CDK5 Involved in APP Membrane Relocalisation

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cdk5 crystal structureThe amyloid plaques characteristic of Alzheimer’s disease are made up of small peptides formed by cleavage of amyloid precursor protein (APP). Although the primary function of APP is poorly understood, it is believed to regulate synapse formation and neural plasticity. Synaptic activity of APP involves membrane microdomains containing syntaxin whereas amyloidogenic cleavage occurs primarily in cholesterol-rich lipid raft regions containing one of the proteases needed for APP cleavage, BACE. APP preferentially associates with syntaxin microdomains, but neuronal stimulation causes APP to associate instead with BACE-containing microdomains. It is unclear why this trafficking occurs, but a recently published study in the Journal of Cell Biology showed that movement of APP between the two membrane microdomains is an active process, involving cyclin-dependent kinase 5 (CDK5).

roscovitineThe study also showed that treatment of neurons with the CDK5 inhibitor, roscovitine, which is currently undergoing clinical trials as a treatment for cancer, reduced the association of APP with BACE-rich microdomains, and reduced cleavage.

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