Upregulation of casein kinase 1 epsilon may be involved in tau pathology in Alzheimer's disease brain

Abstract

Background: Dysfunction of microtubule-associated protein tau and tau aggregates are prominent features in Alzheimer disease (AD) and other tauopathies, but the mechanisms underlying loss of Tau function-related synaptic and cognitive deficits remain poorly understood. Here we investigated whether loss of tau function in tau knock out (KO) mice can induce synaptic, cognitive and motor deficits and whether these deficits can be treated with supplements in diet. Methods: Young to middle-aged and aged tau KO mice and age-matched C57 wild type control mice were used for the experiment that was raised on PMI 5015 with some 18:n-3 but no long chain n-3. Treatment intervention includes DHA and the combination of DHAwith a -lipoate. Results: Aged (19-20 months old) but not middle-aged (8-9 months old) tau knockout (KO) mice develop severe hippocampal excitatory synaptic marker loss and behavior deficits implying an age-related failure to compensate for loss of tau by other microtubule-associated proteins (MAP1 and MAP2). We also find that in aged tau KO mice, the dietary n-3 fatty acid docosahexaenoic acid (DHA) partially protected, while DHA plus a -lipoate fully protected against synaptic and cognitive deficits by maintaining active MAPs and microtubule stability via inhibition of C-Jun N-terminal kinases (JNKs). Motor deficits and loss of tyrosine hydroxylase (TH) appeared in middle-aged tau KO mice without further decline in aged tau KO mice, the combination of DHA with a -lipoate diet prevented the loss of TH in OKOmice. Our preliminary data also suggested hippocampal loss of the neuronal marker NeuN and rescue by DHA/ALA. Conclusions: Our results imply loss of tau function with aging contributes to synaptic, cognitive and motor deficits that can be treated by safe interventions that rescue MAPs.