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Hydrogen peroxide-inducible clone 5 (Hic-5) and paxillin are members of the Group III LIM domain protein family that localize toboth cell nuclei and focal adhesions and link integrin-mediated signaling to the actin cytoskeleton. Prior in vitro studies have implicated paxillin in β-amyloid-induced cell death, but little is known about the expression and function of Hic-5 and paxillin in the brain. We performed a blinded retrospective cross-sectional study of Hic-5 and paxillin expression in the hippocampi of Alzheimer disease (AD) and control subjects using immunohistochemistry and laser scanning confocal microscopy. The analysis included assessment of the expression of phosphorylated isoforms of paxillin that reflect activation of distinct signaling pathways. We found changes in the subcellular distribution of Hic-5, paxillin, and specific phosphorylated isoforms of paxillin in the AD brains. The Hic-5 and phosphorylated isoforms of paxillin colocalized with neurofibrillary tangles. Paxillin was predominantly found in reactive astrocytes in the AD hippocampi, and activated paxillin was also detected in granulovacuolar degeneration bodies in AD. These data indicate that these important scaffolding proteins that link various intracellular signaling pathways to the extracellular matrix are modified and have altered subcellular distribution in AD.