title: Curcumin suppresses soluble tau dimers and corrects molecular chaperone, synaptic, and behavioral deficits in aged human tau transgenic mice.
abstract: The mechanisms underlying Tau-related synaptic and cognitive deficits and the interrelationships between Tau species, their clearance pathways, and synaptic impairments remain poorly understood. To gain insight into these mechanisms, we examined these interrelationships in aged non-mutant genomic human Tau mice, with established Tau pathology and neuron loss. We also examined how these interrelationships changed with an intervention by feeding mice either a control diet or one containing the brain permeable beta-amyloid and Tau aggregate binding molecule curcumin. Transgene-dependent elevations in soluble and insoluble phospho-Tau monomer and soluble Tau dimers accompanied deficits in behavior, hippocampal excitatory synaptic markers, and molecular chaperones (heat shock proteins (HSPs)) involved in Tau degradation and microtubule stability. In human Tau mice but not control mice, HSP70, HSP70/HSP72, and HSP90 were reduced in membrane-enriched fractions but not in cytosolic fractions. The synaptic proteins PSD95 and NR2B were reduced in dendritic fields and redistributed into perikarya, corresponding to changes observed by immunoblot. Curcumin selectively suppressed levels of soluble Tau dimers, but not of insoluble and monomeric phospho-Tau, while correcting behavioral, synaptic, and HSP deficits. Treatment increased PSD95 co-immunoprecipitating with NR2B and, independent of transgene, increased HSPs implicated in Tau clearance. It elevated HSP90 and HSC70 without increasing HSP mRNAs; that is, without induction of the heat shock response. Instead curcumin differentially impacted HSP90 client kinases, reducing Fyn without reducing Akt. In summary, curcumin reduced soluble Tau and elevated HSPs involved in Tau clearance, showing that even after tangles have formed, Tau-dependent behavioral and synaptic deficits can be corrected.
authors.affiliation: Department of Neurology, David Geffen School of Medicine at the University of California, Los Angeles, the Geriatric, Research, and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073, USA.
authors.forename: Qiu-Lan
authors.initials: QL
authors.lastname: Ma
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Zuo
authors.forename: Fusheng
authors.initials: F
authors.lastname: Yang
authors.forename: Oliver J
authors.initials: OJ
authors.lastname: Ubeda
authors.forename: Dana J
authors.initials: DJ
authors.lastname: Gant
authors.forename: Mher
authors.initials: M
authors.lastname: Alaverdyan
authors.forename: Edmond
authors.initials: E
authors.lastname: Teng
authors.forename: Shuxin
authors.initials: S
authors.lastname: Hu
authors.forename: Ping-Ping
authors.initials: PP
authors.lastname: Chen
authors.forename: Panchanan
authors.initials: P
authors.lastname: Maiti
authors.forename: Bruce
authors.initials: B
authors.lastname: Teter
authors.forename: Greg M
authors.initials: GM
authors.lastname: Cole
authors.forename: Sally A
authors.initials: SA
authors.lastname: Frautschy
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000493:pharmacokinetics*; D001522:Behavior, Animal / Q000187:drug effects*; D003474:Curcumin / Q000494:pharmacology*; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D006360:Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D055503:Protein Multimerization / Q000187:drug effects* / Q000235:genetics; D059748:Proteolysis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D051076:Proto-Oncogene Proteins c-fyn / Q000235:genetics / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D013569:Synapses / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D024801:Tauopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D006360:Heat-Shock Proteins; D047908:Intracellular Signaling Peptides and Proteins; C054369:MAPT protein, human; D008565:Membrane Proteins; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D016875:tau Proteins; C494957:FYN protein, human; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn; D051057:Proto-Oncogene Proteins c-akt; D003474:Curcumin