Alzheimer’s alters the internal clock of individual cells

Nights of fragmented sleep, daytime naps, sundowning syndrome: having a haywire biological clock is one of the first symptoms of Alzheimer’s, a strain for patients and their families that generates additional stress and promotes the progression of dementia. But this striking alteration of circadian rhythms corresponds to another, deeper and less visible one, which concerns individual brain cells. In fact, Alzheimer’s appears to alter the times and sequences of activation of the genes that regulate very important functions for the brain.

It is as if the disease throws off many tiny clocks that give time to the cells that keep the brain free of waste products, preventing them from functioning in synchronization. The discovery, of a somewhat technical nature and published on Nature Neurosciencehowever, it could have important implications in therapies. Restoring altered circadian rhythms in cells could be one way to slow the progression of Alzheimer’s.

The circadian clock, the internal biological clock that regulates the alternation of various biological processes, acts on 20% of the genes in human DNA, controlling when digestive, immune or sleep-wake rhythm mechanisms are turned on or off. Among these genes, there are several that have been associated with the risk of developing Alzheimer’s, because they control the brain’s “cleaning” systems of waste, levels of inflammation or other processes related to the disease.

For example, a protein called YKL-40, which regulates amyloid beta protein levels in the brain, is known to change concentrations during the circadian cycle. When there is too much of it, a common occurrence in those at risk of Alzheimer’s, it is more likely for accumulations of amyloid (a neurotoxic protein) to form in the brain. However, given the complexity of Alzheimer’s disease, it was logical that other proteins (and therefore other genes) would follow similar fluctuations.

A group of neuroscientists from the Washington University School of Medicine examined, every two hours and for 24 hours, gene expression (i.e. the process in which information contained in genes is transformed into molecules) in the brains of mice with accumulations of amyloid that mimicked the early stages of Alzheimer’s, and compared it with that which occurred in healthy mice. This work made it possible to understand which genes were active during each phase of the circadian cycle.

It was thus discovered that where accumulations of amyloid were present, the daily rhythms of hundreds of genes in microglial cells and astrocytes had also ended up “out of sync”.

Microglia are the set of cells that contribute to the brain’s immune response, sweeping away toxins and dead cells, while astrocytes have a role in supporting and facilitating communications between neurons.

Alzheimer’s seemed to have messed up the usually orderly sequence of instructions that allows these cells to clear waste from the brain. Not only that: the presence of amyloid plaques in mice was associated with new rhythms in hundreds of genes that generally do not have a circadian pattern of activity, in many cases involved in the brain’s inflammatory response to infections.

Although much remains to be clarified, the discoveries seem to indicate a path to finding new treatment possibilities. Restoring “normal” circadian rhythms in microglia and astrocytes could help rebuild a healthy brain environment free from toxic accumulations for neurons.