Tuesday , January 26 2021

New information on the pathological mechanisms of Alzheimer's disease

Researchers have indicated that the accumulation of abnormal tau triggers the safety valve mechanism in otherwise well-regulated cell membranes …


Alzheimer's disease is associated with two neuropathologies: amyloid plaques and tau aggregates or tau proteins accumulated in neurofibrillary glomeruli in neurons. Brain amyloid plaques are a more well-known pathology, but the value of tau is equally important for the progression of the disease.

"It seems that in Alzheimer's disease, the accumulation of amyloids in the brain begins first, but symptoms usually occur after the pathology of amyloids induces tau pathology, after which the death of neurons and the loss of synapses begin to accelerate," says Henri Hattunen, an assistant professor at the Center for Neurobiology Helsinki University (a division of HiLIFE).

“It seems that tau accumulation is a really harmful element of the disease.”

Tau is also found in healthy neurons, but the accumulation of improperly folded, pathological Tau plays a key role in Alzheimer's disease.

It used to be that Tau aggregates only gain access outside the cells as soon as the cells die, but in recent years it has been discovered that Tau pathology can move from sick to healthy cells. However, prior to this, the molecular mechanisms that help tau penetrate the cell membrane have not been understood.

A recent study by the research team of Henri Hattunen and Rijk-Liis Uronn shows that the accumulation of abnormal tau causes the mechanism of the safety valve in an otherwise well-regulated cell membrane.

“As the regulatory mechanisms of the tau protein are given, the protein enters the cell membrane and not into the cytoskeleton of the cell. The cholesterol-rich lipid rafts of the cell membrane appear to play a central role in this mechanism of tau secretion, ”says Hattunen.

The study used cultured neurons and adapted reporter proteins to carefully observe the transfer of tau between cells.

Typically, the cell membrane keeps the inner and outer parts of the cell strictly apart. The membrane is a fatty film whose permeability to proteins, neurotransmitters and other biomolecules is carefully regulated.

In terms of drug development, detection introduces a new mechanism by which pharmacological molecules can be targeted. The accumulation of tau and amyloid in the cerebrospinal fluid and brain is already used in the diagnosis of diseases.

Molecular data on how Tau interacts with cell membranes can potentially be used to slow down Alzheimer's disease and other diseases belonging to the group known as tauopathy.

Unlike amyloid plaques, tau protein aggregates are also found in other neurodegenerative diseases, such as frontotemporal dementia.

“We can currently treat the symptoms of these disorders, which makes the development of a treatment that slows the progression of the disease is an important goal,” explains Hattunen.

The project, led by Hattunen, has already noticed that cell membranes are sensitive to manipulation and that omega-3 fatty acids are particularly effective in preventing tau penetration into the membrane.

Neuronal cell membranes contain much more omega-3 fatty acids than other cell types, and there is epidemiological evidence indicating their importance for brain health, as reflected in current dietary recommendations.

“When Omega-3 fatty acid was added to cell cultures, Tau secretion from cells was destroyed. It seems that omega-3 fatty acids modify the microstructure of the cell membrane to become less permeable to tau aggregates, capturing protein in the cell, ”says Hattunen.

The study was published in Cellular Reports magazine.

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