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O3‐14‐05: RESTORATION OF AXONAL TRAFFICKING OF MITOCHONDRIA AVERTS COGNITIVE DECLINE IN MOUSE MODELS OF FAMILIAL ALZHEIMER'S DISEASE
Author(s) -
Trushina Eugenia,
Zhang Liang,
Zhang Song,
Trushin Sergey,
Maezawa Izumi,
Jin LeeWay,
Hua Duy H.
Publication year - 2014
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2014.04.351
Subject(s) - cognitive decline , mitochondrion , genetically modified mouse , neuroscience , disease , transgene , medicine , biology , microbiology and biotechnology , biochemistry , dementia , gene
Background: Expression of the non-proline-dependent casein kinase 1 delta (CK1d) is highly elevated in Alzheimer’s disease (AD) brain tissue where it plays an important, early role in phosphorylation of the microtubule associate protein tau, and regulates aspects of the cell cycle which has recently been shown to reactivate in AD neurones leading to cell death. CK1d also regulates the levels of the period proteins Per1 and Per2 that control circadian rhythmwhich is often disturbed in AD. Thus, CK1d represents a potentially important target for drug development in AD and further analysis of the activity of different CK1d-mediated pathways is required. Methods: We have previously developed two selective CK1d inhibitors, PS110 & PS278-05 that are orally available and enter the brain at therapeutic levels with no overt signs of toxicity. Both compounds improved cognitive performance in the TMHT transgenic mouse model of tauopathy. Effects on tau phosphorylation were monitored using targeted mass spectrometry and western blotting with decreased phosphorylation at several sites including Threonine 231 and Serine 396, and a general reduction in level of total tau phosphorylation compared with vehicle-treated controls. Results: As expected, active CDK5 levels were substantially reduced, consistent with a significant reduction of total CK1d protein levels seen in treated animals. Finally, levels of Per1 and Per2 were reduced in treated animals although there was a marked difference between Per1 and Per2 suggesting different modes of action for PS110 and PS278-05. To further understand this we are applying a global phosphorylation workflow, SysQuant, to determine the cross-pathway effects of CK1d inhibition in mouse brain tissue. Results will be presented at the meeting.Conclusions: Ck1d appears to play a role in several aspects of AD pathology and clinical symptoms, and represents a tractable drug target. Inhibition of CK1d is likely to affect multiple cell signaling pathways and we will present data showing which pathways are most active in a mouse model of tauopathy and how these are modulated by CK1 inhibition