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(American Journal of Pathology. 2004;165:795-805.)
© 2004 American Society for Investigative Pathology

Calpain Mediates Calcium-Induced Activation of the Erk1,2 MAPK Pathway and Cytoskeletal Phosphorylation in Neurons

Relevance to Alzheimer’s Disease

Veeranna^*, Takahide Kaji, Barry Boland^*, Tatjana Odrljin^*, Panaiyur Mohan^*, Balapal S. Basavarajappa, Corrinne Peterhoff^*, Anne Cataldo^*¶, Anna Rudnicki^¶, Niranjana Amin^||, Bing Sheng Li^||, Harish C. Pant^||, Basalingappa L. Hungund, Ottavio Arancio^* and Ralph A. Nixon^***

From the Center for Dementia Research,^* Nathan Kline Institute for Psychiatric Research, Orangeburg, New York; the Department of Psychiatry, New York University School of Medicine, New York, New York; the Department of Cell Biology,^** New York University School of Medicine, New York, New York; the Division of Analytical Psychopharmacology, New York State Psychiatric Institute and Nathan Kline Institute for Psychiatric Research, Orangeburg, New York; Mitsubishi-Tokyo Pharmaceuticals, Inc., Yokohama, Japan; McLean Hospital,^¶ Belmont, Massachusetts; and the Laboratory of Neurochemistry,^|| National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland

Aberrant phosphorylation of the neuronal cytoskeleton is an early pathological event in Alzheimer’s disease (AD), but the underlying mechanisms are unclear. Here, we demonstrate in the brains of AD patients that neurofilament hyperphosphorylation in neocortical pyramidal neurons is accompanied by activation of both Erk1,2 and calpain. Using immunochemistry, Western blot analysis, and kinase activity measurements, we show in primary hippocampal and cerebellar granule (CG) neurons that calcium influx activates calpain and Erk1,2 and increases neurofilament phosphorylation on carboxy terminal polypeptide sites known to be modulated by Erk1,2 and to be altered in AD. Blocking Erk1,2 activity either with antisense oligonucleotides to Erk1,2 mRNA sequences or by specifically inhibiting its upstream activating kinase MEK1,2 markedly reduced neurofilament phosphorylation. Calpeptin, a cell-permeable calpain inhibitor, blocked both Erk1,2 activation and neurofilament hyperphosphorylation at concentrations that inhibit calpain-mediated cleavage of brain spectrin. By contrast, inhibiting Erk1,2 with U-0126, a specific inhibitor of Mek1,2, had no appreciable effect on ionomycin-induced calpain activation. These findings demonstrate that, under conditions of calcium injury in neurons, calpains are upstream activators of Erk1,2 signaling and are likely to mediate in part the hyperphosphorylation of neurofilaments and tau seen at early stages of AD as well as the neuron survival-related functions of the MAP kinase pathway.

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