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EphA 4 protein kinase activity in hippocampal brain tissue of patients with Alzheimer ’ s disease

The dysfunction of synapses and the subsequent loss of neurons are major pathological hallmarks of Alzheimer's disease (AD). These events occur early and correlate well with cognitive decline observed in patients with mild cognitive impairment. Loss of synaptic functions involves aberrant signalling of the Ephrin receptor tyrosine kinase A4 (EphA4) which is highly expressed in the adult hippocampus. We recently reported an altered distribution of EphA4 with neuritic amyloid beta plaques and tau tangles early in AD. Whether this re-localisation affects the EphA4 kinase activity remains elusive. To test this hypothesis, we investigated the EphA4 kinase activity in human hippocampal brain tissue lysates derived from AD and non-demented control cases. Since the currently available technologies to analyse the activity of one specific protein kinase in brain tissue lysates are limited, we developed a novel kinase immunodepletion assay (KID) and employed it in combination with kinase activity profiling. We found that the KID method can be used to deplete EphA4 from brain tissue lysates and to determine the change in kinase activity after depletion of EphA4. The kinase activity of EphA4 was unchanged in brain tissue of AD patients compared to non-demented controls. These findings reveal that the re-localisation of EphA4 happens independently of its kinase activity.