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, gradually causing memory and cognitive impairment. There is growing evidence that the disease also affects the blood supply to the brain, but how remains unknown. Researchers at the University of Manchester may finally have solved this mystery.

Alzheimer’s disease, the incidence of which increases after the age of 65, is the most common form of dementia in the elderly. According to the latest estimates, almost 1.2 million people could be affected in France. There is no treatment for this disease, but good progress has been made in understanding its mechanisms in recent years. The disease mainly results from the buildup of the beta-amyloid protein, which is naturally present in the brain and eventually forms toxic deposits for nerve cells.

However, according to a recent study from the University of Manchester, the disease is also linked to certain changes in the blood vessels in the brain, which could pave the way for the development of new drugs to stop the disease from progressing. ” More than 500 drugs have been tested so far […]. All of them targeted cranial nerves and none of them were successful. By showing exactly how Alzheimer’s disease affects small blood vessels, we’ve 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 the arteries in the brain

Cerebral small vessel disorders are increasingly recognized as important contributors to functional and cognitive decline in patients with Alzheimer’s disease. The surface of the brain is lined with small arteries called “pial arteries,” which control the flow of blood and oxygen to the brain. This microcirculation performs two key functions: maintaining blood flow in the face of immediate changes in blood pressure and localized increases in blood flow based on neural activity.

However, if these arteries narrow 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 the disease of the small cerebral arteries. It results from amyloid deposits in the walls of small and medium-sized cerebral vessels. This disorder, common in older people, is strongly associated with Alzheimer’s disease. This is one of the causes of memory loss that occurs in people with this condition.

dr Greenstein and his colleagues therefore tested the hypothesis that overexpression of the beta-amyloid protein in Alzheimer’s disease would have a direct impact on cerebral artery function. They found that a smaller version of the protein called amyloid beta 1-40 (Aβ 1-40) specifically accumulates 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 expression of the amyloid precursor protein seven times higher than normal – resulting in a cerebrovascular phenotype similar to that of patients with Alzheimer’s disease and cerebral amyloid angiopathy. The researchers examined the pial arteries of rodents.

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

BK channel activity is mediated by the release of calcium ions (known as “calcium sparks”). When functioning normally, the potassium channel sends out a signal that causes the arteries to dilate. However, when the researchers exposed cerebral arteries of healthy young mice to Aβ(1-40) peptides, the latter disrupted the vasculoregulatory mechanism of the BK channel and partially recapitulated the resistance arterial dysfunction phenotype observed in mouse models of Alzheimer’s. In other words, Aβ 1-40 caused a decrease in the frequency of the calcium spark, which blocked the channel’s signals and caused narrowing of the arteries.

The team now plans to identify the part of Aβ 1-40 responsible for this blockade so that drugs that prevent this phenomenon can be developed and tested in order to prevent the progression of Alzheimer’s disease. ” This research is an important step in our understanding of Alzheimer’s disease. Over half a million people in the UK are living with the disease and this number is expected to increase as the population ages. These findings could lead to a much-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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