Based on the recent statistics, one in eight individuals over the age of 65 has Alzheimer’s disease, and for every 68 seconds that pass, yet another individual in the United States develops the disease.
The pathophysiology of Alzheimer’s disease has long been established as the presence of amyloid plaques, aggregates of the amyloid-β peptide. The progression of the disease is characterized by neuronal impairment and cell loss. Now, what remains missing from this puzzle is a connecting piece that links the pathology with neuronal dysfunction.
A recent paper published in Nature Neuroscience worked to find this missing puzzle piece by investigating the role of the amyloid-β oligomers in neuronal impairment. Strittmatter and his research team showed that amyloid-β oligomers selectively bind to a naturally occurring cellular prion protein. This binding, in turn, triggers a kinase-signaling pathway, which results in the loss of neuronal function.
An important factor for a fully functional synapse (site of neuronal communication) is the expression of NMDA receptors, glutamate receptors that regulate learning and memory. Alterations in NMDA receptor function are known to contribute to Alzheimer’s disease pathogenesis. Using tools of molecular manipulation, the research team showed that activation of the kinase-signaling pathway causes a transient increase in the expression of NMDA receptors, followed by a rapid loss of surface NMDA receptors. Thus, synaptic function is greatly compromised upon amyloid-β oligomers binding to cellular prion proteins.
To adapt to increased synaptic activity, healthy neurons increase their number of dendritic spines to enhance their communication with neighboring neurons in a process called synaptic plasticity. One of the major neuropathological findings in Alzheimer’s disease, however, is a loss of these synaptic contacts. The research team showed that activation of the kinase-signaling cascade resulted in a loss in these dendritic spines, suggesting reduced synaptic activity.
A common measure of cell toxicity is the amount of lactate dehydrogenase that is released from neurons. After the kinase-signaling pathway was activated, the research team showed that the neurons released large amounts of lactate dehydrogenase, indicating excitotoxicity, a phenomenon that precedes neuronal impairment and cell death.
Taken together, this study helped elucidate the amyloid-β oligomer signal transduction pathway that requires cellular prion protein and kinase activity to alter synaptic function, with detrimental consequences in Alzheimer’s disease. This knowledge puts yet another piece into the Alzheimer’s puzzle, but we will need many more pieces before we will fully understand the disease.Um J.W., Nygaard H.B., Heiss J.K., Kostylev M.A., Stagi M., Vortmeyer A., Wisniewski T., Gunther E.C. & Strittmatter S.M. (2012). Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons, Nature Neuroscience, 15 (9) 1227-1235. DOI: 10.1038/nn.3178 Image adapted by Lawrence Manning/Corbis.