The role of smooth muscle cell metabolism of amyloid beta in cerebral amyloid angiopathy

Dr. Gordon A. Francis
St. Paul’s Hospital, UBC
Q: What did we learn?

Leakage of blood vessels in the brain due to build up the protein amyloid beta is thought to be a significant cause of dementia in both Alzheimer’s disease and vascular dementia. In the blood vessels there is loss of smooth muscle cells (SMCs), the main cell type in arteries, and replacement of these cells by the amyloid beta protein, which is thought to lead to the leakiness. We posed the hypothesis that SMCs have a defect in their ability to take up and remove amyloid beta when compared to the major “garbage removal” cell type in brain, a form of white blood cell called microglial cells. Our research supported by the CLEAR Foundation has found that SMCs have a defect in the ability to take up amyloid beta, and a defect in their ability to move amyloid beta to sites of degradation within the cell, when compared to the microglial cells that are capable of performing these processes. We believe that these defects lead to accumulation of amyloid beta around the SMCs, which ultimately leads to death of the SMCs. Further experiments are being performed to confirm these results for publication.

Q: Why is this knowledge important?

We believe these results provide a major clue as to how the loss of brain artery SMCs occurs, leading the leakiness of brain blood vessels that is one of the causes of loss of brain function in Alzheimer’s Disease and vascular dementia. By identifying this defect it opens up a new pathway to attempt to reduce amyloid collection around the SMCs, or to discover novel treatments that would increase amyloid beta removal by brain SMCs.

Q: What are the next steps?

We will confirm our results with further cell culture experiments prior to submitting these findings for publication. An additional line of studies would be to determine the relative toxicity of increasing concentrations of amyloid beta on SMCs in culture and the time course of this toxicity (hours, days, weeks).

ABSTRACT

The research goal is to understand how the harmful protein, amyloid beta, deposits in blood vessels of the brain, leading to dementia.

A key change in the brains of individuals with Alzheimer’s and other forms of dementia is the accumulation of amyloid beta in arteries, in regions normally occupied by smooth muscle cells, the main cell type in arteries.

We will examine why smooth muscle cells have difficulty breaking down this protein compared to other brain cells, microglial cells. We will do these studies using smooth muscle and microglial cells in dishes and using sections of brain tissue donated from autopsies of patients who did or did not have dementia. By understanding why smooth muscle cells fail to degrade this harmful protein it is hoped that this can be prevented to reduce the incidence of Alzheimer’s and other dementias.

Imagine a world without Alzheimer disease.