Diabetes Linked With Collapse of Brain Cilia and Impaired Neurogenesis
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Type 1 and type 2 diabetes mellitus are worldwide problems that have risen to pandemic proportions. Current estimates indicate that age-standardized diabetes prevalence in adults has escalated in almost every country, from 108 million in 1980 to 422 million in 2014. This chronic disease affects several target organs, including the brain. Diabetes is a significant risk factor for cognitive impairment and dementia.
Read more: global cost of diabetes
Relatively little is known about the earliest stages of diabetic brain damage, when preventive measures might provide complete recovery. An international team of scientists, led by Universidad Austral-CONICET, Argentina, and Technische Universität Dresden, Germany, researchers, investigated the initial diabetic lesions in the subventricular zone, an area of the brain capable of generating new neurons throughout life. The subventricular zone is located in the lateral wall of the lateral ventricles, and is associated with a specialized region called the ependymal epithelium. The neuroprogenitor stem cells residing in this area migrate to the olfactory bulb in rodents and to the striatum in primates and humans, where they differentiate into functional neurons.
See: postnatal neurogenesis
They used a compound called streptozotocin, to specifically damage insulin-producing cells in the pancreas to produce diabetes mellitus type 1 condition in mice. They also used a combination of streptozotocin with the vitamin nicotinamide to produce the type 2 condition. Both diabetic types could then be evaluated within the same time line and compared to non-diabetic animals. Metabolic disorders were observed in both diabetes conditions.
After just one week of induced-diabetes, type 2 mice showed significant impairment of neuronal growth while type 1 animals showed no evidence of damage to neurogenic processes despite having much higher glucose concentration in their blood and cerebrospinal fluid. The subventricular zone of type 2 mice displayed significant decreases in cell number, a reduction of cell proliferation and a downregulation of markers of neuron generation. The stem cells also followed abnormal migration pathways.
Secondly, using scanning electron microscopy, they found that ependymal cilia, the small hair-like structures lining the ventricles in the brain, became entangled and stuck to each other in type 2 diabetic mice, particularly at their tips. Entanglement and collapse of ciliary tufts, often oriented in different directions, suggested alterations in ciliary movement. It is well-known that the coordinated movement of cilia is crucial to facilitate circulation of cerebrospinal fluid, allowing transportation of signaling molecules as well as detoxifying a wide variety of substances. Considering that the normal beating of ependymal cilia provides directional cues for the proper migration of stem cells from the ventricular zone to the olfactory bulbs, the ciliary defects observed in induced-type 2 diabetes most likely contributed to their abnormal migration. Ciliary alterations could be detected after 4 days of induced-diabetes, before effects on the stem cells were seen.
Learn more: restoring cilia restores sense of smell
Thirdly, in type 2 mice, the scientists saw a reduction of the ciliary protein prominin-1 (also called CD133) in ependymal cells and its delocalization from ciliary tips. In prominin-1-null mice, although its absence did not alter the general orientation of ciliary tufts or the orientation of single cilia, the researchers found that cilia clumped together either at their tips or all along their length, which implicates prominin-1 as an early diabetic target.
Fourthly, they performed experiments with primary ependymal cells in culture and demonstrated that delocalization of prominin-1 and altered ciliary morphology were not a direct effect of the drugs used to induce diabetes or the elevated glucose concentration.
All together they demonstrated, using animal models, that type 2 diabetes provoked a far more severe effect on the cells in the subventricular zone than type 1 during the first week of diabetes. This is consistent with recent clinical studies showing that the risk for dementia is greater in type 2 diabetes.
To our knowledge, this is the first study recognizing the early effect of diabetes on the subventricular zone, and the initial damage of cilia and prominin-1, which might represent the primary targets of type 2 diabetes.