Thyroid Hormone Negatively Regulates the Transcriptional Activity of the β-Amyloid Precursor Protein Gene

Belandia, Borja; Latasa, Maria Jesús; Villa, Ana; Pascual, Ángel

doi:10.1074/jbc.273.46.30366

Cited by 100 publications

(76 citation statements)

References 43 publications

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“…Treatment of hPANC-1 cells with T 3 induces changes in cell morphology, promotes cell differentiation into insulin-producing b-cells, upregulates insulin and glucose transporter protein-2 transcripts, and increases insulin release into the medium (30). Furthermore, T 3 affects the splicing and secretion of b-amyloid precursor proteins (APP) isoforms (31) and represses the expression of the APP gene in neuroblastoma cells (32). Whether T 3 has a similar effect on islet amyloid polypeptide, a potential cytotoxic protein for b cells, is not known.…”

Section: Discussionmentioning

confidence: 99%

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals

Ortega

Koška²,

Pannacciulli³

et al. 2008

European Journal of Endocrinology

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Background: Thyroid hormones (TH) may influence glucose metabolism. Hyperthyroid subjects have higher insulin secretion rates when compared with euthyroid individuals. Objective: To evaluate the association between TH concentrations and insulin secretion in euthyroid, healthy Pima Indian adults (nZ55, 29G7 years, females/males 36/19) with normal glucose tolerance (NGT) admitted to a Clinical Research Unit. Methods: TSH, free thyroxine (FT 4 ), 3,5,30 -L-tri-iodothyronine (FT 3 ), and fasting plasma insulin (FPI) concentrations were measured in fasting plasma samples, percentage of body fat (%BF) by dual energy x-ray absorptiometry (DXA), acute insulin response (AIR), and incremental area under the curve (AUC) of insulin in response to a 25 g intravenous glucose tolerance test (IVGTT) and 75 g oral glucose tolerance test (OGTT) respectively and insulin action (M) during an euglycemic clamp. Results: FT 3 concentrations were associated with FPI, AIR, and insulin AUC both before (rZ0.33, PZ0.01; rZ0.29, PZ0.03; and rZ0.35, PZ0.008 respectively) and after adjustment for age, sex, %BF, glucose (fasting concentrations or glucose AUC), and M (bZ0.09, PZ0.01; bZ0.16, PZ0.03; and bZ0.24, PZ0.0007 respectively). No associations were found for TSH or FT 4 . Conclusion: FT 3 was associated with several measurements of insulin secretion in euthyroid individuals with NGT. T 3 concentrations may play a role in the regulation of insulin secretion.

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Section: Discussionmentioning

confidence: 99%

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals

Ortega

Koška²,

Pannacciulli³

et al. 2008

European Journal of Endocrinology

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“…4 and 5), that the T3-responsive sequence is located in a region 3Ј from the transcription initiation site of the trkB gene. It is interesting to note that the T3RE location downstream of the transcriptional start site has also been reported in other T3 negatively regulated genes (11,38,40,41). The mechanism by which T3R represses transcription in a strictly ligand-dependent manner has been elusive.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, gene repression may play an important role in the regulation of brain development by T3, because many of the new T3-regulated genes are also transcriptionally repressed in brain (34,38,39). Moreover, it has been suggested that neurotrophins and their receptors could mediate some of the known functions of T3 during the central nervous system development (21).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Repression of Neurotrophin Receptor trkBby Thyroid Hormone in the Developing Rat Brain

