NEUROPATHOGENIC FUNCTION OF A NOVEL TAU REGULATOR IN TAU MODELS OF ALZHEIMER’S DISEASE

Abstract

Abnormal modification of tau and its deposition in brains is a marked characteristic of Alzheimer's disease. Tau phosphorylation by kinases including GSK3ß and CDK5 leads to its accumulation in the somatodendritic compartment of neurons, forming aggregates and neurofibrillary tangles at last. Those aggregates and NFTs are neurotoxic and result in neuronal cell death. HT22, SH-SY5Y cells were transfected with full-length human ALK to activate downstream signal. Antagonistic/agonistic antibody (mAb30, mAb46) were treated to primary hippocampal neurons to inhibit or activate ALK. The roles of ALK in tau-mediated neurotoxicity and memory loss were investigated in vivo, using Tau fly model and 3xTg-AD mouse model. ALK activation by overexpression or ALK agonistic antibody treatment causes tau phosphorylation and increased tau stability in neuronal cell lines and primary neurons. Tauopathic effect of ALK relies on its tyrosine kinase activity and downstream tau kinases, ERK and CDK5. Furthermore, ALK impedes tau degradation by inhibiting autophagy flux in a CDK5 dependent manner, resulting in tau accumulation. D. melanogaster fly model with neuronal expression of ALK shows aggravated tau rough eye phenotype and shortened lifespan,whereas expression of kinase-dead ALK fails to develop those phenotypes. In mammals, primary hippocampal neurons treated with agonistic antibody displays reduced synaptic density. In addition, ALK activation by lentivirus injection accelerates memory loss in 3x-AD mice, while administration of ALK inhibitor (Ceritinib) recovers the memory impairment. Aberrant regulation of ALK activity in neurons is crucial for tau pathology found in AD.