Researchers Find That Tangles are Responsible for Alzheimer’s Disease Onset in Neocortical Networks

Researchers from Bar-Ilan University and the University of Edinburgh were able to characterize for the first time changes in early-stage Alzheimer’s disease that occur inside individual brains. Results from the study published in the journal Neuron suggest that Alzheimer’s-affected cells result in a reduction of electrical activity throughout the cerebral cortex — the brain’s center of higher mental function and cognition.

The research team is led by Edward Stern, Dana Cohen and Tara Spires-Jones. As Dr. Edward Stern, the lead author of the study, recently explained in a news release, the study’s results are due to a research focus on a brain cell pathology known as “tangles.”

“Alzheimer’s disease is associated with three pathologies: cell death, extra-cellular build-up of amyloid plaques, and tangles — the abnormal twisting of the cellular filaments which hold the neuron in its proper shape,” Stern said, adding that tangles are caused by an aberrant form of a protein known as tau.

“While it was already known that pathological tau is associated with dementia, ours is the first study to reveal the tau-linked changes in cell- and network-based activity that underlies neurodegeneration. Significantly, we found that if even a small number of cells have tangles, this amplifies into a devastating effect across the entire network, characterized by long latencies between spikes of inter-neuron communication, as well as a reduction in the overall level of synaptic activity.”

For the study, the team used a technique that allowed the placement of electrodes inside individual cells in the intact anesthetized brains of transgenic mice. The mice were altered genetically in order to produce tangle-triggering abnormal tau protein. Then they measured the sub-threshold fluctuation of electrical activity and the neuronal activity patterns change in response to stimulation.

Results revealed that pathological tau disrupts single cells’ activity and the neocortex intra-cellular communication. The authors mentioned that these findings suggest that the symptoms of Alzheimer’s — long known as caused by the overacumulation of amyloid-beta — are also caused by over accumulation of tau.

Results showed that by decreasing the rate at which individual neurons fire, tangles are able to suppress the synaptic function in the broader neocortical network, causing a reduction in cognitive function. According to Dr. Stern, the two pathologies have an effect in the change of the brain patterns of neuronal activity leasing to the symptoms of Alzheimer’s disease.

This research is the first to uncover that a malfunction in the neuronal physiology is associated with alterations in the behavior of the brain on the network level. The new information may lead to an effective method for identifying the onset of Alzheimer’s disease.

“Now that we have characterized patterns of neocortical electrical activity in the presence of tangle-afflicted cells and amyloid-beta affected brains, it may be possible to screen for these patterns with EEG,” he said in a news release, referring to electroencephalogram, a non-invasive technique commonly used to identify epilepsy and other brain disorders. “This could someday form the basis of early AD diagnosis.”

The author also said that these results are relevant for the longer-term aim of effective treatment for Alzheimer’s disease. “The key is to compare pathological to normal neurons, and identify ways in which abnormal neural activity might be reversed,” he said in the news release. “Since a change in brain cell activity is what causes disease symptoms, a clearer understanding of abnormal neural physiology may bring us closer to what we all want, and what the world needs — a treatment for Alzheimer’s disease.”