Worldwide, about 55 million people are thought to be living with dementia, which refers to impairments in memory and thinking that impact a person's ability to live a normal life. Dementia gets progressively worse over time, and is a major cause of disability and death. Alzheimer's disease is the most common form of dementia, and causes around 65 percent of dementia cases, according to the World Health Organization. A major feature of Alzheimer's disease is the death of neurons in the brain, but the reason or reasons for this loss has been unclear and researchers have been searching for the cause for many years.
Models for Alzheimer's disease that effectively capture the features of the disease have been challenging to develop. One hallmark of the disorder is amyloid plaques, tangles of misfolded proteins that build up in the brain. Scientists have now used a model in which human neurons were put into mouse brains that carried amyloid plaques. The researchers found that the human neurons, but not mouse neurons, died. When they were exposed to amyloid plaques, human neurons, but not mouse neurons, displayed tau tangles, another feature of Alzheimer's disease. In this model, only human neurons triggered a cell death program known as necroptosis, and died off.
The investigators also found a way to prevent this neuronal death. The findings have been reported in Science. The study has also suggested that Alzheimer's disease cannot be recapitulated in typical rodent models.
In the human neurons, there were abnormally high levels of an RNA molecule from a gene called MEG3. This has also been observed in Alzheimer's patients. The researchers showed that in neurons in culture, MEG3 alone could activate the necroptosis pathway.
"Our study sheds light on the previously murky waters of Alzheimer's disease, revealing a potential key player in neuronal loss - an RNA gene called MEG3, and the process of necroptosis. These findings are an important step forward in furthering our understanding of the basic mechanisms underlying this complex and often misunderstood disease," said study co-leader Professor Bart De Strooper, group leader at the UK Dementia Research Institute (UK DRI) at UCL and VIB-KU Leuven Center for Brain and Disease Research.
When MEG3 levels were reduced, necroptosis was prevented and neurons stopped dying off. While more research will be needed to understand this process, it may one day offer a new way to treat dementia.
"Necroptosis is already an active area of drug development in cancer and ALS. While there's much more to explore, our findings open up promising avenues for potential therapies targeting AD, alongside traditional approaches aimed at amyloid and tau," said Strooper.
Sources: Medical Research Council, Science
