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The reason that alzheimer’s strikes the elderly has been uncovered as the ageing brain fuels a toxic protein linked to the disease, according to new research.
Years before symptoms appear the faulty chemical called tau forms into tangles – eventually leading to memory loss and confusion,
Now experiments in mice show the spread is caused by factors within ageing grey matter – not by how long the protein has been expressed by neurons.
Identifying these could lead to the development of drugs that target them, say the US team.
It offers hope of better therapies for a host of neurodegenerative illnesses – ranging from dementia to Parkinson’s disease and multiple sclerosis.
Senior author Professor Bradley Hyman, a neuroscientist at Massachusetts General Hospital, said: “The fact that sporadic Alzheimer’s disease and other neurodegenerative disorders are age-related is evident – but the reasons why are unknown.
“Existing animal models, such as mice born with a mutation predisposing them to accumulate tau-containing tangles as they age, cannot distinguish between whether the age of the animal or the lifetime exposure of the brain to increased tau is responsible for the pathologic effects.”
So his team developed a technique to inject a gene via a harmless virus that induces expression of either deformed or normal human tau.
The virus also applies a fluorescent label to neurons that directly express tau – differentiating them from those where it has spread from adjacent cells.
This is believed to reflect how Alzheimer’s triggered by the accumulation of tau spreads through the brain.
Introducing the virus into the entorhinal cortex (EC) – the brain structure where Alzheimer’s often first appears – induced expression and spread of human tau in the lab rodents.
The researchers then used it to start expression in the EC of either the misfolded pathologic or the unmutated form of tau.
They found the presence of the misfolded protein was not required for the spread of tau to adjacent cells.
But the spread was faster and more extensive when induced by misfolded tau.
They then compared the effects of inducing expression of the pathologic form of tau in the brains of young and aged mice
The rate of spread from the EC to adjacent regions was around twice as high in the older mice.
They also accumulated more misfolded tau than did younger animals.
However, the same effects were not seen when the virus was introduced into striatal neurons – which are rarely affected in Alzheimer’s.
Lead author Dr Susann Wegmann, who is now at the German Institute for Neurodegenerative Diseases, said: “Although age is the highest non-genetic risk factor for Alzheimer’s, until now it has not been tested whether age by itself can render the brain vulnerable to pathologic changes and spread of tau.
“Now we and others need to work on the question of what makes the ageing brain a better platform for tau spreading and what determines the vulnerabilities of certain brain regions.”
Prof Hyman said: “We hope learning more about how the physiology of the ageing brain contributes to the development of Alzheimer’s disease will lead to better preventive and therapeutic options for many neurodegenerative diseases.”
