Abbondante, Serena (2012) Toward the understanding and treatment of human neurodegenerative disorders: a mouse model approach. [Tesi di dottorato] (Unpublished)


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Item Type: Tesi di dottorato
Resource language: English
Title: Toward the understanding and treatment of human neurodegenerative disorders: a mouse model approach
Date: 1 February 2012
Number of Pages: 122
Institution: Università degli Studi di Napoli Federico II
Istituzioni (extra): TIGEM – Telethon Insitute of Genetics and Medicine
Scuola di dottorato: SEMM – European School of Molecular Medicine
Dottorato: PhD in Molecular Medicine (Molecular Oncology or Human Genetics)
Ciclo di dottorato: 23
Coordinatore del Corso di dottorato:
Di Bernardo,
Date: 1 February 2012
Number of Pages: 122
Keywords: MPS II, ERT, Diabetes
Settori scientifico-disciplinari del MIUR: Area 06 - Scienze mediche > MED/03 - Genetica medica
Additional information: Ciclo V/XXIII, Curriculum Human Genetics
Date Deposited: 15 Feb 2012 23:27
Last Modified: 12 Jan 2015 13:46

Collection description

Part 1 : Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by the deficiency of the lysosomal enzyme iduronate 2 sulphates (Ids). The inactivity of this enzyme results in the progressive accumulation of heparan and dermatan sulfates within the lysosomes of various tissues and organs, with consequent cellular degeneration. Patients affected by the severe form of MPS II are characterized, in addition, by a devastating involvement of the central nervous system. The MPSII mouse model reproduces the features of MPSII patients. The characterization of brain phenotype of mouse MPS II showed a progressive GAGs accumulation in almost all the regions of the brain, an increase in inflammation and severe neurodegeneration. Moreover, behavioral tests, showed a deficit in learning and motor coordination. Up to now, the only treatment for MPS II patients is the enzyme replacement therapy (ERT) with the systemic infusion of Ids enzyme; however, this treatment only obtains amelioration of visceral defects, but not of neurological ones. To this aim, we developed a new protocol of ERT to treat both, visceral and neurological defects. Importantly, we were successful in having the infused Ids enzyme reaching the brain with a good rescue of the CNS phenotype and behavioral performances. Among the ERT protocols tested, the one using low Ids concentration, was effective on young and adult MPS II mice. Part 2: Growing evidence suggest comorbidity between diabetes mellitus (DM) and Alzheimer's disease (AD); indeed, diabetic patients show increased risk of developing AD and cognitive deficits, while, AD patients show impaired insulin function and glucose metabolism. However, the molecular mechanisms linking these two disorders are still not fully understood. Here, we hypothesize that DM induces tau hyperphosphorylation generating the cognitive decline observed in AD. Interestingly, our results show that induction of type 1 DM by streptozotocin (STZ) administration in WT mice support our hypothesis showing, in these mice, tau hyperphosphorylation, decreased activity of the Insulin Receptor (IR)/PI3K/AKT pathway and increased phosphorylation of glycogen synthase kinase 3β (GSK3β), a kinase strongly involved in the pathogenesis of AD. At the behavioral levels, WT-STZ mice showed learning and memory deficits. Importantly, when type 1 DM was induced in knockout mice lacking tau proteins (here referred as mtauKO STZ), the behavioral and cellular phenotypes found in WT-STZ mice were not observed. Associated with these cognitive deficits, WT-STZ mice displayed a significant decrease of synaptic markers. Overall, our results indicate that tau phosphorylation is a critical and essential molecular mechanism underlying the link between DM and AD.


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