RUOLO PREDITTIVO DELL'ESPRESSIONE DEL RECETTORE SCAVENGER CD36 NELLA MALATTIA DI ALZHEIMER
Tesi di Dottorato
Data di Pubblicazione:
2011
Citazione:
RUOLO PREDITTIVO DELL'ESPRESSIONE DEL RECETTORE SCAVENGER CD36 NELLA MALATTIA DI ALZHEIMER / M. Giunta ; tutor: Silvano Gabriele Cella ; coordinatore: Alberto Panerai. Universita' degli Studi di Milano, 2011 Jan 17. 23. ciclo, Anno Accademico 2010. [10.13130/giunta-marialuisa_phd2011-01-17].
Abstract:
Among pathologies of the old people, dementia represent one of the main sanitary problems. Approximately 70% of the dementia cases it is represented by the Alzheimer’s Disease, a neurodegenerative cerebral pathology, whose prevalence is supposed to be increased in the next years. One pathological hallmark is represented by amyloid-beta (Aβ) plaques, which represent the key element to oxidative and pro-inflammatory mechanisms by the activated microglia. The interaction, in fact, between activated microglia and plaques of Aβ induces the release of pro-inflammatory citokynes, like interleukin-6 (IL-6), or neurotoxic factors, like the tumor necrosis factor-α, and stimulates the expression by the microglia of some scavengers receptors, deputies to remove the Aβ plaques: among them the multifunctional protein of class B type I (SRBI) CD36. Currently an effective diagnosis of AD is possible only post mortem: for this reason during the last few years has been intensified the search for biological and hormonal markers that could be useful in the early diagnosis of AD. These markers are expressed also from the peripheral leucocytes, cells easily obtainable, which express virtually all hormones and hormone receptors, which are under the same regulatory mechanisms that control their expression in the brain. So the leucocytes may be profitably used as tools to investigated the changes occurring in brain areas reportedly inaccessible in humans. In particular, it has been recently demonstrated that the leukocyte expression of CD36 is significantly reduced in patients with AD and in patients with mild cognitive impairment (MCI), a prodromic phase of AD. CD36 could represent an earlier marker of increased neurodegenerative risk. Epidemiologic studies have shown a greater incidence of AD in the individuals of female sex. A possible cause of this is represented by the modifications of the endocrine functions, that occur during the menopausal transition and that develop an unfavorable hormonal milieu predisposing to the neurodegeneration. It is demonstrated that estrogens have a neuroprotective and neurotrophic role by the binding to specific receptors, present in two isoformes (ER-α and ER-β), and that in course of AD they prevent the formation of the Aβ-fibrils, inhibit the inflammatory reaction due to the plaque deposition, and protect the cells from their cytotoxic action. The diminished estrogen secretion in postmenopausal age, in fact, is correlated inversely with the “cerebral health” and directly with the entity of the cognitive deterioration. An other female sexual hormone, the progesterone, seems to carry out multiple functions centers different from the riproduction function: the regulation of the cognitive processes, the mitochondrial function of the neuronal cell, the neurogenesis and the repair of the damaged nervous tissue. The neuronal response regulated from the progesterone are mediated by the receptors PR-A and PR-B, included some forms derived from alternative splicing. At the level of the central nervous system them (CNS), therefore, the estrogens and the progesterone cooperate in regulating some neuronal functions, such as the neuroprotection and various cognitive processes. The PR gene contains promoter sequences able to bind ER; therefore, the gene expression of PR supposes the existence of one (efficient) estrogenic stimulation. Moreover, it has been demonstrated the existence of points of convergence between intracellular signaling of estrogens and the factor of insulin-like growth factor type 1 (IGF-1), a neuromodulator that regulates the synaptic plasticity and has been involved in the tissue regeneration, guaranteeing protection during the neurodegenerative processes. Based on this, in the present thesis we e
Tipologia IRIS:
Tesi di dottorato
Keywords:
Alzheimer's Disease; CD36; menopausal transition; estrogen receptors; progesterone receptor; IGF-1; IL-6; topi APP23
Elenco autori:
M. Giunta
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