bonuccelli, Ubaldo; Clerico, Aldo; Zucchi, Riccardo

doi:10.1007/s12020-016-0897-6

Cited by 26 publications

(18 citation statements)

References 25 publications

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“…The association of altered thyroid hormone metabolism with the severity of Alzheimer’s disease was demonstrated in a recent clinical study. These Alzheimer’s patients had reduced Cerebral Spinal Fluid T3 and elevated rT3, consistent with reduced T4 to T3 conversion, and this correlated with disease severity (Accorroni, et al, 2017).…”

Section: Alteration Of Thyroid Hormones In Traumatic Brain Injury mentioning

confidence: 86%

“…Alzheimer’s patients have altered Cerebral Spinal Fluid TH levels, and have an increased incidence of thyroid disease (Accorroni, et al, 2017). TH has been shown to influence APP (beta-amyloid precursor protein) gene expression in the brain and in neuronal culture (Contreras-Jurado & Pascual, 2012; O’Barr, Oh, Ma, Brent, & Schultz, 2006).…”

Section: Approaches To Thyroid Hormone Treatment and Protection Frmentioning

confidence: 99%

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Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury

Liu

Brent

2018

Pharmacology & Therapeutics

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Thyroid hormone (TH) is essential for normal brain development and may also promote recovery and neuronal regeneration after brain injury. TH acts predominantly through the nuclear receptors, TH receptor alpha (THRA) and beta (THRB). Additional factors that impact TH action in the brain include metabolism, activation of thyroxine (T4) to triiodothyronine (T3) by the enzyme 5'-deiodinase Type 2 (Dio2), inactivation by the enzyme 5-deiodinase Type 3 (Dio3) to reverse T3 (rT3), which occurs in glial cells, and uptake by the Mct8 transporter in neurons. Traumatic brain injury (TBI) is associated with inflammation, metabolic alterations and neural death. In clinical studies, central hypothyroidism, due to hypothalamic and pituitary dysfunction, has been found in some individuals after brain injury. TH has been shown, in animal models, to be protective for the damage incurred from brain injury and may have a role to limit injury and promote recovery. Although clinical trials have not yet been reported, findings from in vitro and in vivo models inform potential treatment strategies utilizing TH for protection and promotion of recovery after brain injury.

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Section: Alteration Of Thyroid Hormones In Traumatic Brain Injury mentioning

confidence: 86%

Section: Approaches To Thyroid Hormone Treatment and Protection Frmentioning

confidence: 99%

Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury

Liu

Brent

2018

Pharmacology & Therapeutics

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“…It has also been known for some time that decreased thyroid hormone action in the CNS is detrimental while increased thyroid hormone action in the CNS correlates with clinical benefit in AD and other diseases of cognitive impairment. [44][45][46][47][48][49][50] Our finding that TREM2 is a thyroid hormone regulated gene whose expression is increased by T3 acting on TR in microglia suggests a mechanistic connection between elevated levels of T3 in the CNS and clinical benefit in AD and related disorders. The beneficial effect of increased T3 in the brain may in part relate to increased stimulation of TREM2 expression in microglia and increased activity through the TREM2 pathway.…”

Section: Discussionmentioning

confidence: 99%

TREM2is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

Ferrara

Chaudhary

DeBell

et al. 2021

Preprint

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Triggering receptor expressed on myeloid cells-2 (TREM2) is a cell surface receptor on macrophages and microglia that senses and responds to disease associated signals to regulate the phenotype of these innate immune cells. The TREM2 signaling pathway has been implicated in a variety of diseases ranging from neurodegeneration in the central nervous system to metabolic disease in the periphery. We report here that TREM2 is a thyroid hormone regulated gene and its expression in macrophages and microglia is stimulated by thyroid hormone. Both endogenous thyroid hormone and sobetirome, a synthetic thyroid hormone agonist drug, suppress pro-inflammatory cytokine production from myeloid cells including macrophages that have been treated with the SARS-CoV-2 spike protein which produces a strong, pro-inflammatory phenotype. Thyroid hormone agonism was also found to induce phagocytic behavior in microglia, a phenotype consistent with activation of the TREM2 pathway. The thyroid hormone antagonist NH-3 blocks the anti-inflammatory effects of thyroid hormone agonists and suppresses microglia phagocytosis. Finally, in a murine experimental autoimmune encephalomyelitis (EAE) multiple sclerosis model, treatment with Sob-AM2, a CNS-penetrating sobetirome prodrug, results in increased Trem2 expression in disease lesion resident myeloid cells which correlates with therapeutic benefit in the EAE clinical score and reduced damage to myelin. Our findings represent the first report of endocrine regulation of TREM2 and provide a unique opportunity to drug the TREM2 signaling pathway with orally active small molecule therapeutic agents.

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“…TSH receptor inhibitors, both monoclonal antibodies and small molecules, will also feature [ 43 ]. In basic research, we can expect to learn more about the application of regenerative medicine in thyroidology [ 44 ] and we will hear a lot more about the role of thyroid hormones in dementia [ 45 ]. The general themes that are likely to prevail include personalised medicine (especially as applied to the management of thyroid cancer), data mining and artificial intelligence, all of which are already beginning to be introduced into thyroidology [ 46 , 47 ].…”

Section: The Futurementioning

confidence: 99%

A decade of thyroidology

Perros

2018

Hormones

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Significant scientific progress has been achieved in the past decade in thyroidology driven by scholarly enquiry, unmet patient needs, and investment by the pharmaceutical and diagnostics industry. In this review, nine publications have been selected for their impact in pushing the frontiers of knowledge and understanding. They include new perspectives in the diagnosis, pathophysiology, epidemiology and management of thyroid cancer, understanding of thyroid hormone physiology, and new treatments for Graves’ orbitopathy.

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Thyroid hormone levels in the cerebrospinal fluid correlate with disease severity in euthyroid patients with Alzheimer’s disease

Cited by 26 publications

References 25 publications

Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury

Thyroid hormone and the brain: Mechanisms of action in development and role in protection and promotion of recovery after brain injury

TREM2is thyroid hormone regulated making the TREM2 pathway druggable with ligands for thyroid hormone receptor

A decade of thyroidology

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