title: Olfactory Deprivation Hastens Alzheimer-Like Pathologies in a Human Tau-Overexpressed Mouse Model via Activation of cdk5.
abstract: Olfactory dysfunction is a recognized risk factor for the pathogenesis of Alzheimer's disease (AD), while the mechanisms are still not clear. Here, we applied bilateral olfactory bulbectomy (OBX), an olfactory deprivation surgery to cause permanent anosmia, in human tau-overexpressed mice (htau mice) to investigate changes of AD-like pathologies including aggregation of abnormally phosphorylated tau and cholinergic neuron loss. We found that tau phosphorylation in hippocampus was increased at Thr-205, Ser-214, Thr-231, and Ser-396 after OBX. OBX also increased the level of sarkosyl-insoluble Tau at those epitopes and accelerated accumulation of somatodendritic tau. Moreover, OBX resulted in the elevation of calpain activity accompanied by an increased expression of the cyclin-dependent kinase 5 (cdk5) neuronal activators, p35 and p25, in hippocampus. Furthermore, OBX induces the loss of the cholinergic neurons in medial septal. Administration of cdk5 pharmacological inhibitor roscovitine into lateral ventricles suppressed tau hyperphosphorylation and mislocalization and restored the cholinergic neuron loss. These findings suggest that olfactory deprivation by OBX hastens tau pathology and cholinergic system impairment in htau mice possibly via activation of cdk5.
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ke
authors.initials: K
authors.lastname: Li
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fang-Fang
authors.initials: FF
authors.lastname: Liu
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Chun-Xue
authors.initials: CX
authors.lastname: He
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: He-Zhou
authors.initials: HZ
authors.lastname: Huang
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Ao-Ji
authors.initials: AJ
authors.lastname: Xie
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Fan
authors.initials: F
authors.lastname: Hu
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. wangjz@mails.tjmu.edu.cn.
authors.forename: Jian-Zhi
authors.initials: JZ
authors.lastname: Wang
authors.affiliation: Pathophysiology Department, Key Laboratory of Neurological Disease of Education Committee of China, China-Canada Cooperation Platform on Neurological Disorder, Institute of Brain Research, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China. zhulq1979@gmail.com.
authors.forename: Ling-Qiang
authors.initials: LQ
authors.lastname: Zhu
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology* / Q000473:pathology*; D000818:Animals; D002154:Calpain / Q000378:metabolism; D059329:Cholinergic Neurons / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism*; D003712:Dendrites / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D051379:Mice; D009830:Olfactory Bulb / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology* / Q000601:surgery; D010766:Phosphorylation / Q000187:drug effects; D011687:Purines / Q000494:pharmacology; D000077546:Roscovitine; D012686:Septal Nuclei / Q000187:drug effects / Q000378:metabolism; D012995:Solubility; D024801:Tauopathies / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D011687:Purines; D016875:tau Proteins; D000077546:Roscovitine; D051360:Cyclin-Dependent Kinase 5; D002154:Calpain
keywords: Alzheimer’s disease; Cholinergic neurons; Olfactory deprivation; cdk5