Link between proteins points to possibilities for future Alzheimer’s treatments
Researchers from Rick Livesey group have found that the proteins that control the progression of Alzheimer’s are linked in a pathway, and that drugs targeting this pathway may be a way of treating the disease, which affects 40 million people worldwide. The findings were published in the journal Cell Reports.
The scientists found that as a protein called amyloid precursor protein (APP) is broken down into toxic protein fragments called amyloid-beta, it affects changes in the way that another key protein, tau, behaves. Though links between these proteins have been described in earlier work, this research has identified a new association between them, and found that manipulating the rate at which APP is broken down is directly connected to levels of tau.
While it is not known exactly what causes Alzheimer’s, it is known that amyloid-beta and tau build up in the brain, forming ‘plaques’ and ‘tangles’ which disrupt the connections between neurons, eventually killing them. There are no treatments to stop or reverse the progression of the disease, although researchers are starting to understand the mechanisms which cause it to progress.
Most people who develop Alzheimer’s will first start showing symptoms in later life, typically in their sixties or seventies. However, between one and five percent of individuals with Alzheimer’s have a genetic version of the disease which is passed down through families, with onset typically occurring in their thirties or forties.
The researchers used skin cells from individuals with the genetic form of Alzheimer’s and reprogrammed them to become induced pluripotent stem cells, which can become almost any type of cells in the body. The stem cells were then directed to become neurons with all the characteristics of Alzheimer’s.
Working with these clusters of human neurons – in essence, ‘mini brains’ – the researchers used three classes of drugs to manipulate the rate at which APP is ‘chewed up’ by inhibiting the secretase enzymes which are responsible for breaking it into amyloid-beta fragments. By using drugs to increase or decrease the rate at which APP is broken down, they observed that levels of tau can be altered as well.
Moore S, Evans LDB, Andersson T, Portelius E, Smith J, Dias TB, Saurat N, McGlade A, Kirwan P, Blennow K, Hardy J, Zetterberg H, Livesey FJ. APP Metabolism Regulates Tau Proteostasis in Human Cerebral Cortex Neurons. Cell Reports. DOI: http://dx.doi.org/10.1016/j.celrep.2015.03.068