One step closer to understanding the underlying causes of Alzheimer’s disease

Lazy protein police in Alzheimer's disease

Healthy cells and Alzheimer's cells
In Alzheimer’s, branches of the protein police are understaffed (green)and overstaffed (red).

Researchers of Utrecht University found that in Alzheimer’s disease, the protein quality control system, responsible for ensuring correct protein folding and clearance of tangles, is altered. Alzheimer’s is caused by the misfolding of a protein, called Tau, leading to the buildup of tangles which are harmful to the brain cells. Understanding why these tangles are formed and are toxic to the cell, is key to finding a way to intervene in the disease. The study by Margreet Koopman and Stefan Rüdiger, may bring us closer to understanding the underlying causes of Alzheimer’s disease and is published on BioRxiv.

Protein quality control acts as a police force

Tau keeps the neurons’ microtubules, similar to railway tracks, tightly together. In Alzheimer’s, Tau is trapped in tangles. Initially, this is not a problem, yet somehow over the years the aggregation can be detrimental to neurons. Normally, the protein quality control, the cell’s protein police, can successfully prevent aggregation. If a protein ‘misbehaves’, namely misfolds or aggregates, the protein police recognizes and arrests it. The protein is then given a chance to ‘behave’ – either refold or disaggregate – otherwise it is removed. Protein quality control is not perfect, but incidental misbehavior will eventually be cleaned up. This way, neurons can survive a long time, despite the continuous presence of Tau. However, Koopman and Rüdiger found changes in the protein police in Alzheimers’ brains, which may lead to a decreased capacity of neurons to deal with protein aggregates.

Slight changes in police force of Alzheimer brain

Koopman and Rüdiger performed a meta-analysis on a database to compare protein levels in Alzheimers’ and healthy brains. “Interestingly, the majority of players in the field [the protein police] remain unaffected”, the researchers state.  However, a certain branch of the protein police, called Hsp90, was decreased in all damaged brain regions of Alzheimers’ patients, while another branch that is upregulated by cellular stress, was increased. Therefore, Koopman and Rüdiger think that these changes in the protein police observed in Alzheimers’ brains make it harder for cells to get rid of the Tau tangles.

Future perspectives    

Koopman and Rüdiger pinpoint possible key players in Alzheimer's disease. The next step is to test in living cells how these changes in protein policing affect Tau aggregation. Understanding these Alzheimer’s specific changes in the protein policing network may allow for intervention in the future.

Publication

Alzheimer cells on their way to derailment show selective changes in protein quality control network. Margreet Koopman* en Stefan Rüdiger*. BioRxiv, 19 mei 2020.

*Authors affiliated with Utrecht University