Ageing in the mammalian brain

Khojah, Sohair Mohammed (2015) Ageing in the mammalian brain. PhD thesis, University of Glasgow.

Abstract

With a globally ageing population diseases associated with this natural process are becoming major issues worldwide. Research into the process of ageing and its concomitant issues is rapidly expanding; the need for new tools and models to investigate this rapidly expanding arena of research is paramount. The discovery of a spontaneous mutation in the AS rat strain which introduces a premature stop mutation into the gene encoding protein kinase C  (PKC lead to the development of a model for one such age related disorder, Parkinson‟s disease. Consequently, this model has been selected to investigate age related changes in specific areas of the brain (the cerebellum, basal ganglia, cerebral cortex and brainstem). These regions were selected because they have previously been shown to demonstrate changes with age (cerebellum, cerebral cortex and basal Ganglia), they show differences between the AS and AS/AGU strains (basal ganglia) or they show differences in PKC knockout models (cerebellum). The Brainstem was selected as it shows little change due to age and shows no differences in PKC knockouts or AS/AGU rats. This study used established qPCR methods to measure a validated biomarker of ageing, CDKN2A (the transcript for p16INK4a) in the brains of these rats to determine whether this model is in fact a genuine model for accelerated ageing. This thesis demonstrates that CDKN2A expression, in combination with senescence-associated -galactosidase staining, provides clear evidence of accelerated ageing in the brains of AS/AGU rats when compared with the parent AS strain.
These investigations were furthered by an investigation of members of the Sirtuin family of proteins. The changes in expression of these Sirtuins indicates that there may be increased levels of cellular stress, disruption of metabolism and DNA damage in the AS/AGU rats, this would be congruent with the accelerated ageing phenotype present in this strain. Furthermore, the levels of these Sirtuins were in line with the predictions from the MTR trinity in regards to the accelerated ageing phenotype. Whilst some of the changes in senescence and metabolic disruption may be attributable to the PKC mutation in the AS/AGU rats, it would appear that there is some element of accelerated ageing that is independent of this mutation.

• Item Type: Thesis (PhD)
• Qualification Level: Doctoral
• Keywords: Ageing, Mammalian, Brain, AS/AGU rats, PKC, CDKN2A, cerebellum, cerebral cortex, basal Ganglia, brainstem, senescence-associated, beta galactosidase staining, Sirtuins, DNA global methylation.
• Subjects: Q Science > Q Science (General); Q Science > QH Natural history > QH301 Biology; Q Science > QH Natural history > QH345 Biochemistry
• Colleges/Schools: College of Medical Veterinary and Life Sciences > School of Life Sciences
• Supervisor's Name: Payne, Prof. Anthony and Shiels, Prof. Paul
• Date of Award: 2015
• Depositing User: mrs sohair khojah
• Unique ID: glathesis:2015-6244
• Copyright: Copyright of this thesis is held by the author.
• Date Deposited: 23 Apr 2015 12:06
• Last Modified: 30 Apr 2015 14:01
• URI: https://theses.gla.ac.uk/id/eprint/6244