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 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.
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Qiu-Lan
QL
Ma
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073, Department of Neurobiology and Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 10053, China.
Xiaohong
X
Zuo
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Fusheng
F
Yang
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Oliver J
OJ
Ubeda
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Dana J
DJ
Gant
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Mher
M
Alaverdyan
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Nicolae C
NC
Kiosea
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Sean
S
Nazari
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Ping Ping
PP
Chen
Axonal Regeneration and Growth/Physiopathologie des Maladies du Système Nerveux Central, INSERM U952, Centre National de la Recherche Scientifique, Unité Mixte de Recherche 7224, Université Pierre et Marie Curie, 75005 Paris, France, and.
Fatiha
F
Nothias
Department of Neurobiology and Neurology, Beijing Institute of Geriatrics, Xuanwu Hospital, Capital Medical University, Beijing 10053, China.
Piu
P
Chan
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073.
Edmond
E
Teng
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073, gmcole@ucla.edu frautsch@ucla.edu.
Sally A
SA
Frautschy
Department of Neurology, University of California, Los Angeles, California 90095, Geriatric Research, Education and Clinical Center, Greater Los Angeles Veterans Affairs Healthcare System, Los Angeles, California 90073, gmcole@ucla.edu frautsch@ucla.edu.
Greg M
GM
Cole
D000375:Aging / Q000187:drug effects / Q000235:genetics / Q000473:pathology*; D000544:Alzheimer Disease / Q000150:complications / Q000235:genetics / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D004281:Docosahexaenoic Acids / Q000008:administration & dosage; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006624:Hippocampus / Q000187:drug effects / Q000473:pathology*; D007859:Learning Disabilities / Q000178:diet therapy / Q000209:etiology; D018782:Maze Learning / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009069:Movement Disorders / Q000178:diet therapy / Q000209:etiology; D011597:Psychomotor Performance / Q000502:physiology; D011930:Reaction Time / Q000187:drug effects; D013378:Substantia Nigra / Q000378:metabolism / Q000473:pathology; D013569:Synapses / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D008063:Thioctic Acid / Q000008:administration & dosage; D016875:tau Proteins / Q000172:deficiency*
D016875:tau Proteins; D004281:Docosahexaenoic Acids; D008063:Thioctic Acid
Alzheimer's disease; MAPs; Morris Water Maze; knock-out; synaptic markers; tau