A compound that stopped brain cells from dying in an animal model of Alzheimer’s disease could lead to new treatments for people with the condition who live with depression and deterioration in memory and thinking.
In a report recently published in the journal Biological Psychiatry, researchers describe how an experimental compound called P7C3-S243 prevented death of brain cells, or neurons, in a rat model of Alzheimer’s disease.
The research team — which was led by Andrew Pieper, a professor of psychiatry at the University of Iowa in Iowa City — found that the compound stopped the animals from developing behavioral symptoms of depression, and later on, the problems with memory and learning that often follow.
The study is significant because, while P7C3-S243 appeared to stop the rats from developing symptoms akin to Alzheimer’s, it did so without altering other hallmarks of the disease — such as the buildup of toxic proteins in their brains.
Alzheimer’s disease is the most common cause of dementia, a progressive brain-wasting disease that gradually erodes people’s ability to think, remember, make decisions, communicate, and take care of themselves.
As well as problems with memory and thinking, Alzheimer’s is also tied to a number of psychiatric illnesses, including depression. In fact, the researchers note that depression can often arise before the changes in memory and thinking appear, and that developing depression for the first time later in life is thought to be a significant risk factor for Alzheimer’s.
Around 65 percent of the 47 million people worldwide who have dementia are thought to have Alzheimer’s disease.
In the United States, where Alzheimer’s is the sixth leading cause of death, it is the only one of the top 10 killers for which there is currently no cure or way to prevent or even slow it down.
Need for new treatments
In recent years, deaths from many major causes have fallen, but in the case of Alzheimer’s disease, they have risen significantly. Between 2000 and 2014, for example, deaths from Alzheimer’s rose by 89 percent, while deaths from heart disease — the number one killer in the U.S. — fell by 14 percent.
At present, there are around 5.5 million U.S. people living with Alzheimer’s disease. By 2050, this figure could rise to 16 million, in line with increasing numbers of older people.
The brains of people with Alzheimer’s develop several characteristic hallmarks. Prominent among these are clumps, or “plaques,” of a protein called amyloid beta, and “neurofibrillary tangles” of another protein called tau. These features are accompanied by inflammation and the loss of connections between — and the eventual death of — neurons.
In their study paper, the team outlines the current treatments available for people with Alzheimer’s disease. For example, some include drugs that increase the signaling between brain cells, while others aim to help people manage their environment and adapt to new challenges.
So far, however, there are no treatments that “prevent the progressive neuronal cell death that drives deteriorating neuropsychiatric function in patients.” Drug research has tended to focus on preventing the early stages of inflammation and stopping the formation of plaques and tangles that tends to precede loss of neurons.
“Unfortunately,” the researchers note, “this approach has thus far failed to help patients,” and in the meantime, the Alzheimer’s crisis is escalating, as is “an ever-increasing need for disease-modifying treatments.”
Targeting brain cell death
The new study addresses an area of research that has not been explored before: the targeting of brain cell death, without necessarily addressing the other features of Alzheimer’s — such as the plaques, tangles, and inflammation — that precede this stage.
“We have known for a long time,” says Prof. Pieper, “that the brains of people with Alzheimer’s disease have amyloid plaques and neurofibrillary tangles of abnormal tau protein, but it isn’t completely understood what is cause or effect in the disease process.”
The new study builds on previous work using a compound based on P7C3 — which Prof. Pieper and his team discovered nearly 10 years ago.
A wealth of evidence on P7C3 compounds shows that they can protect new and mature brain cells from cell death in several animal models of neurodegenerative conditions, including: amyotrophic lateral sclerosis; Parkinson’s disease; traumatic brain injury; and stroke.
There is also evidence to suggest that P7C3 compounds can prevent depression-like symptoms in animals in whom stress causes the death of nerve cells in the hippocampus, which is a brain region that plays a key role in thinking, memory, and mood.
Neurons saved, protein buildup not affected
For their investigation, Prof. Pieper and his team used a rat model of Alzheimer’s disease wherein, as the animals age, they develop problems with memory and learning that are similar to the cognitive decline seen in humans with the condition.
However, as they worked with the mice, the researchers found for the first time that this particular genetically engineered breed develops symptoms of depression at the age of 15 months. This is before problems with memory typically begin to appear.
They tested the effects of P7C3-S243 in Alzheimer’s and normal, or “wild-type,” rats, dividing each type into two groups: one received a daily dose of P7C3-S243, while the other was treated with a placebo. Treatment started when the rats were 6 months old, and they were examined at 15 months old and then at 24 months.
At the age of 15 months old, all of the rats in all of the groups showed normal memory and learning ability. That being said, the Alzheimer’s disease rats that received the placebo showed noticeable depression-like behavior, whereas the Alzheimer’s disease rats that received P7C3-S243 did not. The authors note that in fact, the treated mice behaved more like the normal mice.
By the time they reached old age at 24 months old, the Alzheimer’s disease rats that had not received P7C3-S243 were showing problems with memory and learning that were over and above those of the normal rats. However, the treated Alzheimer’s disease rats did not; their memory and learning abilities were on a par with those of normal rats.
When they examined the animals’ brains, the team found the same amount of inflammation, plaques, and tangles in the Alzheimer’s rats, regardless of whether they had been treated with P7C3-S243 or a placebo. There was, however, a significant difference in the number of neurons; many more had survived in the brains of the treated Alzheimer’s disease rats.
“Our study shows that keeping neurons alive in the brain helps animals maintain normal neurologic function, regardless of earlier pathological events in the disease, such as accumulation of amyloid plaque and tau tangles.”
Prof. Andrew Pieper