A South Korean research team has identified a key factor that accelerates the vicious cycle of Alzheimer's disease, raising the prospect of a treatment that eases multiple pathologies at once by targeting a single molecule.
A team led by Won-Suk Chung, associate director of the Center for Vascular Research at the Institute for Basic Science (IBS), has identified a core regulatory factor that disrupts the balance between neural circuits and synapses in Alzheimer's disease and successively worsens its progression, the Ministry of Science and ICT said on the 27th. The study, supported by the ministry through the IBS basic science research centers program, was published the same day in Nature, one of the world's most prestigious academic journals.
Alzheimer's is a degenerative brain disease marked by declining memory and cognitive function, and its main feature is the abnormal buildup of amyloid beta in the brain. Because other abnormal changes also occur together — excessive excitation of neural circuits, synapse loss and inflammatory responses in glial cells — drugs that only clear amyloid have shown limited effect. The underlying cause of the disease has also remained unclear, as the various pathologies influence one another and create a vicious cycle.
The researchers therefore focused on the imbalance between neural circuits and synapses that appears from the early stages of the disease. Analyzing the hippocampus of Alzheimer's model mice, they found that the imbalance in synapse loss ultimately stems from an abnormally active state in neurons. On that basis, they discovered that the ERBB4 receptor, normally present in inhibitory neurons in a healthy brain, was markedly increased in a specific group of excitatory neurons. ERBB4 is a receptor protein that detects external signals at the cell membrane and regulates cell growth and differentiation as well as neuronal function.
Identifying ERBB4 as the key factor behind the circuit abnormality, the team used gene-editing technology to selectively remove ERBB4 only from excitatory neurons in Alzheimer's model mice. Excessive activity in the excitatory neurons declined, and activity in some inhibitory neurons that had been suppressed was restored. Abnormal synapse elimination and inflammatory responses in glial cells also eased, while the area and number of amyloid plaques fell by more than 50%. Memory and spatial cognition improved significantly as a result.
The team further demonstrated the mechanism at work: when ERBB4 increases, signaling pathways that regulate cell growth and metabolism become excessively activated, spreading the pathology to surrounding areas. An analysis of brain tissue from 446 people also showed significantly higher ERBB4 expression in the excitatory neurons of Alzheimer's patients. The higher the expression, the greater the accumulation of amyloid plaques and the more severe the decline in cognitive function.
"These findings offer a new clue for understanding the amplification process of Alzheimer's disease from multiple angles," Chung said. "We expect this to contribute to opening up new treatment strategies that target the key link in the disease's vicious cycle and ease its complex and varied pathologies at the same time."
