Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.684424
Title: Calcium homeostasis and calciumactivated proteins in Alzheimer's disease
Author: Kurbatskaya, Ksenia
ISNI:       0000 0004 5921 2155
Awarding Body: King's College London
Current Institution: King's College London (University of London)
Date of Award: 2015
Availability of Full Text:
Access from EThOS:
Access from Institution:
Abstract:
Ca2+ dyshomeostasis is considered to be an early pathogenic event in Alzheimer’s disease (AD). Abnormal levels and activity of Ca2+-regulated proteins are detected in post mortem AD brain, elevated neuronal Ca2+ is found in many cell and animal models of AD, and Ca2+-dependent signalling pathways are recognized to contribute to neurodegeneration in these models. The aims of this project were 1) to further investigate changes in the levels or activity of Ca2+-activated proteins in association with tau and Aβ accumulation during the progression of AD, and 2) elucidate novel mechanisms underlying Ca2+ dysregulation in AD. Post-mortem brain tissue was obtained from controls and AD cases at different stages of disease development (Braak II-VI). Biochemical analysis of these tissues revealed that calpain-1 activity is increased in Braak stage II to VI brain in comparison to controls, suggesting that changes in Ca2+-sensitive signalling pathways occur very early during disease development. Elevated calpain-1 activity was associated with a transient upregulation of the endogenous calpain inhibitor, calpastatin, and preceded Aβ1-42 accumulation, activation of tau kinases, increased tau phosphorylation and synapse loss. These results corroborate findings from cell and animal models that Ca2+ dysregulation and calpain activation are upstream of tau phosphorylation and synapse loss in AD. In addition, end-stage (Braak stage VI) AD brains displayed elevated calpain-mediated cleavage of the sodium calcium exchanger 3 (NCX3), which normally extrudes excess cellular Ca2+, suggesting that deficiencies in NCX3 function might contribute to the accumulation of excess intraneuronal Ca2+ in AD. In support of this, knockdown of NCX3 in primary neurons sensitized neurons to the toxic effects of Aβ1-42. In addition, treatment of neuronal cells with Aβ1-42 resulted in neurotoxicity which was associated with activation of poly(ADP-ribose) polymerase (PARP)-1, Ca2+ entry through transient receptor potential melastatin type 2 (TRPM2) channels, elevations in cytosolic Ca2+, activation of calpain, calpain-regulated tau kinases and tau phosphorylation at epitopes of relevance to AD and synapse loss. Overall, this work lends further support to the hypothesis that altered Ca2+ homeostasis plays an important role in early AD pathogenesis, and has identified novel mechanisms in this process including abnormal regulation of PARP-1/TRPM2 signalling and NCX3 function.
Supervisor: Hanger, Diane Pamela ; Noble, Wendy Jane Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.684424  DOI: Not available
Share: