Scientists from Sanford-Burnham have pieced together a complex neuronal pathway that leads to brain cell abnormalities in individuals with both Down’s syndrome and Alzheimer’s disease. The findings are important because they could one day assist in the development of treatments to help slow the loss of brain cells in patients with conditions such as these. The work has been published in Cell Reports.
It’s been known for some time that Alzheimer’s disease and Down’s syndrome share a genetic connection. By the age of 65, 75% of individuals with Down’s syndrome present symptoms of Alzheimer’s, and at the age of 40 almost 100% have the same brain changes that are associated with this neurodegenerative disease. While this much was known, the links between the two conditions were hazy.
Lead researcher Huaxi Xu started to unravel this mystery a few years back when he and his colleagues began examining the function of a brain cell protein called sorting nexin 27 (SNX27). Mice that were missing the gene for this protein were found to present similar brain characteristics to individuals with Down’s syndrome, and humans with this condition presented depleted SNX27 levels. Further digging revealed that this protein is necessary for the maintenance of a crucial cell surface receptor that is necessary for neurons to communicate. Without SNX27, neuronal activity is reduced and thus learning and memory is compromised.
But the complex story doesn’t end there. In the new study, the researchers revealed that the extra chromosome present in individuals with Down’s syndrome, chromosome 21, results in increased levels of a small RNA molecule called miRNA-155. This molecule doesn’t contain the instructions for the production of a protein like many stretches of RNA, but instead decreases the production of SNX27.
Alongside regulating receptor expression, SNX27 was found to be critical for the generation of a protein called β-amyloid. It carries out this important function by preventing the activity of an enzyme called gamma-secretase. This particular enzyme chops up the precursor of β-amyloid to produce β-amyloid proteins. When SNX27 levels are reduced, there is more active gamma-secretase hanging around in cells, and hence β-amyloid levels are elevated because more precursor proteins can be chopped up.
When β-amyloid proteins build up inside cells, they start to stick together, or aggregate, in clumps, which is detrimental to the health of the cell. These damaging clumps, which are known as plaques, are found in the brains of both individuals with Down’s syndrome and Alzheimer’s disease and are thought to be responsible for the pathology of Alzheimer’s.
Another important discovery was that deleting the SNX27 gene promoted the production of β-amyloid and also brain cell death. Furthermore, increasing SNX27 levels in mouse models of Alzheimer’s reduced the levels of β-amyloid in the brains of these mice.
To take this further, the researchers are now searching for molecules that can reduce the levels of miRNA-155, which will hopefully restore normal levels of SNX27. If successful, this may eventually lead to new treatment avenues to help reduce brain cell loss in individuals with both Alzheimer’s and Down’s syndrome.
