Neurons die earlier than researchers had previously thought of Alzheimer’s disease, and a new study from Tokyo Medical and Dental University in Japan shows that stopping the cycle may prevent the disease from ever emerging.
Alzheimer’s disease is the leading cause of dementia, and there are as many as 5 million people living with the disease in the US. This causes a range of symptoms that start with memory loss and confusion before progressing to coordination, thought, and speech difficulties.
There is no cure for Alzheimer’s at this time, and the exact cause of the disease remains unclear. Scientists have, however, found sticky clumps of a protein called beta-amyloid in the brains of people who died from the disease. Until now, this protein has been a major research target.
Drug trials aimed at beta-amyloid have so far been unsuccessful. Some scientists think this is because it is too late to start the treatments.
They believe that the process leading to Alzheimer’s disease begins many years before diagnosis, and that it may be too late to help them once people join clinical trials. Therefore the early stages of the disease represent a critical window for intervention.
The critical window
Scientists from Tokyo Medical and Dental University began looking at an earlier period of cognitive decline called mild cognitive impairment (MCI) to find out what’s happening in the brain before Alzheimer’s disease progresses.
MCI explains the small changes to brain function that may arise before Alzheimer’s disease— including forgetting the names of objects or losing things more often than normal.
Though not always the case, people with MCI are more likely to later develop Alzheimer’s disease. Because of this, researchers think it is a window into the very early stages of the disease.
From mouse to man
In the current research, which appears in Nature Communications, the scientists assessed neuronal death—a key mechanism underlying dementia symptoms—in Alzheimer’s disease mouse models, as well as in people with MCI and those with Alzheimer’s.
They measured how many neurons died using a protein called HMGB1, which releases dying neurons. Researchers tested this protein levels in the fluid around the spinal cord in 26 people with MCI and 73 people with Alzheimer’s disease.
The researchers also performed an innovative new study, using a new biomarker named pSer46-MARCKS to recognize dying neurons in the brains of Alzheimer’s disease model mice and people with MCI at various stages of the disease.
“Neuronal death is obviously very important in Alzheimer’s development, but it is notoriously hard to detect in real time because dying cells cannot be marked using chemical or immunohistological methods,” notes the study’s lead author, Hikari Tanaka.
The researchers were surprised to find the neurons died much earlier than expected. The patients with MCI actually experienced more neuronal death than those with Alzheimer’s disease.
Trapped YAP
The scientists may also have discovered what causes neurons to die too early in the disease process, indicating that responsibility lies with a protein called YAP.
Previous genetic studies found a connection between YAP and Alzheimer’s disease. YAP, which regulates neuronal death, was present in humans with MCI at lower levels.
Ironically, the researchers found the missing YAP trapped within beta-amyloid clumps — the deposits that have the most well-known Alzheimer’s disease connection. This discovery could change the way researchers think about Alzheimer’s disease.
The popular view among scientists is that the beta-amyloid protein is the first cause for Alzheimer’s disease, which contributes to neuron death. This is what they call the amyloid theory.
These new findings, however, indicate that the loss of the YAP protein— which happens before amyloid builds up in the brain — may potentially be the major cause of neuronal death.
“This finding could alter the amyloid hypothesis,” says Hitoshi Okazawa, the senior author.
A new treatment option?
What does that mean to patients, though? The researchers excitingly believe their findings could lead to a new treatment for Alzheimer’s disease. “We predict the development of novel Alzheimer’s disease therapies by showing that neuronal[ death] is YAP-dependent and starts before the onset of most symptoms,” Okazawa states.
The team had given the mice gene therapy to replace the missing YAP protein to test a potential treatment. The treatment stopped the neurons of the animals from dying, improved cognitive function and even hindered the formation of beta-amyloid plaques.
“[…] it was hugely exciting to witness the almost revolutionary effects of YAP supplementation,” continues Okazawa. Although this is a very exciting finding, these studies have not yet been conducted in people by the researchers, and they will have to address important safety problems before they can.
The researchers also suggest their method of measuring dying neurons could make diagnosis of people with MCI or Alzheimer’s disease simpler for doctors. There are currently no specific biomarkers available to assist in the diagnosis of MCI.
