title: Mechanisms of tau and Aβ-induced excitotoxicity.
abstract: Excitotoxicity was originally postulated to be a late stage side effect of Alzheimer׳s disease (AD)-related neurodegeneration, however more recent studies indicate that it may occur early in AD and contribute to the neurodegenerative process. Tau and amyloid beta (Aβ), the main components of neurofibrillary tangles (NFTs) and amyloid plaques, have been implicated in cooperatively and independently facilitating excitotoxicity. Our study investigated the roles of tau and Aβ in AD-related excitotoxicity. In vivo studies showed that tau knockout (tau(-/-)) mice were significantly protected from seizures and hippocampal superoxide production induced with the glutamate analog, kainic acid (KA). We hypothesized that tau accomplished this by facilitating KA-induced Ca(2+) influx into neurons, however lentiviral tau knockdown failed to ameliorate KA-induced Ca(2+) influx into primary rat cortical neurons. We further investigated if tau cooperated with Aβ to facilitate KA-induced Ca(2+) influx. While Aβ biphasically modulated the KA-induced Cacyt(2+) responses, tau knockdown continued to have no effect. Therefore, tau facilitates KA-induced seizures and superoxide production in a manner that does not involve facilitation of Ca(2+) influx through KA receptors (KAR). On the other hand, acute pretreatment with Aβ (10 min) enhanced KA-induced Ca(2+) influx, while chronic Aβ (24 h) significantly reduced it, regardless of tau knockdown. Given previously published connections between Aβ, group 1 metabotropic glutamate receptors (mGluRs), and KAR regulation, we hypothesized that Aβ modulates KAR via a G-protein coupled receptor pathway mediated by group 1 mGluRs. We found that Aβ did not activate group 1 mGluRs and inhibition of these receptors did not reverse Aβ modulation of KA-induced Ca(2+) influx. Therefore, Aβ biphasically regulates KAR via a mechanism that does not involve group 1mGluR activation.
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: Susanne_pritchard@urmc.rochester.edu.
authors.forename: Susanne P
authors.initials: SP
authors.lastname: Pallo
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY, USA. Electronic address: john.dimaio@rochester.edu.
authors.forename: John
authors.initials: J
authors.lastname: DiMaio
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: acook2015@gmail.com.
authors.forename: Alexis
authors.initials: A
authors.lastname: Cook
authors.affiliation: Department of Chemistry, University of Rochester, Rochester, NY, USA. Electronic address: nilsson@chem.rochester.edu.
authors.forename: Bradley
authors.initials: B
authors.lastname: Nilsson
authors.affiliation: Department of Anesthesiology, University of Rochester Medical Center, Rochester, NY, USA. Electronic address: gail_johnsonvoll@urmc.rochester.edu.
authors.forename: Gail V W
authors.initials: GVW
authors.lastname: Johnson
mesh_terms: D000544:Alzheimer Disease / Q000150:complications / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D007608:Kainic Acid / Q000008:administration & dosage; D051379:Mice; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D018092:Kainic Acid Receptors / Q000819:agonists / Q000378:metabolism; D018094:Receptors, Metabotropic Glutamate / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced / Q000209:etiology / Q000378:metabolism*; D013481:Superoxides / Q000378:metabolism; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D016229:Amyloid beta-Peptides; D002118:Calcium; D007608:Kainic Acid; D017382:Reactive Oxygen Species; D018092:Kainic Acid Receptors; D018094:Receptors, Metabotropic Glutamate; D013481:Superoxides; D016875:tau Proteins; C558298:Mapt protein, mouse; C104077:metabotropic glutamate receptor type 1
keywords: Alzheimer׳s disease; Amyloid beta; Excitotoxicity; Group 1 metabotropic glutamate receptors; Kainate receptors; Tau