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Tau Proteins Spread More Easily In The Aging Brain

P301Ltau misfolding

Certain molecules involved in Alzheimer’s disease called tau-proteins spread more easily in the aging brain, new research in mice from German investigators suggests. The study was carried out in collaboration with researchers in the US at Harvard Medical School and Massachusetts General Hospital.

Alzheimer’s disease usually begins with memory decline and later affects other cognitive abilities. Two different kinds of protein deposits in the patient’s brain are involved in the disease: amyloid beta plaques and tau neurofibrillary tangles.

The emergence of tau neurofibrillary tangles reflects disease progression: they first manifest in the brain’s memory centers and then appear in other areas in the course of the disease. Tau proteins or tau aggregates probably migrate along nerve fibers and thereby contribute to the spreading of the disease throughout the brain.

Twice As Fast

Using a gene vector – a tailored virus particle – the scientists channeled the blueprint of the human tau protein into the brains of mice. Individual cells then began to produce the protein.

Twelve weeks later, the researchers examined how far the tau protein had travelled from the production site.

“Human tau proteins spread about twice as fast in older mice as compared to younger animals,”

said researcher Susanne Wegmann of the German Center for Neurodegenerative Diseases (DZNE) in Berlin.

mutant P301Ltau in vivo
Enhanced neuron-to-neuron propagation of mutant P301Ltau in vivo.
Credit: Susanne Wegmann, et al. CC-BY

The experimental part of the study was carried out in the laboratory of Bradley Hyman at Harvard Medical School in Boston, USA, where Susanne Wegmann worked for several years. In 2018, she moved to the DZNE’s Berlin site, where her research group addresses various questions on tau-related disease mechanisms and the major part of data analysis and summarizing the results took place.

Pathological Tau

The experimental setting also allowed the scientists to analyze tau propagation in more detail. The protein exists in a healthy, soluble form in every neuron of the brain.

However, in Alzheimer’s disease, it can change its shape and convert into a pathological form prone to aggregate into fibrils.

“It has long been thought that it is primarily the pathological form of tau that passes from one cell to the next. However, our results show that the healthy version of the protein also propagates in the brain and that this process increases in old age. Cells could also be harmed by receiving and accumulating large amounts of healthy tau,”

said Wegmann.

The findings from the study raise a number of questions that Wegmann will now tackle with her research group at the DZNE: Which processes underlie the increased spreading of tau in the aging brain? Is too much tau protein produced or too little defective protein removed? Answering these questions may open up new therapeutic options in the long term.

Susanne Wegmann, Rachel E. Bennett, Louis Delorme, Ashley B. Robbins, Miwei Hu, Danny McKenzie, Molly J. Kirk, Julia Schiantarelli, Nahel Tunio, Ana C. Amaral, Zhanyun Fan, Samantha Nicholls, Eloise Hudry, Bradley T. Hyman
Experimental evidence for the age dependence of tau protein spread in the brain
Science Advances 26 Jun 2019: Vol. 5, no. 6, eaaw6404 DOI: 10.1126/sciadv.aaw6404

Top Image: Susanne Wegmann, et al. CC-BY