Is cardiovascular health the key to protecting the brain against dementia?

Can “good” cholesterol protect against age-related cognitive decline? A trio of papers from researchers in Dr. Cheryl Wellington’s lab illustrate new context for the role of high-density lipoproteins (HDL) – commonly described as good cholesterol – in protecting the brain against disease.

The newest paper, and the culmination of the lab’s work over the past year, was published today in the journal eLife and represents a considerable advance in understanding the role of vascular health in Alzheimer disease.

The brain is home to 25 per cent of the body’s total cholesterol. Cholesterol is a fatty substance necessary for hormone production and metabolic processes. As it’s insoluble in water, cholesterol needs to be transported through the bloodstream by specific carriers including low-density lipoproteins (LDL), thought of as “bad cholesterol” for its links to cardiovascular disease, and HDL, thought as “good cholesterol” for its beneficial role in blood vessel health. Because the brain is among the most vascularized organ in the body and is composed of hundreds miles of blood vessels, it is not surprising that maintaining good blood vessel health might be beneficial to neurodegenerative disease.

In Alzheimer disease, a protein called beta-amyloid is responsible for the plaques that form in the brain and contribute to cognitive decline. Cerebral blood vessels play an important role in dementia, carrying proteins in and out of the brain. Importantly, cardiovascular disease risk factors increase dementia risk as well. Up to 90 per cent of people with Alzheimer disease also show signs of cerebral amyloid angiopathy (CAA), a disease of the blood vessels of the central nervous system due to beta-amyloid deposition.

Earlier this year researchers in the Wellington lab engineered a human vascular model to study the role of HDL in CAA. This unique model allowed researchers including Dr. Jerome Robert, post-doctoral fellow and first-author on the eLife paper, to demonstrate the routes by which HDL contributes to clearing the proteins that contribute to plaques in the vessels.

“We know that cardiovascular health and brain health are connected, but until now it was not well understood how cardiovascular diseases affect neurodegeneration associated with Alzheimer disease and dementia,” says Dr. Robert. “What we’re able to show is that good cholesterol – HDL – might have a more significant neuroprotective role due to its beneficial functions on the blood vessels in the brain than has previously been thought.”

In the CAA model, Drs. Wellington and Robert, and PhD students Emily Button and Guilaine Boyce discovered that HDL purified from blood acts in partnership with another lipid transporter present in the brain, known as apolipoprotein E (ApoE), to enable beta-amyloid from getting stuck in cerebral vessels. HDL also stopped inflammation of the brain’s blood vessels.

“Given the socioeconomic and deeply personal costs of Alzheimer disease and dementia on our communities and families, it’s important to be able to conduct our research in a human context,” says Dr. Robert. “By creating this type of bioengineered disease model, we can observe the cardiovascular mechanisms through which beta-amyloid deposits and clears, hopefully speeding up our understanding of the role of cardiovascular health in brain disease.”

Alzheimer disease is the leading cause of dementia world-wide, with over 44 million people affected. According to the Alzheimer Society of Canada, 25,000 new cases of dementia are diagnosed in Canada each year, with an annual cost to Canadians of $10.4 billion.

“The benefit of using lab-made human blood vessels is that we are able to fill a huge gap in how we study the cardiovascular system’s impact on cognitive decline,” says Dr. Robert. “Until now, we have been limited by cell cultures that can’t accommodate the complexity of cellular interactions in the blood and brain, or models that do not always replicate human biology, particularly regarding fat metabolism.”

“Our next step is to see if improving HDL function in those with risk factors for dementia is helpful in preventing or treating cognitive decline,” says Dr. Robert.

Dr. Robert’s research has been supported The Swiss National Foundation, with ongoing support from Bright Focus, the Weston Brain Institute, and a DMCBH catalyst grant. 

Citation:

J. Robert, E. Button, B. Yuen, M. Gilmour, K. Kang, A. Bahrabadi, S. Stukas, W. Zhao, I. Kulic, C. Wellington. Clearance of beta-amyloid is facilitated by apolipoprotein E and circulating high-density lipoproteins in bioengineered human vessels. eLife, 2017. https://doi.org/10.7554/eLife.29595.

Related work:

• G. Boyce, E. Button, S. Soo, C. Wellington. The pleiotropic vasoprotective functions of high density lipoproteins (HDL). Journal of Biomedical Research, 2017. PMID: 28550271.
• J. Robert, E. Button, S. Stukas, G. Boyce, E. Gibbs, C. Cowan, M. Gilmour, WH Cheng, S. Soo, B. Yuen, A. Bahrabadi, K. Kang, I. Kulic, G. Francis, N. Cashman, C. Wellington. High-density lipoproteins suppress Aβ-induced PBMC adhesion to human endothelial cells in bioengineered vessels and in monoculture. Molecular Degeneration, 2017. https://doi.org/10.1186/s13024-017-0201-0.