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We now know that Alzheimer’s disease is characterized by extracellular deposits of a protein called amyloid beta (Aβ) and intracellular deposits of tau proteins in the brain. These lesions develop over the years, gradually causing impairment of memory and cognition. There is mounting evidence that the brain’s blood supply is also affected by disease, but how it is is still unknown. Researchers at the University of Manchester may have finally solved this mystery.
Alzheimer’s disease, whose incidence increases after age 65, is the most common form of dementia in older adults. Nearly 1.2 million people in France could be affected, according to the latest estimates. There is no cure for this disease, but understanding its mechanisms has made good progress in recent years. The disease is primarily caused by a buildup of beta-amyloid protein, which is naturally present in the brain, which ends up forming deposits that are toxic to neurons.
But according to a recent study from the University of Manchester, the disease is also associated with certain changes in the blood vessels in the brain, which may pave the way for the development of new drugs to halt the progression of the disease. ” So far, more than 500 drugs have been tested […]. All of them targeted the brain nerves and none of them succeeded. By showing exactly how Alzheimer’s disease affects the small blood vessels, we’ve opened the door to new avenues of research to find an effective treatment. Dr. Adam Greenstein, co-author of the study, said.
A specific form of beta-amyloid affects the arteries in the brain
Microvascular diseases are increasingly recognized as important contributors to functional and cognitive decline in Alzheimer’s patients. The surface of the brain is covered with small arteries called “granule arterioles,” which control the brain’s supply of blood and oxygen. Microcirculation performs two main functions: maintaining blood flow in the face of momentary changes in blood pressure, and locally increasing blood flow based on neuronal activity.
However, if these arteries are narrowed for too long, they can no longer regulate blood flow and the brain does not receive enough nutrients. Cerebral vasculopathy is a special form of disease of the small cerebral arteries. It is caused by amyloid deposits in the walls of small and medium cerebral vessels. This disorder, common in the elderly, is closely related to Alzheimer’s disease. This is one of the causes of memory loss that appears in people with the disease.
So Dr. Greenstein and colleagues tested the hypothesis that overexpression of beta-amyloid protein in Alzheimer’s disease would have a direct effect on cerebral arterial function. They found that a smaller version of the protein, called amyloid beta 1-40 (Aβ 1-40), specifically builds up in the walls of small arteries, reducing blood flow to the brain.
A protein that causes a decrease in vasodilation
In this study, the researchers used a mouse model with expression of amyloid precursor protein seven times higher than normal–resulting in an Alzheimer’s-like cerebrovascular phenotype and cerebral vasculopathy. The researchers took a closer look at the rodents’ arteries.
They found that they produced a very high amount of Aβ1-40 and showed significantly greater contractility compared to healthy mice of the same age. This arterial narrowing was caused by Aβ disruption of a calcium-activated potassium channel (termed BK), in cells lining blood vessels by Aβ. BK channels are involved in many physiological processes; In particular, they contribute to the regulation of neuronal excitability and circadian rhythms.
The activity of the BK channel is mediated by the release of calcium ions (the so-called “calcium spark”). When the potassium channel is functioning normally, it sends a signal that causes the arteries to widen. But when the researchers exposed the cerebral arteries of healthy young mice to Aβ(1-40) peptides, the latter disrupted the vasoregulatory machinery of the BK channel, partially recapitulating the resistant artery defect phenotype observed in mouse models of Alzheimer’s disease. In other words, Aβ 1-40 reduced the calcium spark frequency, blocking signals from the duct and causing arterial stenosis.
The team now plans to identify the Aβ portion of 1-40 that is responsible for this blockage, so that drugs that prevent this phenomenon can be developed and tested as a treatment to prevent the development of Alzheimer’s disease. ” This research is an important step in our understanding of Alzheimer’s disease. More than half a million people in the UK live with this condition, and this number is expected to rise with age. These findings could lead to a much-needed treatment for this devastating disease Professor Metin Avkiran, associate medical director of the British Heart Foundation, said:
Source: J. Taylor et al., PNAS
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