FOCAL ADHESION KINASE EXPRESSED BY NERVE-CELL LINES SHOWS INCREASED TYROSINE PHOSPHORYLATION IN RESPONSE TO ALZHEIMERS ALPHA-BETA PEPTIDE

A beta is a 39-43-amino acid peptide that accumulates as extracellular aggregates in Alzheimer's disease-afflicted brain tissue. Contact bet ween these aggregates and neurons is potentially pathogenic, although little is known about the cellular transduction mechanisms. We have in vestigated the impact of A beta aggregates on the neuronal control of protein tyrosine phosphorylation, which underlies signal transduction for multiple families of growth factor and adhesion receptors. Added t o cultures of rat and human nerve cell lines, A beta aggregates evoked a non-desensitizing increase (1.3-3.6-fold) in tyrosine phosphorylati on in a band at 118 kDa. The 118-kDa protein was determined by immunop recipitation to be pp125(FAK), not previously documented in cells of n euronal lineage. Immunoblots with anti-focal adhesion kinase (FAK) sho wed that A beta aggregates had no effect on FAK protein levels. The in crease in FAK tyrosine phosphorylation occurred at doses of A beta agg regates that evoked lactate dehydrogenase release; evoked tyrosine pho sphorylation preceded the first detectable lactate dehydrogenase relea se by 4 h. Like degeneration, the FAK response was dependent on A beta aggregation and neuronal differentiation. Since tyrosine phosphorylat ion of FAK is essential to its activity as a transduction component of integrin-, peptide-, and lysophosphatidic acid-mediated signaling, th e data establish a link between A beta aggregates and signal transduct ion pathways implicated in diverse cell functions including neurite ou tgrowth, control of the cell cycle, and apoptosis.