a discovery improves our understanding of the disease

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We now know that Alzheimer’s disease is characterized by extracellular deposits of a protein called beta-amyloid (Aβ) and intracellular deposits of tau proteins in the brain. These lesions progress over the years, progressively causing memory and cognitive impairment. There is growing evidence that the blood supply to the brain is also affected by the disease, but how is not yet known. 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 the elderly. Almost 1.2 million people could be affected in France, according to the latest estimates. There is no treatment for this disease, but the understanding of its mechanisms has progressed a lot in recent years. The disease results primarily from the buildup of beta-amyloid protein, naturally present in the brain, which ends up forming toxic deposits on nerve cells.

But according to a recent study from the University of Manchester, the disease is also associated with certain changes in the blood vessels of the brain, which could pave the way for the development of new drugs to stop the progression of the disease. ” To date, more than 500 drugs have been tested. […]. All of them targeted brain nerves and none were successful. By showing exactly how Alzheimer’s disease affects small blood vessels, we have opened the door to new avenues of research to find an effective treatment. said Dr. Adam Greenstein, co-author of the study.

A specific form of beta-amyloid that affects arteries in the brain

Diseases of the small cerebral vessels are increasingly recognized as important contributors to functional and cognitive decline in patients with Alzheimer’s disease. The surface of the brain is covered with small arteries, called “pial arteries,” which control the supply of blood and oxygen to the brain. This microcirculation performs two key functions: maintaining blood flow in the face of instantaneous changes in blood pressure, and localized increases in blood flow based on neural 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 amyloid angiopathy is a special form of disease of the small cerebral arteries. It is the result of amyloid deposits in the wall of small and medium cerebral vessels. This disorder, common in the elderly, is strongly associated with Alzheimer’s disease. This is one of the causes of memory loss seen in people with the disease.

Therefore, Dr. Greenstein and colleagues tested the hypothesis that amyloid-beta protein overexpression in Alzheimer’s disease would have a direct impact on the function of cerebral arteries. They found that a smaller version of the protein, called amyloid beta 1-40 (Aβ 1-40), accumulates specifically in the walls of small arteries, reducing blood flow to the brain.

A protein that causes a reduction in vasodilation

For this study, the researchers used a mouse model with amyloid precursor protein expression seven times higher than normal, leading to a cerebrovascular phenotype similar to that of patients with Alzheimer’s disease and cerebral amyloid angiopathy. The researchers looked closely at the rodents’ pial arteries.

They found that they overproduced Aβ1-40 and showed significantly more constriction compared to age-matched healthy mice. This narrowing of the arteries was due to Aβ 1-40 inactivation of a calcium-activated potassium channel (called BK) in the cells lining the blood vessels. BK channels are involved in many physiological processes; in particular, they help regulate neuronal excitability and circadian rhythms.

BK channel activity is mediated by the release of calcium ions (known as “calcium spark”). When it works normally, the potassium channel 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 mechanism of the BK channel, partially recapitulating the resistance artery dysfunction phenotype observed in mouse models of Alzheimer’s. In other words, Aβ 1-40 caused a reduction in the calcium spark frequency, which blocked the channel’s signals and caused the arteries to narrow.

The team now plans to identify the part of Aβ 1-40 responsible for this blockage, so that drugs that prevent this phenomenon can be developed and tested as a treatment to prevent the progression 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 are living with the condition, and this number will increase as the population ages. These findings could lead to a desperately needed treatment for this devastating disease. said Professor Metin Avkiran, associate medical director of the British Heart Foundation.

Source: J. Taylor et al., PNAS

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