Loss of MAP function leads to hippocampal synapse loss and deficits in the Morris Water Maze with aging
Hyperphosphorylation and accumulation of tau aggregates are prominent features in tauopathies, including Alzheimer's disease, but the impact of loss of tau function on synaptic and cognitive deficits remains poorly understood. We report that old (19-20 months; OKO) but not middle-aged (8-9 mont...
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Published in | The Journal of neuroscience Vol. 34; no. 21; pp. 7124 - 7136 |
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Main Authors | , , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
Society for Neuroscience
21.05.2014
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Subjects | |
Online Access | Get full text |
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Summary: | Hyperphosphorylation and accumulation of tau aggregates are prominent features in tauopathies, including Alzheimer's disease, but the impact of loss of tau function on synaptic and cognitive deficits remains poorly understood. We report that old (19-20 months; OKO) but not middle-aged (8-9 months; MKO) tau knock-out mice develop Morris Water Maze (MWM) deficits and loss of hippocampal acetylated α-tubulin and excitatory synaptic proteins. Mild motor deficits and reduction in tyrosine hydroxylase (TH) in the substantia nigra were present by middle age, but did not affect MWM performance, whereas OKO mice showed MWM deficits paralleling hippocampal deficits. Deletion of tau, a microtubule-associated protein (MAP), resulted in increased levels of MAP1A, MAP1B, and MAP2 in MKO, followed by loss of MAP2 and MAP1B in OKO. Hippocampal synaptic deficits in OKO mice were partially corrected with dietary supplementation with docosahexaenoic acid (DHA) and both MWM and synaptic deficits were fully corrected by combining DHA with α-lipoic acid (ALA), which also prevented TH loss. DHA or DHA/ALA restored phosphorylated and total GSK3β and attenuated hyperactivation of the tau C-Jun N-terminal kinases (JNKs) while increasing MAP1B, dephosphorylated (active) MAP2, and acetylated α-tubulin, suggesting improved microtubule stability and maintenance of active compensatory MAPs. Our results implicate the loss of MAP function in age-associated hippocampal deficits and identify a safe dietary intervention, rescuing both MAP function and TH in OKO mice. Therefore, in addition to microtubule-stabilizing therapeutic drugs, preserving or restoring compensatory MAP function may be a useful new prevention strategy. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 PMCID: PMC4028492 Author contributions: Q.-L.M., S.A.F., and G.M.C. designed research; Q.-L.M., X.Z., F.Y., O.J.U., D.J.G., M.A., N.C.K., S.N., P.P.C., S.A.F., and G.M.C. performed research; F.N. and P.C. contributed unpublished reagents/analytic tools; Q.-L.M., D.J.G., N.C.K., E.T. and S.A.F. analyzed data; Q.-L.M., S.A.F., and G.M.C. wrote the paper. S.A.F. and G.M.C. contributed equally to this work. |
ISSN: | 0270-6474 1529-2401 |
DOI: | 10.1523/JNEUROSCI.3439-13.2014 |