How Alzheimer's Disease Spreads Through the Brain

• Accumulation of tau protein is typically associated with progression of Alzheimer's disease, as it leads to neuron death.
• This research shows that the spreading of tau is not immediately harmful, but it does disrupt cellular processes over time.
• This potentially means that intervening during the first stages of tau accumulation could stop the development of neurodegenerative diseases, like Alzheimer's disease.

This article was published on NeuroscienceNews.com.

Tau can quickly spread between neurons but is not immediately harmful, according to research in mouse neurons published in Journal of Neuroscience. Intervening during the initial accumulation of tau could potentially halt the progression of Alzheimer’s disease.

A hallmark of Alzheimer’s disease is the accumulation of tau protein in neurons, which leads to their death. A diseased version of tau folds itself incorrectly, which leads to the buildup. Researchers did not know the timescale of this process and how misfolded tau can spread to other cells.

Hallinan et al. introduced diseased tau into mouse neurons growing in a cell culture. Within days, the activated tau had spread to other neurons and began misfolding and accumulating. Despite the tau buildup, both the donating and accepting neurons remained healthy and capable of sending electrical messages. These results show that tau buildup itself is not harmful, but rather it is the cellular processes it disrupts that kill neurons.

ABSTRACT

Neurofibrillary tangles, formed of misfolded, hyperphosphorylated tau protein, are a pathological hallmark of several neurodegenerations, including Alzheimer’s disease. Tau pathology spreads between neurons and propagates misfolding in a prion-like manner throughout connected neuronal circuits. Tauopathy is accompanied by significant neuronal death, but the relationships between initial tau misfolding, propagation across connected neurons and cytotoxicity remain unclear. In particular the immediate functional consequence of tau misfolding for the individual neuron is not well understood. Here, using microfluidic devices to recreate discretely organised neuronal connections, we show that the spread and propagation of misfolded tau between individual murine neurons is rapid and efficient; it occurs within days. The neurons containing and propagating tau pathology display selective axonal transport deficits but remain viable and electrically competent. Therefore, we demonstrate that seed-competent misfolded tau species do not acutely cause cell death, but instead initiate discrete cellular dysfunctions.

SIGNIFICANCE STATEMENT

Public awareness of progressive neurodegenerations such as dementias associated with ageing or repetitive head trauma is rising. Protein misfolding underlies many neurodegenerative diseases including tauopathies, where the misfolded tau protein propagates pathology through connected brain circuits in a prion-like manner. Clinically, these diseases progress over the course of years. Here we show that the underlying protein misfolding propagates rapidly between individual neurons. Presence of misfolded tau is not directly cytotoxic to the neuron; the cells remain viable with limited deficits. This suggests that neurons with tau pathology could be rescued with a therapeutic disease modifier and highlights an under-appreciated time window for such therapeutic intervention.

This study was published in Journal of Neuroscience in October 2019.