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- Title
Loss of MAP Function Leads to Hippocampal Synapse Loss and Deficits in the Morris Water Maze with Aging.
- Authors
Qiu-Lan Ma; Xiaohong Zuo; Fusheng Yang; Ubeda, Oliver J.; Gant, Dana J.; Alaverdyan, Mher; Kiosea, Nicolae C.; Nazari, Sean; Ping Ping Chen; Nothias, Fatiha; Piu Chan; Edmond Teng; Frautschy, Sally A.; Cole, Greg M.
- Abstract
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 affectMWMperformance, whereasOKOmice showedMWMdeficits 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 ofMAP2andMAP1Bin OKO. Hippocampal synaptic deficits inOKOmice 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 ageassociated 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 compensatoryMAPfunction may be a useful new prevention strategy.
- Subjects
MICROTUBULE-associated protein kinase; HIPPOCAMPUS (Brain); SYNAPTIC pruning; PSYCHOLOGICAL aspects of aging; PHOSPHORYLATION; TAU proteins; MEDICAL equipment; ALZHEIMER'S disease; LABORATORY mice
- Publication
Journal of Neuroscience, 2014, Vol 34, Issue 21, p7124
- ISSN
0270-6474
- Publication type
Article
- DOI
10.1523/JNEUROSCI.3439-13.2014