Tau phosphorylation and tau mislocalization mediate soluble Aβ oligomer-induced AMPA glutamate receptor signaling deficits.
In our previous studies, phosphorylation-dependent tau mislocalization to dendritic spines resulted in early cognitive and synaptic deficits. It is well known that amyloid beta (Aβ) oligomers cause synaptic dysfunction by inducing calcineurin-dependent AMPA receptor (AMPAR) internalization. However, it is unknown whether Aβ-induced synaptic deficits depend upon tau phosphorylation. It is also unknown whether changes in tau can cause calcineurin-dependent loss of AMPARs in synapses. Here, we show that tau mislocalizes to dendritic spines in cultured hippocampal neurons from APPSwe Alzheimer's disease (AD)-transgenic mice and in cultured rat hippocampal neurons treated with soluble Aβ oligomers. Interestingly, Aβ treatment also impairs synaptic function by decreasing the amplitude of miniature excitatory postsynaptic currents (mEPSCs). The above tau mislocalization and Aβ-induced synaptic impairment are both diminished by the expression of AP tau, indicating that these events require tau phosphorylation. The phosphatase activity of calcineurin is important for AMPAR internalization via dephosphorylation of GluA1 residue S845. The effects of Aβ oligomers on mEPSCs are blocked by the calcineurin inhibitor FK506. Aβ-induced loss of AMPARs is diminished in neurons from knock-in mice expressing S845A mutant GluA1 AMPA glutamate receptor subunits. This finding suggests that changes in phosphorylation state at S845 are involved in this pathogenic cascade. Furthermore, FK506 rescues deficits in surface AMPAR clustering on dendritic spines in neurons cultured from transgenic mice expressing P301L tau proteins. Together, our results support the role of tau and calcineurin as two intermediate signaling molecules between Aβ initiation and eventual synaptic dysfunction early in AD pathogenesis.
Department of Neuroscience, University of Minnesota, 2101 6th St. SE, Minneapolis, MN, 55455, USA; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN, USA; N. Bud Grossman Center for Memory Research and Care, University of Minnesota, Minneapolis, MN, USA.
Eric C
EC
Miller
Peter J
PJ
Teravskis
Benjamin W
BW
Dummer
Xiaohui
X
Zhao
Richard L
RL
Huganir
Dezhi
D
Liao
D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials; D051379:Mice; D055369:Miniature Postsynaptic Potentials; D009154:Mutation; D010446:Peptide Fragments / Q000633:toxicity*; D010766:Phosphorylation; D021381:Protein Transport; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016559:Tacrolimus / Q000494:pharmacology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D019703:Calcineurin; D065095:Calcineurin Inhibitors; D010446:Peptide Fragments; D018091:Receptors, AMPA; D016559:Tacrolimus; D016875:tau Proteins; C558298:Mapt protein, mouse; C075222:amyloid beta-protein (1-42)
Abeta oligomers; Alzheimer's disease; dendritic spines; mEPSC; synaptic deficits; tau phosphorylation