The prevalence of neurodegenerative conditions like Alzheimer’s disease rises as the population ages. Proteinopathies, abnormal protein buildups in the brain that impede neuronal function, distinguish these disorders. For instance, the accumulation of beta-amyloid and tau proteins is responsible for Alzheimer’s. Trying to lessen amyloid-beta peptide and tau protein aggregation in neurons is the most extensively researched therapeutic method for developing medications to treat Alzheimer’s.
However, the medications must first pass across the blood-brain barrier (BBB) to reach their targets in the brain. Endothelial cells, which line the smallest blood vessels in the brain, regulate the exchange of blood and the brain. They maintain a balance that enables vital molecules like glucose to pass through while restricting the entry of most pharmaceuticals, including the latest and much-hyped drug, lecanemab.
The equilibrium becomes disturbed when these brain endothelial cells acquire a disease. The brain fights to get the molecules it needs back into the bloodstream and rejects those that could harm it. The brain and other body organs are thus constantly communicating, whether in health or disease.
Insulin and the Brain
The hormone insulin is necessary for life. It continues to be a crucial component of diabetes pharmaceutical treatment because of its impact on blood sugar management, for which it is best recognized. Researchers have discovered vascular and metabolic problems in a sizable proportion of dementia patients in recent years.
Indeed, Type 2 diabetes, in which insulin resistance occurs in the later stages, is a significant Alzheimer’s risk. Some published data point to reduced insulin sensitivity in the Alzheimer’s brain. While some other studies have indicated that insulin can enhance memory, leading to the initiation of clinical trials on insulin’s impact on Alzheimer’s.
However, we are still unaware of the cell types and mechanisms responsible for insulin’s effect on the brain and its lack of action. The pancreas produces the majority of insulin and secretes it into the blood. For insulin to affect the brain, it must first interact with the BBB and its endothelial cells, which are in direct touch with the blood and have receptors for insulin.
The Insulin Receptors and Alzheimer’s
According to a cohort study, the site of insulin-binding receptors is predominantly in the microvessels, so BBB itself. Additionally, people with Alzheimer’s have less of this receptor overall. A decline of insulin responsiveness in the Alzheimer’s brain could result from this decline.
The researchers also tested their hypothesis in mice to more precisely regulate the experimental factors and gauge the insulin receptor’s reaction. In situ cerebral perfusion involves injecting insulin directly into the carotid artery, a neck artery, to ensure it fully reaches the brain. They claim that microvessels in the brain are where circulating insulin primarily stimulates receptors.
Despite the widespread belief that insulin penetrates the BBB to reach deeper-lying brain tissue cells like neurons, their findings indicated that only a tiny percentage of insulin does so. Thus, these two findings support the idea that the bulk of insulin must interact with BBB cells before affecting the brain.
The researchers also treated transgenic genetically altered to imitate Alzheimer’s using the same approach. They discovered that in these diseased mice, there was no activation of the insulin receptor, and the response to insulin at the BBB was defective.
Thus, the research established that the brain insulin receptor is present predominantly at the BBB in both humans and animals, and Alzheimer’s impairs its capacity to respond to blood insulin.
A Substantial Advancement
In conclusion, the findings imply that changes in insulin receptor quantity, conformation, and function at the level of BBB endothelial cells may be a factor in the cerebral insulin resistance seen in Alzheimer’s.
The researchers further proposed a study alternative with two chief advantages by focusing on metabolic dysfunction in the brain instead. The first is that since the endothelial cells become the therapeutic target, they can use treatments that do not need to pass the BBB barrier. The second strategy is “drug repurposing,” which entails leveraging the extraordinary treatment arsenal already authorized to combat diabetes and obesity in the setting of Alzheimer’s.
It should be kept in mind that the few medications we have only slightly improve symptoms. Trying to combat insulin resistance in the brain would allow researchers to break the vicious circle between neuropathology (brain disease) and diabetes, potentially slowing the disease’s progression.
- Biessels, G.J. and Despa, F., 2018. Cognitive decline and dementia in diabetes mellitus: mechanisms and clinical implications. Nature Reviews Endocrinology, 14(10), pp.591-604.
- Arnold, S.E., Arvanitakis, Z., Macauley-Rambach, S.L., Koenig, A.M., Wang, H.Y., Ahima, R.S., Craft, S., Gandy, S., Buettner, C., Stoeckel, L.E. and Holtzman, D.M., 2018. Brain insulin resistance in type 2 diabetes and Alzheimer disease: concepts and conundrums. Nature Reviews Neurology, 14(3), pp.168-181.
- Kellar, D. and Craft, S., 2020. Brain insulin resistance in Alzheimer’s disease and related disorders: mechanisms and therapeutic approaches. The Lancet Neurology, 19(9), pp.758-766.
- Leclerc, M., Bourassa, P., Tremblay, C., Caron, V., Sugère, C., Emond, V., Bennett, D.A. and Calon, F., 2021. Cerebrovascular insulin receptors are defective in Alzheimerˈs disease. bioRxiv.
- Why does the Alzheimer’s brain become insulin-resistant?. The Conversation. https://theconversation.com/why-does-the-alzheimers-brain-become-insulin-resistant-196016. Accessed: 28/12/2022.