Pharmacological Inhibition of p-21 Activated Kinase (PAK) Restores Impaired Neurite Outgrowth and Remodeling in a Cellular Model of Down Syndrome

Down syndrome (DS) is characterized by the trisomy of chromosome 21 and by cognitive deficits that have been related to neuronal morphological alterations in humans, as well as in animal models. The gene encoding for amyloid precursor protein (APP) is present in autosome 21, and its overexpression in DS has been linked to neuronal dysfunction, cognitive deficit, and Alzheimer's disease-like dementia. In particular, the neuronal ability to extend processes and branching is affected. Current evidence suggests that APP could also regulate neurite growth through its role in the actin cytoskeleton, in part by influencing p21-activated kinase (PAK) activity. The latter effect is carried out by an increased abundance of the caspase cleavage-released carboxy-terminal C31 fragment. In this work, using a neuronal cell line named CTb, which derived from the cerebral cortex of a trisomy 16 mouse, an animal model of human DS, we observed an overexpression of APP, elevated caspase activity, augmented cleavage of the C-terminal fragment of APP, and increased PAK1 phosphorylation. Morphometric analyses showed that inhibition of PAK1 activity with FRAX486 increased the average length of the neurites, the number of crossings per Sholl ring, the formation of new processes, and stimulated the loss of processes. Considering our results, we propose that PAK hyperphosphorylation impairs neurite outgrowth and remodeling in the cellular model of DS, and therefore we suggest that PAK1 may be a potential pharmacological target.

 

Comments:

Your research findings suggest that in a cellular model of Down syndrome (DS), there is an overexpression of the amyloid precursor protein (APP), increased caspase activity, elevated cleavage of the C-terminal fragment of APP, and enhanced phosphorylation of p21-activated kinase 1 (PAK1). These molecular changes are associated with impaired neurite outgrowth and remodeling, which may contribute to the cognitive deficits observed in DS.

The overexpression of APP, which is located on chromosome 21, has been linked to neuronal dysfunction, cognitive deficits, and the development of Alzheimer's disease-like dementia in DS. In this study, you observed that increased APP levels led to elevated caspase activity and enhanced cleavage of the C-terminal fragment of APP, resulting in the release of the carboxy-terminal C31 fragment. The presence of this fragment has been associated with neuronal morphological alterations.

Furthermore, your findings indicate that APP may also regulate neurite growth through its involvement in the actin cytoskeleton and its influence on PAK1 activity. The increased phosphorylation of PAK1, likely caused by the overexpression of APP and the release of the C31 fragment, negatively impacted neurite outgrowth and remodeling. To investigate this further, you inhibited PAK1 activity using FRAX486, which resulted in increased neurite length, more crossings per Sholl ring (a measure of neurite complexity), enhanced formation of new processes, and stimulated the loss of existing processes.

Based on these observations, you propose that PAK1 hyperphosphorylation impairs neurite outgrowth and remodeling in the cellular model of DS. Consequently, you suggest that PAK1 may be a potential pharmacological target for intervention in Down syndrome. Further research and validation are required to explore the therapeutic implications of targeting PAK1 and its potential to mitigate the neuronal and cognitive deficits associated with DS.

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