Download DNA Damage and Apoptosis in Cerebral White Matter Lesions

DNA Damage and Apoptosis in Cerebral White Matter Lesions
Supervisors: S B Wharton and P G Ince
Background
Cerebral white matter lesions (WML) are areas of myelin pallor and loss that occur at a high
prevalence in ageing and that can be associated with dementia and depression. The
cause(s) of WML, however, remain incompletely understood. They are associated with
vascular risk factors, such as hypertension, stroke and heart disease, suggesting a role for
hypoperfusion1. However, other factors, such as blood brain barrier breakdown and
immunological mechanisms may play a role. Microglial activity is up-regulated in WML, but is
also widespread in non-lesional white matter from cases with WML, suggesting that there is
a field-effect of abnormal white matter in which WML occur2. This leads to a potentially
complex model for the development of WML.
Aims of the Study
Many of the putative aetiological factors for WML, including ageing, ischaemia and
inflammatory mechanisms can cause cell injury, oxidative stress and DNA damage. The
purpose of this project is to investigate the hypothesis that DNA damage contributes to the
pathogenesis of WML through activation of apoptosis and senescence pathways leading to
loss of glial cell function and cell death. The study will determine i) whether DNA damage
occurs in astrocytes, oligodendrocytes and vascular endothelial cells in WML, ii) whether this
is associated with the induction of apoptosis and senescence pathways, iii) whether there is
a field-effect of widespread DNA damage in white matter in cases with WML, iv) whether
there is damage to gene promoter regions, which may result in reduced expression of key
genes involved in white matter function.
Methods
The project is based on human autopsy brain tissue, derived from the MRC Cognitive
Function and Ageing Study. This is a population-based study examining the
neuropathological basis of dementia and frailty in ageing 3. Expression of DNA damage,
apoptosis and senescence related molecules with be determined by immunohistochemistry,
using double-labelling methods to determine cell-type and Western blotting. Methylation of
cytosine bases in promoter regions will be assessed using methylation-specific PCR. The
relationship to dementia in the cohort will be assessed by incorporating DNA damage data
into our multivariable models for cognitive impairment.
Key References
1. Stroke 2006; 37:1391-8
2. Neuropathol Appl Neurobiol 2007; 33:670-83
3. Lancet 2001; 357:169-75