Tesi etd-05122018-152815
Link copiato negli appunti
Tipo di tesi
Perfezionamento
Autore
ACCORRONI, ALICE
URN
etd-05122018-152815
Titolo
Role of thyroid hormones and 3-iodothyronamine in dementia: potential biomarkers and novel therapeutic approaches for Alzheimer’s disease.
Settore scientifico disciplinare
BIO/09
Corso di studi
SCIENZE MEDICHE - Translational Medicine
Commissione
relatore Prof. CLERICO, ALDO
Parole chiave
- 3-iodothyronamine
- Alzheimer's disease
- dementia.
- thyroid hormones
Data inizio appello
12/07/2018;
Disponibilità
completa
Riassunto analitico
During my PhD, I had the chance to conduct three parallel projects with the aim to explore different aspects of the relationship between thyroid hormones (TH), their derivative 3-iodothyronamine (T1AM) and cognitive decline. The hypothesis behind the three projects was that TH may play a role in cognitive dysfunction, specifically in memory impairment and in the development of dementia. In fact, the initial assumption that the adult brain can buffer pathological changes in TH levels with no effect on its functioning has been challenged by several pieces of research that suggested that both overt and subclinical thyroid disease can affect cognitive function. In addition, evidence coming from preclinical and clinical studies supports the role of TH and of T1AM as decisive factors involved in the development of dementia and specifically of Alzheimer’s disease (AD).
The initial aim of the first project was to evaluate the effects of thyroid disease on memory in mouse models of hyperthyroidism, hypothyroidism and hypothyroidism treated with different combinations of TH and T1AM. Unfortunately, due to the complex and lengthy bureaucratic procedure for the submission and approval of the animal research project, it has not been possible to start this study during my PhD. Therefore, it was decided to assay the levels of TH in the brain and other extrathyroidal tissues in hypothyroidism and hyperthyroidism in rats with a mass spectrometry (MS)-based technique. We demonstrated that our MS-based assay is a highly sensitive tool that provides accurate measurements of tissue TH and we could appreciate the large variability of TH concentrations in different tissues. This variability indicates that both serum TH levels and local TH metabolism regulate tissue TH levels. With this regard, the brain has been demonstrated to be mainly dependent on the local TH metabolism rather than on serum TH levels. This finding is further supported by the evidence that only about 20% of brain 3,5,3’-triiodo-L-thyronine (T3) derives from the circulation.
In the second section of this thesis, I discuss the results coming from the evaluation of TH levels in the cerebrospinal fluid (CSF) of patients with AD, fronto-temporal dementia and motor neuron disease. The CSF, being the fluid that occupies the subarachnoid space and that is accessible through lumbar puncture, represents the best tool to estimate brain TH levels in vivo in the clinical setting. We identified a significant association between 3,3’,5’-triiodothyronine (rT3) and rT3/T3 ratio and disease severity only in AD. Also, CSF rT3 and rT3/T3 ratio had a greater predictive value for AD severity than any other known CSF biomarker used in the clinical setting.
In the last section, I describe the effects of T1AM on beta amyloid (Aβ)-induced impairment of long-term potentiation (LTP) (one of the basic neurophysiological mechanism underlying memory formation) and on associative and non-associative memory. T1AM restored LTP in an exogenous model of Aβ toxicity and in the early stages of neurodegeneration in the mouse model of AD, hAPP-J20. As demonstrated by the use of selective antagonist and agonist, this effect may be mediated by trace amine-associated receptor 1, a recognised T1AM receptor. Also T1AM restored associative and non-associative memory in hAPP-J20 mouse, as assessed by different behavioural tests based on novel object recognition.
In conclusion, these findings support the role of TH in AD, suggest that CSF rT3 and rT3/T3 ratio may represent novel biomarkers of disease severity and progression in AD and point to a potential role of T1AM in counteracting Aβ-induced toxicity in a mouse model of AD and in an exogenous model of Aβ pathology.
The initial aim of the first project was to evaluate the effects of thyroid disease on memory in mouse models of hyperthyroidism, hypothyroidism and hypothyroidism treated with different combinations of TH and T1AM. Unfortunately, due to the complex and lengthy bureaucratic procedure for the submission and approval of the animal research project, it has not been possible to start this study during my PhD. Therefore, it was decided to assay the levels of TH in the brain and other extrathyroidal tissues in hypothyroidism and hyperthyroidism in rats with a mass spectrometry (MS)-based technique. We demonstrated that our MS-based assay is a highly sensitive tool that provides accurate measurements of tissue TH and we could appreciate the large variability of TH concentrations in different tissues. This variability indicates that both serum TH levels and local TH metabolism regulate tissue TH levels. With this regard, the brain has been demonstrated to be mainly dependent on the local TH metabolism rather than on serum TH levels. This finding is further supported by the evidence that only about 20% of brain 3,5,3’-triiodo-L-thyronine (T3) derives from the circulation.
In the second section of this thesis, I discuss the results coming from the evaluation of TH levels in the cerebrospinal fluid (CSF) of patients with AD, fronto-temporal dementia and motor neuron disease. The CSF, being the fluid that occupies the subarachnoid space and that is accessible through lumbar puncture, represents the best tool to estimate brain TH levels in vivo in the clinical setting. We identified a significant association between 3,3’,5’-triiodothyronine (rT3) and rT3/T3 ratio and disease severity only in AD. Also, CSF rT3 and rT3/T3 ratio had a greater predictive value for AD severity than any other known CSF biomarker used in the clinical setting.
In the last section, I describe the effects of T1AM on beta amyloid (Aβ)-induced impairment of long-term potentiation (LTP) (one of the basic neurophysiological mechanism underlying memory formation) and on associative and non-associative memory. T1AM restored LTP in an exogenous model of Aβ toxicity and in the early stages of neurodegeneration in the mouse model of AD, hAPP-J20. As demonstrated by the use of selective antagonist and agonist, this effect may be mediated by trace amine-associated receptor 1, a recognised T1AM receptor. Also T1AM restored associative and non-associative memory in hAPP-J20 mouse, as assessed by different behavioural tests based on novel object recognition.
In conclusion, these findings support the role of TH in AD, suggest that CSF rT3 and rT3/T3 ratio may represent novel biomarkers of disease severity and progression in AD and point to a potential role of T1AM in counteracting Aβ-induced toxicity in a mouse model of AD and in an exogenous model of Aβ pathology.
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