Klann LAB Projects

Aging and Alzheimer’s Disease

Cellular and molecular basis of synaptic failure and memory impairments in aging and AD

Although many years ago we found that reactive oxygen species (ROS) are required for full expression of hippocampal LTP and memory, it is clear that the aged and diseased brain handle ROS much differently as many studies have pointed to a role for excessive ROS and oxidative stress in age-related cognitive decline and impaired memory associated with Alzheimer's disease (AD). We have studied the role of ROS in aging-related impairments in LTP and memory that are associated with normal aging, and have conducted studies to that ROS derived from mitochondria are responsible for oxidative stress-induced impairments in synaptic plasticity and memory in mice that model AD. In addition, we have identified signaling pathways that are activated as part of the integrated stress response in response to soluble amyloid-beta and in AD model mice. Notably, we have found that prolonged activation of these pathways results in altered translational control, which contributes to synaptic dysfunction and memory deficits in AD model mice.

Selected important publications since 2009:

Massaad, C.A., Washington, T.M., Pautler, R.G., and Klann, E. (2009) Overexpression of SOD-2 reduces hippocampal superoxide and prevents memory deficits in a mouse model of Alzheimer’s disease. Proc. Natl. Acad. Sci. USA 106: 13576-13581. PMCID: PMC2726352

Ma, T., Hoeffer, C.A., Wong, H., Massaad, C.A., Zhou, P., Iadecola, C., Murphy, M.P., Pautler, R.G., and Klann, E. (2011) Amyloid β-induced impairments in hippocampal synaptic plasticity are rescued by decreasing mitochondrial superoxide. J. Neurosci. 31: 5589-5595. PMCID: PMC3095121

Ma, T., Trinh, M.A., Wexler, A.J., Bourbon, C., Gatti, E., Pierre, P., Cavener, D.R., and Klann, E. (2013) Suppression of eIF2α kinases alleviates Alzheimer’s disease-related plasticity and memory deficits. Nat. Neurosci. 16: 1299-1305. PMCID: PMC3756900

Ma, T., Chen, Y., Vingtdeux, V., Zhao, H., Viollet, B., Marambaud, P., and Klann, E. (2014) Inhibition of AMP- activated protein kinase signaling alleviates impairments in hippocampal synaptic plasticity induced by amyloid β.
J. Neurosci. 34: 12230-12238. PMCID: PMC4152616