Grant: Project Grant

Alzheimer's dementia (AD) is the progressive loss of cognitive function with brain atrophy that is characterized by the progressive accumulation of soluble and insoluble aggregated amyloid-beta (Abeta). However there are very major gaps in our understanding of the development of dementia. Research on postmortem brains from elderly controls with no dementia compared to AD patients with dementia reported a surprising discovery. Many elderly people that did not have dementia still had significant Abeta levels and Abeta plaques characteristic of AD patients that had dementia This shows that there is a significant knowledge gap in our understanding of the causes of dementia in Alzheimer's. Abeta alone is not sufficient to cause dementia. Post mortem studies identified that the key difference was the robust glial activation with neuroinflammation that occurred in brains from dementia AD patients. This indicates that a secondary response is required in addition to Abeta accumulation. In this grant we are investigating this secondary responses of glial activation and neuroinflammation because understanding how these occur may provide new therapies to prevent the development of dementia. Neuroinflammation refers to the unique pattern of inflammation in the brain and spinal cord that is thought to cause dementia and neuronal death (neurodegeneration) in several diseases such as Alzheimer's and Parkinson's. The brain's glial cells, called microglia and astrocytes, underlie neuroinflammation in the brain in response to infections, tissue damage or amyloid beta, the protein that causes dementia in Alzheimer's Disease (AD). We have discovered characteristic changes in the properties of the activated glial cells that we predict will lead to neurodegeneration and dementia. Our experiments will investigate strategies that will reduce and mitigate these glial changes to prevent neuroinflammation and thereby protect neurons from neurodegeneration and prevent dementia.