Characterization of gene expression in the cerebral cortices of rat brains containing subcortical lesions.

Abstract

Neurotoxic lesion of the nucleus basalis of Meynert in the rat brain, which results in the loss of subcortical cholinergic innervation to the cerebral cortex, is an animal model for the cortical cholinergic deficits that are characteristic of Alzheimer's disease. Previously, we have shown that amyloid precursor protein is induced in the cortex in response to this disrupted innervation. We have investigated the synthesis and accumulation of proteins in lesioned versus control cortices. Total proteins from cortices were separated by high resolution two-dimensional gel electrophoresis and visualized by silver stain. Of the greater than 1,000 polypeptides examined, only one exhibited a consistent alteration in the lesioned sample. This unidentified protein (Mr 34 kD, pI 5.5) was normally present in scant amounts but was virtually absent in the lesioned cortex (0.056% total integrated density (TID) and 0.008% TID, respectively; p < 0.04). To investigate gene expression more directly, polysomes purified from lesioned and control cortices were assayed in vitro. Examination of [35S] incorporation into translation products by two-dimensional gels and autoradiography revealed three newly synthesized polypeptide differences in the lesioned samples. One protein (M(r) 47 kD, pI 6.1) exhibited elevated levels with the lesion (0.05% to 0.16%; p = 0.02) while two other proteins (M(r) 34 kD, pI 5.5, and M(r) 33 kD, pI 5.7) exhibited reduced levels (0.20% to 0.04%, p < 0.02, and 0.34% to 0.12%, p = 0.04, respectively).