In Alzheimer’s disease, neurons in the cortex and other brain regions degenerate over time, and any therapy to delay neurodegeneration could have a huge impact.
Although various mutations can cause early onset AD, the key factor is aging, and nerve cell degeneration is thought to be due in part to loss of neuronal vitality with age. The main focus of research in Steward’s lab is on regenerating connections after spinal cord injury, and you’ve seen our progress in doing this by targeting a gene called PTEN. PTEN is a gene that down-regulates neuronal growth after development is complete, and our approach has been to use viral vectors to knock down or delete PTEN, which transforms fully mature neurons to a more youthful state in which they are capable of growing. This is, by definition, rejuvenation (to make young again, to restore to youthful vigor), and our research has shown that this rejuvenation accounts for the regeneration-enabling effect of PTEN deletion.
The focus is to test whether neurons that have been converted to a youthful state will resist neurodegeneration in a mouse model of Alzheimer’s disease. These mice were created by introducing human genes that carry 5 mutations that cause early onset of Alzheimers. Genetically modified mice are called “transgenic mice” and this particular strain is called 5XFAD because they carry the 5 mutations. 5XFAD mice exhibit the same pathology as people do who have Alzheimer’s disease, including age-related nerve cell degeneration and loss of cognitive abilities and memory impairment. The mice also develop Amyloid-beta (Aß) plaques early in life which are a signature feature of Alzheimer’s disease in people. The really interesting part is that the neurons that project to the spinal cord exhibit the most extensive degeneration!
The lab will test whether knockdown of PTEN using viral vector-based technologies will prevent or delay neurodegeneration in 5XFAD mice as well as the development of (Aß) plaques and loss of cognitive ability and memory impairment. We will selectively target neurons in the cortex using AAV-retro, which happen to be the same neurons that project to the spinal cord.