Dr. Margaret Flanagan Subproject

Project: Research project

Project Details


According to the World Health Organization approximately 50 million people worldwide suffer from
cognitive disorders. The incidence of dementia increases with age, especially for those over 65.
CNS white matter lesions are also known to increase with age and to increase the risk of developing
dementia. Vascular dementia (VD) is the second most common cause of cognitive abnormalities in the
elderly behind Alzheimer’s disease (AD). VD has been associated with various cardiovascular
maladies, which are thought to contribute to diffuse white matter disease leading to dementia.
The underlying hypothesis of this proposal is that the impact of the cytotoxic
environment created by disruptions to the CNS vasculature associated with aging and diverse
cardiovascular disorders are particularly detrimental to oligodendrocyte viability and
function. We posit that the heightened sensitivity to cellular stress that oligodendrocytes
display due to their unique metabolic demands makes them particularly vulnerable to the
changing extracellular environment that develops with advancing age and in response an
altered cerebral circulation. The white matter abnormalities that occur as a consequence
of oligodendrocyte perturbation are likely critical to the development of neurodegenerative,
cognitive and behavioral changes. The goal of the current proposal is to a gain a mechanistic
understanding of the impact of ageing and cerebrovascular abnormalities on oligodendrocytes, both
in humans and in mouse models. Our focus will be on examining the role that intrinsic
cytoprotective pathways play in the response of oligodendrocytes to the adverse cytotoxic
environment created by these conditions. We will focus on three cytoprotective pathways:
the integrated stress response (ISR) pathway is initiated by a variety of stresses including
oxidative stress, hypoxia and inflammation; the nuclear factor erythroid 2-related factor 2 (NRF2)
pathway is activated in response to oxidative stress; and the hypoxia-inducible factor 1 (HIF-1)
pathway is the master transcriptional regulator of the cellular response to hypoxia. We will
examine human postmortem samples from individuals with vascular dementia for activation of
these pathways in oligodendrocyte lineage cells, and we will similarly assess their activation in
ageing mice, which are known to display oligodendrocyte and myelin deficiencies. We will also
examine a mouse model of heart failure with preserved ejection fraction (HFpEF) for oligodendrocyte
and myelin abnormalities linked to ISR, NRF2 and HIF activation. HFpEF is a common
cardiovascular abnormality associated with dementia. We will also use a genetic approach
to further examine the response of these cytoprotective pathways to the adverse CNS
environment created by ageing and cerebrovascular abnormalities. Together, these efforts will
substantially increase our understanding of the response of oligodendrocytes to the cytotoxic CNS
environment created by ageing and cerebrovascular dysfunction. A better appreciation of the
contribution of myelinating glia dysfunction to the pathogenesis of dementia is essential to our
understanding of this growing health concern and may serve as the basis for the design of
neuroprotective therapeutic strategies.
Effective start/end date5/1/214/30/24


  • National Institute on Aging (1RF1AG072080-01)


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