Mouse as a Model for Stroke Patients

Some 250,000 people per year in Germany sustain a stroke. The majority of people affected then suffer from consequential damages such as paralysis and language or vision disorders. In collaboration with French colleagues, researchers led by Professor Dr. Norbert Hübner of the MDC have now developed a mouse model enabling the detailed study of risk factors for stroke development. In doing so, the researchers based their work on the hereditary disease CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortial Infarcts and Leukoencephalopathy). CADASIL can lead to a form of stroke affecting in particular the smallest blood vessels. In contrast to the classic cerebral infarct, frequently caused by arteriosclerosis, CADASIL is linked to changes in a gene called “Notch 3”. CADASIL is amongst the most frequent genetically caused cerebral infarcts, yet is considered one of the rarer diseases: Some four people out of 100,000 inhabitants are affected. An early symptom is a migraine-like headache, caused by the characteristic constriction of vessels. Over the years, transient ischaemic attacks or strokes occur repeatedly, ultimately leading to a decrease in mental performance and even dementia. So far, there is no effective treatment. To prevent those “mini” strokes, it is recommended - in addition to medication with acetylsalicylic acid - to minimise risk factors and maintain parameters such as blood pressure, blood sugar and blood lipids within the optimal range.

Even so, CADASIL plays an important role in medical research: “It has model character for other epidemiologically significant diseases such as microangiopathic stroke, where the smallest blood vessels are constricted, or vascular dementia, where the blood flow in the brain is impaired. Due to similar pathology, we can learn much from this specific disease”, says Hübner.

The MDC researchers could successfully insert an altered human Notch 3 gene into a mouse by way of an artificial chromosome. In order to accomplish this, they built the altered Notch 3 gene into an artificial circular chromosome (plasmid) and inseminated egg cells of mice with this via microinjection. Since it cannot be controlled where the new genetic material is inserted into the mouse’s genome, Hübner and his team also inserted the large regulatory areas to the left and right of the Notch 3 gene into the plasmid. These regulatory areas are essential for Notch 3 being copied correctly and to the normal degree.

The experiment which the MDC researchers conducted for the first time for the CADASIL disease, was successful: The gene was built into the mouse genome and the genetically altered animals developed a whole series of preliminary stages of the disease also occurring in humans. Constriction and blockage of small blood vessels did indeed occur, resulting in stroke and deteriorating mental performance. “With these results – in addition to cell biological studies – it now at last is possible to simulate microangiopathic diseases in animal models. We can now research why this disease actually occurs in humans and test whether there are other risk factors beyond those known so far and in what measure these actually lead to the development of stroke”, says Norbert Hübner. “And, of course, our research also focuses on how it can happen in the first place that the mutation in the Notch 3 gene leads to stroke in CADASIL patients and how this can be prevented in future.”