Pombo

Barettino

Espliguero

et al. 2000

Journal of Biological Chemistry

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Expression of the neurotrophin receptor trkB is regulated by thyroid hormone (T3) during development of the rat brain. trkB mRNA levels, coding for the fulllength and the truncated isoforms, are increased in the cerebral cortex of neonatal experimental hypothyroid animals. Run-on transcription assays with nuclei from postnatal day 15, hypothyroid, and control cerebral cortices demonstrated that an increase in the transcription rate of the trkB gene accounts for the observed effect. Transient transfection experiments using a reporter plasmid containing a 7-kilobase pair DNA fragment upstream of the mouse trkB gene showed that unliganded thyroid hormone receptor (T3R) increases promoter activity, whereas addition of T3 reverses that activity below basal levels. Deletion analysis shows that the T3-dependent repression requires binding of the T3R to a specific region located downstream of the transcription start site. This region, at nucleotide position ؊465/؊432, contains an array of thyroid hormone response halfsites that bind preferentially T3R as heterodimers with retinoid X receptor and whose deletion causes loss of the T3-dependent repression. These half-sites are able to confer negative regulation by T3 to a heterologous promoter, thus indicating the functionality of these sequences. These results demonstrate that, in the developing rat brain, T3 down-regulates the expression of the trkB gene through the active repression of a novel negative response element located downstream of its transcription initiation site.

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“…Although stress and HPA axis activity are known to participate in the onset and progression of both depressive disorder and AD, Zvěřová et al [29] reported that an increased plasma cortisol level in patients with AD had relatively little effect on comorbid depressive symptoms. Rather, they found that the level of plasma cortisol reflected the degree of cognitive impairment in AD rather than the severity of comorbid depression.…”

Section: Discussionmentioning

confidence: 99%

“…T4 is then converted to its bioactive form, T3 and the inactive isomer, rT3. T3 has been shown to negatively regulate the expression of the amyloid precursor protein gene [29], T4 has been shown to modulate choline acetyltransferase activity [30], and transthyretin has been shown to create soluble β-amyloid complexes [31]. Compared with age-matched controls [32], the level of transthyretin has been reported to be lower in the cerebrospinal fluid (CSF) of patients with AD, suggesting a possible reduction in T4 transport into the brain in patients with AD.…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Thyroid Status, Cortisol Level, Cognition And Neuropsychiatric Symptoms In Patients With Alzheimer Disease

Chang¹,

Wu²,

Wang³

et al. 2018

Neuropsychiatry

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Objective: Growing evidence suggests an association between alterations in thyroid function and cortisol level and the pathogenesis and progression of Alzheimer disease (AD). The aim of this study was to investigate whether these hormones are related to the cognitive and neuropsychiatric manifestations in the patients with AD.Methods: This was a cross-sectional, case control study. Cortisol level and thyroid status were evaluated in 40 outpatients with mild to moderate AD and 20 normal controls, and cognitive and neuropsychiatric assessments were performed using the Cognitive Ability Screening Instrument (CASI), Neuropsychiatric Inventory, and Geriatric Depression Scale. Results:The patients had worse cognitive function and lower free triiodothyronine (FT3) level than the controls. Those with aberrant motor behavior had a lower FT3 level, and those with dysphoria had a higher cortisol level than those without these symptoms. The patients with a higher level of FT3 also had higher concentration and abstract thinking/judgment scores on the CASI, and those with a higher level of cortisol were associated with a decline in global cognition. Conclusion:Our results indicate a possible association between thyroid hormones and neuropsychiatric manifestations as well as cognitive function in euthyroid patients with AD, and suggest the potential efficacy of adjunctive T3 treatment in these patients. We hypothesize that patients with dysphoria subjectively experience more stress. Further studies are needed to elucidate whether this would increase the risk of depression or exacerbate cognitive function, and to investigate whether a non-pharmacological approach can relieve dysphoria symptoms according to the psychological attachment theory.

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Thyroid Hormone Negatively Regulates the Transcriptional Activity of the β-Amyloid Precursor Protein Gene

Cited by 100 publications

References 43 publications

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals

Free triiodothyronine plasma concentrations are positively associated with insulin secretion in euthyroid individuals

Transcriptional Repression of Neurotrophin Receptor trkBby Thyroid Hormone in the Developing Rat Brain

The Relationship Between Thyroid Status, Cortisol Level, Cognition And Neuropsychiatric Symptoms In Patients With Alzheimer Disease

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