Posted January 14, 2022

Dr. Jacob Raber, Oregon Health and Science University

Neurofibromatosis type 1 (NF1) is a negative regulator of Ras, a proto-oncogene and activator of the mitogen activated protein kinase (MAP kinase) cascade that is often activated by receptor tyrosine kinases. Previous research in drosophila and mouse studies support a genetic interaction between NF1 and Alk, a receptor tyrosine kinase and activator of the Ras-MAP kinase cascade. Orally active Alk inhibitors have been developed for human tumors and have been shown to rescue cognitive impairments in NF1 mutant drosophila and improve spatial memory retention in NF1 mutant mice. Further study has been necessary to assess the effects of prolonged pharmacologic Alk inhibition on sleep, hippocampal neurogenesis, and depressive and anxiety-like behaviors.

With support from a Neurofibromatosis Research Program Fiscal Year 2016 Investigator-Initiated Research Award, Dr. Jacob Raber aimed to test the hypothesis that the pharmacologic inhibition of Alk has short- and long-term effects on behavioral performance, including measures of anxiety, depressive-like behaviors, circadian activity, cognitive performance, and neurogenesis in heterozygous NF1 mutant mice treated in adulthood. Specifically, they tested the optimal timing and dose of pharmacologic Alk inhibition to achieve maximal cognitive performance, the potential benefit of Alk inhibition on altered circadian activity levels, and potential adverse behavioral and cognitive effects of Alk inhibition in wild-type and NF1 heterozygous mice. To test these questions, the Alk inhibitor CH5424802 (Alectinib) was provided to NF1+/- mice in a variety of doses. Findings revealed that short-term treatment (starting 10 days prior to behavioral testing) with Alectinib improved spatial learning of the male mice in the 3.6 mg/kg treatment group, especially during the second and third hidden platform sessions in the water maze test. Long-term treatment (24 weeks) with Alectinib rescued impairments in object recognition and cognitive performance in the water maze. Additionally, their findings determined the effect of the parental gene carrier on the behavioral phenotype of the offspring. Specifically, (1) it appears to matter whether the mother or father were the NF1 HET carrier and (2) mice that received the NF1 gene from their father (paternal carrier) showed increased activity during the dark period (active period) and improved cognitive flexibility with the Alk inhibitor. Furthermore, the Alk inhibitor increased baseline activity during the fear-conditioning test when the mice received the NF1 gene from their mother (maternal carrier).

Taken together, these results indicate that the Alk inhibitor affects behavioral and cognitive phenotypes and that responsiveness to Alk inhibition in heterozygous NF1 offspring may depend on whether the parental carrier is maternal or paternal. Overall, these data and interesting findings support the therapeutic potential of pharmacological Alk inhibition in NF1+/- mice and ultimately may benefit NF patients.

References:

Krenik D, Weiss JB, Raber J. 2021. Role of the parental NF1 carrier in effects of pharmacological inhibition of anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice. Brain Research. 1769:147594. doi: 10.1016/j.brainres.2021.147594.

Krenik D, Weiss JB, Raber J. 2022. Long-term effects of pharmacological inhibition of Anaplastic lymphoma kinase in Neurofibromatosis 1 mutant mice. Behav Brain Res. 22:113767. doi: 10.1016/j.bbr.2022.113767.

Links:

Public and Technical Abstracts: Pharmacological Alk Inhibition to Mitigate Behavioral Changes and Cognitive Injury in Adolescent and Adult NF1 Mutant Mice

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