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Abstract Details

Cdk5 inhibition in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis suppresses neurodegeneration and extends survival.
Aging, Dementia, Cognitive, and Behavioral Neurology
P1 - Poster Session 1 (8:00 AM-9:00 AM)
7-001
Deregulated Cdk5 activity is closely correlated with hyperphosphorylated tau, a common pathology found in neurodegenerative disease. Postmortem study revealed increased Cdk5 immunoreactivity in amyotrophic lateral sclerosis (ALS), however, Cdk5-silencing impacts on ALS are unheralded. Therefore, the effects of Cdk5 inhibition on ALS-model mice and neurons were investigated in this study.
To investigate the effects of cyclin-dependent kinase 5 (Cdk5) inhibition on transgenic mice carrying superoxide dismutase 1 (SOD1G93A) mutation in the perspective of neurodegeneration.

For in vitro study, effects of Cdk5 inhibition on motor neuron cell lines with wild type SOD1 or mutant SOD1G93A and primary neuronal cultures from SOD1G93A mice or wild type mice were evaluated with respect to expression of proteins involved in tau pathology, neuroinflammation, apoptosis, and neuritic outgrowth. For in vivo study, SOD1G93A mice and wild type mice were intrathecally injected with AAV9-scramble(SCR)-shRNA or AAV9-Cdk5-shRNA at the age of 5 weeks. Motor function and longevity were assessed and tissues were collected from 90-day-old or 120-day-old mice.

The neurons with SOD1G93A showed increased phosphorylated tau, attenuated neuritic growth, mislocalization of SOD1, enhanced neuroinflammation and apoptosis, all of which were reverted by Cdk5 inhibition. The SOD1G93A mice treated with AAV9-Cdk5-shRNA had significantly delayed disease onset (p < 0.001), delayed rotarod failure (p = 0.032), and prolonged survival (p = 0.007) compared to those treated with AAV9-SCR-shRNA. The brain and spinal cord of the SOD1G93A mice injected with AAV9-Cdk5-shRNA exhibited suppressed tau pathology, neuroinflammation, apoptosis and increased number of motor neurons compared to those of the SOD1G93A mice injected with AAV9-SCR-shRNA.

Cdk5 inhibition could be a major mechanism for a new therapeutic for ALS.

Authors/Disclosures
Ahwon Kim, MD (Seoul National University Hospital)
PRESENTER
Dr. Kim has nothing to disclose.
Do-Yeon Lee, PhD Ms. LEE has nothing to disclose.
Jung-Joon Sung, MD,PhD (Department of Neurology, Seoul National University Hospital) Prof. Sung has nothing to disclose.