Alzheimer's disease is a neurodegenerative disease and patients often have symptoms like memory loss, language problems, and slow thinking. Its pathological features are extracellular senile plaque deposits of β-amyloid (Aβ) in the brain and fibroid tangles in neurons and neuronal synaptic dysfunction, as well as the loss of a large number of neurons. According to statistics, by 2050, the number of Alzheimer's patients worldwide will reach 152 million. However, despite decades of research, no drug has so far has been discovered to effectively prevent or reverse the disease.

Researchers are striving to figure out the real cause of Alzheimer's disease. A study by Massachusetts General Hospital (MGH) found that Alzheimer's disease-related protein tau is transmitted by the brain and is caused by the aging of the brain itself, instead of by the length of time that the neuron expresses the protein. Their research published in Science Advances laid the groundwork for identifying these factors, which in turn may lead to new treatment strategies.

The facts that sporadic Alzheimer's disease and other neurodegenerative diseases are age-related are quite obvious, but the reasons behind are not clear, according to Bradley Hyman, MD, director of the research center of neurodegenerative disease and Alzheimer's disease, Massachusetts General Hospital. Existing animal models, such as mice with mutations at birth, tend to accumulate tangles containing tau as they age, so it is impossible to tell whether it is the age of the animal or the lifetime accumulation of tau in the brain that leads to pathological effects.

To overcome this limitation, Hyman's team developed a viral gene vector that can induce the pathological or normal form of human tau protein expression. The vector also uses fluorescent markers for neurons that directly express tau, distinguishing them from neurons that diffuse tau in adjacent cells, which may reflect how the pathology and spreading of Alzheimer's tau protein is in the brain.

The researchers first confirmed that introduction of the vector into the entorhinal cortex (EC) – the brain structure of the mouse that first appeared in the tau pathology associated with Alzheimer's disease - could induce the expression and spread of human tau, and the researchers subsequently used the vector to induce EC to express the misfolded pathological or non-mutated form of tau. And it was found that although the diffusion of tau between adjacent cells does not require the presence of misfolded proteins, this diffusion is faster and the range is more when misfolded tau protein is present.

Comparing the effects of induced pathological morphology of tau on the brains of young and old mice, the researchers found that the pathological proteins in older mice spread from EC to adjacent regions at about twice the rate of young mice, while older mice also accumulated more error folding tau. However, when the vector is introduced into striatal neurons, the effect of inducing tau protein expression is different, and striatal neurons are rarely affected in Alzheimer's disease.

Summary

Although age is the highest non-genetic risk factor for Alzheimer's disease, so far, it has not been tested whether age itself will make the brain susceptible to pathological changes and tau protein diffusion. Now the problem presents to researchers is to study what makes the aging brain a better platform for tau protein transmission and what determines the vulnerability of certain areas of the brain. All in all, the top priority is to learn more about how the physiological mechanisms of brain aging contribute to the development of Alzheimer's disease. This, we believe, will help to better prevent and treat many neurodegenerative diseases.

Peptides in Alzheimer's Research

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Reference:
S. Wegmann el al. Experimental evidence for the age dependence of tau protein spread in the brain. Science Advances (2019). DOI: 10.1126/sciadv.aaw6404

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