Right now, in the brain cells of 12 million people around the world, there are messy, abnormal tangles of a protein called tau. Surrounding the neurons of these people (there are 1.6 million of them in Japan and 4 million in the United States) are plaques of a protein fragment called beta-amyloid.
In healthy brains, tau serves to both assemble and support the “scaffolding” systems that give neurons their structure and enable them to function. Somehow, the fragments of beta-amyloid cause tau filaments to change shape and tangle. The tangled fibers can’t support their neurons, which die. Memories fade and are lost, and, eventually, dementia sets it. And as lifespans around the world increase, so will the number of people with neurodegenerative disorders.
Scientists have been trying to find a link between the tangles and the plaques ever since Alois Alzheimer described them in 1906 in the brain of a patient with dementia. And this week, for the first time, the link has been made.
Such programmed cell death is called apoptosis, and it occurs when cells need to be eliminated for proper development, for example, the fingers and toes of a fetus have tissue connecting them and this needs to be removed for them to form properly. Cells also need to be eliminated when they are infected by a virus or a cancer.
Lester Binder and Vincent Cryns of the Feinberg School of Medicine at Northwestern University, Evanston, Ill., knew that in sufferers of Alzheimer’s disease, caspases were activated in dying neurons and that under some circumstances they “cut” the filaments of tau protein. The scientists reasoned that caspases might cut tau into the shorter, abnormal form that make up the tangles in the neurons of Alzheimer-affected patients.
Binder and Cryns demonstrated that exposing neurons to beta-amyloid activates caspases, which then chop up the tau filaments. They then showed that this truncated form of tau was much more prone to forming abnormal filaments that resemble tangles, suggesting that amyloid exposure might promote tangle formation through the action of caspases on tau. Their paper appears in this week’s edition of the Proceedings of the National Academy of Sciences.
To provide additional evidence of the relevance of this result to Alzheimer’s disease, Binder and Cryns also created an antibody that specifically recognizes the truncated form of tau produced by caspases. With this antibody, they demonstrated that tau is commonly cut at the same place in the tangles in Alzheimer’s disease, indicating that caspase chopping of tau may play a role in tangle formation in this disease.
“Tau may be the bullet fired by the amyloid gun,” said Binder. “Amyloid activates the caspases that truncate tau, causing it to form tangles and likely promoting the death of the neuron. Finding the full pathway in the chain of events that now includes amyloid, caspases, tau tangles and neuronal death will be the next challenge.”
By suggesting a new link between the two major brain abnormalities in Alzheimer’s disease, Binder and Cryns hope their work will “provide a common ground between the amyloid and tau proponents and point to the need to consider both of these interrelated pathological events in future studies and therapies.”
There is still a long way to go, though, to untangle the factors contributing to the development of Alzheimer’s. Binder and Cryns have shown that caspase proteins link amyloids and tau, but in a paper published in Nature this week, another group of researchers identify a different protein that protects against the disease.
Cell biologist Kun Ping Lu of Beth Israel Deaconess Medical Center T Harvard Medical School, Boston, Mass., led a team analyzing the brains and behavior of mice lacking a gene called Pin1.
As the mice aged, they began to develop problems with coordination and balance. Abnormal protein tangles were seen inside vulnerable brain cells, and over time neurons began to die off.
Humans with Alzheimer’s, Down’s syndrome and Pick’s disease show similar features.
“We’ve now shown that Pin1 plays a pivotal role in protecting against age-dependent neurodegeneration,” said Lu. “This makes a convincing case that this enzyme should be taken into consideration in future studies of Alzheimer’s disease.”
Test-tube studies found that Pin1 has the ability to restore tangled tau fibers to their original shape. This finding led Lu and his colleagues to hypothesize that Pin1 might also be able to prevent tangle formation and the resulting neurodegeneration.
In another twist, Lu’s laboratory has discovered that Pin1 is dramatically “overexpressed” in many human cancers. This overexpression — the production of too much of a gene’s protein — is critical for these malignancies to develop in the first place.
So it seems that certain cancers share common genetic elements with Alzheimer’s disease, suggesting that Pin1 may prove to be the missing link between these two seemingly distinct areas of disease, both of which grow much more common with age.
“Pin1 represents a new category of genes whose expression is required to guard against age-dependent neurodegeneration,” said Lu.
Eating oily fish, doing crossword puzzles and even knitting are all said to protect against Alzheimer’s. But this week’s research suggests that there might one day be a clinical treatment for the disease that erases memories.
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