Strokes, madness, and micro-starvation in the brain
As people age, they become increasingly prone to strokes and dementia that often lead to death. Frequently these problems begin with damage to small blood vessels, triggering a loss of blood flow to brain tissues – a condition known as ischemic cerebral small vessel disease (SVD). Such damage is often a natural result of aging, but some people inherit a rare mutation that causes strokes and dementia two or three decades earlier than in the general population. Because scientists have lacked a good animal model for the disease, it has been hard to study the process by which defects in a protein called Notch3 lead to SVD. Now Norbert Hübner's lab at the MDC and colleagues in Paris have developed a strain of mouse with a mutation in Notch3 that mimics the course of SVD. Their studies of the animal, which appear in the February 20 issue of the Journal of Clinical Investigation, yield important new insights into the mechanisms that underlie the disease and the origins of some of its symptoms.
This image of a capillary from the brain of a mouse with defective Notch3 shows deposits of the protein (yellow and orange) which have accumulated outside cells. Such deposits are also found in human patients suffering from hereditary SVD.
A careful examination of patients who have died from the hereditary form of SVD has revealed defects in tiny arteries of the brain. The capillaries develop thick walls, surrounded by fibrous deposits of proteins, and lose the smooth muscle cells that control their dilation and contraction as blood flows through. Until now, most researchers have assumed that the symptoms of the disease begin with the accumulation of fibers and loss of muscle cells. The new study suggests a different scenario.
In healthy people, smooth muscle cells produce the Notch3 protein and then slice it into a short and a long version. The short form is mounted in the cell membrane and serves as a sort of plug onto which the longer version attaches itself outside the cell. People with the disease-causing mutation don't have enough copies of the plug. Without this anchor, the long form of the protein is released and accumulates outside the cell, near the fibrous deposits on the blood vessels – possibly as one of their components.
Norbert and his colleagues hoped to discover how the mutation changes Notch3's functions and leads to the symptoms of the disease. To do so, they needed to develop a strain of mouse with a similar defect in Notch3. Norbert's laboratory and others have tried to do so for several years, but so far none of the strains have mimicked the changes in blood vessels or the brain damage found in patients with hereditary SVD. One difficulty is that the human disease arises relatively late in life, which makes it hard to study in animals with short lifespans.
One possible solution was to stimulate the mice's cells to produce abnormally high amounts of the defective molecule, which might accelerate the course of the disease. The authors of the paper have managed to do this by inserting a large piece of the mutated Notch3 into embryonic mice cells. This was necessary because "control regions" in the DNA – which determine where the protein is produced and how much of it cells make – lie far away from the Notch3 gene. Mice that had been given a defective form of Notch3 alone, without the control regions, had not developed the main symptoms of SVD.
This time the experiment was successful: cells in the brains of the mice produced high amounts of mutant Notch3. By the time the animals reached 18-20 months of age, they had developed the typical symptoms of hereditary SVD, including the accumulation of fibrous material and brain damage.
The disease strikes mainly tiny brain capillaries, rather than larger blood vessels; the researchers discovered that this process begins early on and reduces the number of capillaries. This increases the pressure at which blood flows through the arteries, but also reduces the overall amount and prevents enough of it from reaching surrounding tissues. As a result, the brain is starved of blood and eventually suffers irreparable damage.
"This reverses the general picture that we've had about the development of brain damage during the disease," Norbert says. "We discovered that tissue around the blood vessels was undergoing damage before a significant accumulation of fibers or a loss of smooth muscle. Previously, those events were thought to be the causes of the symptoms; now we think they might rather be factors that aggravate the course of the disease in its later stages. So we're shifting our focus to the changes in the structure and behavior of the capillaries themselves, defects in 'microcirculation,' and the resulting starvation of brain tissues as the key mechanisms that trigger the onset of SVD."
Having a strain of mice that faithfully reproduces the symptoms of hereditary SVD will be useful in further studies of the disease. "Such a model is necessary in the development of therapies, which have to be tested in animals before working with human patients," Norbert says. "And the rare, hereditary form of SVD is similar to more common forms of the disease in the general population, so we hope that the findings will be more widely applicable in trying to understand these important causes of strokes and dementia."
- Russ Hodge
Highlight Reference:
Joutel A, Monet-Leprêtre M, Gosele C, Baron-Menguy C, Hammes A, Schmidt S, Lemaire-Carrette B, Domenga V, Schedl A, Lacombe P, Hubner N. Cerebrovascular dysfunction and microcirculation rarefaction precede white matter lesions in a mouse genetic model of cerebral ischemic small vessel disease. J Clin Invest. 2010 Feb;120(2):433-45.
Free full text of the paper
Wikipedia article on brain ischemia
