HEALTH NEWS

Study Title:

Alzheimer's and Increased Blood Brain Barrier Permeability

Study Abstract

Evidence of reduced blood-brain barrier (BBB) integrity preceding other Alzheimer's disease (AD) pathology provides a strong link between cerebrovascular angiopathy and AD. However, the “Vascular hypothesis”, holds that BBB leakiness in AD is likely due to hypoxia and neuroinflammation leading to vascular deterioration and apoptosis. We propose an alternative hypothesis: amyloidogenesis promotes extensive neoangiogenesis leading to increased vascular permeability and subsequent hypervascularization in AD. Cerebrovascular integrity was characterized in Tg2576 AD model mice that overexpress the human amyloid precursor protein (APP) containing the double missense mutations, APPsw, found in a Swedish family, that causes early-onset AD. The expression of tight junction (TJ) proteins, occludin and ZO-1, were examined in conjunction with markers of apoptosis and angiogenesis. In aged Tg2576 AD mice, a significant increase in the incidence of disrupted TJs, compared to age matched wild-type littermates and young mice of both genotypes, was directly linked to an increased microvascular density but not apoptosis, which strongly supports amyloidogenic triggered hypervascularity as the basis for BBB disruption. Hypervascularity in human patients was corroborated in a comparison of postmortem brain tissues from AD and controls. Our results demonstrate that amylodogenesis mediates BBB disruption and leakiness through promoting neoangiogenesis and hypervascularity, resulting in the redistribution of TJs that maintain the barrier and thus, provides a new paradigm for integrating vascular remodeling with the pathophysiology observed in AD. Thus the extensive angiogenesis identified in AD brain, exhibits parallels to the neovascularity evident in the pathophysiology of other diseases such as age-related macular degeneration.

From press release:

University of British Columbia scientists may have uncovered a new explanation for how Alzheimer's disease destroys the brain -- a profusion of blood vessels.

While the death of cells, whether they are in the walls of blood vessels or in brain tissue, has been a major focus of Alzheimer's disease research, a team led by Wilfred Jefferies, a professor in UBC's Michael Smith Laboratories, has shown that the neurodegenerative disease might in fact be caused by the propagation of cells in blood vessel walls.

Examining brain tissue from mouse models of Alzheimer's disease, Jefferies' team found nearly double the density of capillaries compared to normal mice. They also found a similarly higher density of capillaries in brain samples of people who had died of the disease, compared to samples from people who didn't have it.

Jefferies, in an article published online August 31 by PLoS One, theorizes that the profusion of blood vessels is stimulated by amyloid beta, a protein fragment that has become a hallmark of Alzheimer's disease. The blood vessel growth, or "neo-angiogenesis," leads to a breakdown of the blood-brain barrier -- the tightly interlocked network of cells that allows oxygen-carrying blood to reach brain tissue while blocking harmful substances, such as viruses.

"When the blood vessels grow, the cells of the vessel walls propagate by dividing," Jefferies says. "In the process of splitting into two new cells, they become temporarily rounded in shape, and that undermines the integrity of the blood-brain barrier, potentially allowing harmful elements from outside the brain to seep in."

The deterioration of the barrier might in turn allow the depositing of amyloid beta, which accumulates around neurons and eventually kills them.

Previous research had touched on the "leakiness" of the barrier, but it was assumed that it was caused by the death of blood vessels -- not their growth.

Jefferies also sees an intriguing parallel with the "wet" form of age-related macular degeneration, in which blood vessels grow behind the retina and then leak blood and fluid, leading to hemorrhaging, swelling, and formation of scar tissue.

"Given the new link between both conditions, the next logical step in the treatment of Alzheimer's disease would be to look for treatments that specifically target blood vessel growth," says Jefferies, who holds appointments in the departments of microbiology and immunology, medical genetics and zoology, and is also a member of the Biomedical Research Centre and the Brain Research Centre.

Jefferies collaborated with Dara Dickstein, a professor in the department of neuroscience at the Mount Sinai School of Medicine, New York. The team at UBC included graduate student Kaan Biron and technician Rayshad Gopaul.

The research was supported by grants from the Canadian Stroke Network and the Canadian Institutes of Health Research.

Study Information

Biron KE, Dickstein DL, Gopaul R, Jefferies WA.
Amyloid Triggers Extensive Cerebral Angiogenesis Causing Blood Brain Barrier Permeability and Hypervascularity in Alzheimer's Disease
PLos ONE
2011 August
University of British Columbia