New information on the pathological mechanisms of Alzheimer's disease

Researchers at the University of Helsinki have discovered a mechanism by which harmful tau protein aggregates are transmitted between neurons. In addition to amyloid plaques, tau aggregates in the brain play an important role in the progression of Alzheimer's disease.

Alzheimer's disease is associated with two neuropathologies: amyloid plaques and aggregates of tau, or accumulated tau protein in neurofibrillary tangles of neurons. The amyloid plaques of the brain are the most well-known pathology, but the importance of tau protein for the progression of the disease is just as much.

"It seems that in Alzheimer's disease, accumulation of amyloid in the brain starts first, but the symptoms usually appear after the pathology of amyloid induces the pathology of the tau, when neuronal cell death and loss of synapses begin to accelerate, "says Henri Huttunen. docent at the University of Helsinki Neuroscience Center (HiLIFE unit).

"It seems that the accumulation of tau is the really harmful element of the disease."

Tau also occurs in healthy neurons, but the accumulation of poorly folded pathological tau plays a key role in Alzheimer's disease.

Previously, it was thought that tau aggregates were only accessible outside cells after cell death, but in recent years it has been found that the pathology of tau protein can pass from diseased cells to healthy cells. Before that, however, the molecular mechanisms that help the tau to penetrate the cell membrane were not understood.

The recent study of the research group of Henri Huttunen and Riikka-Liisa Uronen, published in the Cell reports log, indicates that the accumulation of pathological tau triggers a safety valve mechanism in the cell membrane otherwise well regulated.

"As the regulatory mechanisms of tau protein pass, the protein is found in the cell membrane instead of the cell's cytoskeleton.The lipid-rich cholesterol rafts of the cell membrane appear to play a central role in this secretory mechanism. of tau ", says Huttunen.

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

Normally, the cell membrane keeps the internal and external parts of the cell strictly separated. The membrane is a fatty film whose permeability to proteins, neurotransmitters and other biomolecules is carefully regulated.

From the point of view of drug development, the discovery introduces a new mechanism for targeting pharmacological molecules. The accumulation of tau and amyloid in the cerebrospinal fluid and the brain is already used in the diagnosis of diseases.

Molecular data on interactions between tau protein and cell membranes can potentially be used to slow down Alzheimer's disease and other diseases belonging to a group called tauopathies.

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

"Currently, we are only able to treat the symptoms of these disorders, which makes the development of a treatment that slows the progression of the disease an important goal," says Huttunen.

The project led by Huttunen had already shown that cell membranes were sensitive to manipulation and that omega-3 fatty acids were particularly effective in preventing the tau from penetrating the membrane.

Neuronal cell membranes contain far more omega-3 fatty acids than other cell types, and epidemiological data suggest their importance to brain health, as evidenced by current dietary recommendations.

"When DHA, an omega-3 fatty acid, was added to cell cultures, the secretion of tau from cells collapsed.It appears that omega-3 fatty acids alter the microstructure of the cell membrane to become less permeable to tau aggregates, thereby capturing the protein in the cell, "says Huttunen.

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More information:
Maria Merezhko et al., The secretion of Tau via an unconventional non-vesicular mechanism, Cell reports (2018). DOI: 10.1016 / j.celrep.2018.10.078