The effect of localized cGMP signaling on learning and memory in the Alzheimer’s disease mouse model
University of Toronto; University of Toyama
Alzheimer’s disease is a devastating progressive mental deterioration characterized by memory loss, dementia, and ultimately neurodegeneration. The disease hallmarks include complex intracellular neurofibrillary tangles and abundant extraneuronal deposits of amyloid-13 (Ai3), contributing to senile plaques. Neurodegenerative disorders like Alzheimer’s disease affect neural activities at various processing levels, including molecular pathways, neuron communication at synapses, neuronal circuits, as well as entire networks. Synaptic strength between two neurons undergoes activity-dependent plasticity, which is characterized by molecular and structural changes at the synapse. The strengthening (long-term potentiation) and weakening (long-term depression) of synapses is achieved through complex signaling cascades, including cyclic AMP (cAMP) and cyclic GMP (cGMP), which transduce information and participate in synaptic plasticity. I have characterized a novel and unique tool for targeted non-invasive, light-dependent control of cGMP signaling in vivo. By temporally and spatially controlling cGMP signaling in an Alzheimer’s disease mouse model, I can essentially pinpoint the time window and the neurons where cGMP signaling is compromised during Alzheimer’s disease. The potential of this tool extends far beyond the goals outlined in my project which is focused solely on Alzheimer’s disease, to all other neurodegenerative diseases where deficient synaptic plasticity and altered cyclic nucleotide signaling occurs (eg. Parkinson’s disease, Huntington’s disease}. Furthermore, the application of specific inhibitors targeting various components of the cGMP signaling cascade can be used to finally decipher the pathways of cGMP signaling in Alzheimer’s disease.
Memory formation in the brain can be understood as a series of biochemical reactions involving small molecular messengers, such as cGMP. These signaling pathways are impaired in memory disorders such as Alzheimer’s disease (AD), and therefore represent an excellent target for drug development. Because of the brain’s innate self-regulation and the technical challenges of targeting specific neurons, it is difficult to experimentally manipulate second messenger pathways. The results available so far are conflicting and often discovered using physiologically irrelevant methods, such as global signaling up-regulation. Therefore, we have characterized a new tool, which can non-invasively photo-activate cGMP messenger production in specific neurons. I first used it to show that cGMP signaling can affect the structure and function of neurons that are involved in memory. Here, I adapted the same technique for light-dependent signaling in the brain of living mice in order to determine the role of cGMP in memory and its therapeutic potential in AD. I found that targeted increase in cGMP signaling was associated with significant improvement in reference memory and a significant increase in social interaction. Interestingly, cGMP was associated with increased levels of anxiety 1.5 hours after stimulation, outlining the importance of understanding both short-term and long-term outcomes of such signaling pathway alterations. Since sociability, memory and anxiety are all important landmarks of AD, it seems more relevant than ever to get a deeper understanding of this essential neuronal cascade and its function in health and disease.