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A murine model of INCL, the PPT1-deficient (<jats:italic>PPT1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>) mouse, is an accurate phenocopy of the human disease. The first pathological change observed in the<jats:italic>PPT1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>brain is regional areas of glial fibrillary acidic protein (GFAP) upregulation, which predicts future areas of neurodegeneration. We hypothesized that preventing GFAP and vimentin upregulation in reactive astrocytes will alter the CNS disease. To test this hypothesis, we generated mice simultaneously carrying null mutations in the<jats:italic>GFAP<\/jats:italic>,<jats:italic>Vimentin<\/jats:italic>, and<jats:italic>PPT1<\/jats:italic>genes (<jats:italic>GFAP<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>Vimentin<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>PPT1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>). Although the clinical and pathological features of the<jats:italic>GFAP<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>Vimentin<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup><jats:italic>PPT1<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mice are similar to INCL, the disease appears earlier and progresses more rapidly. One mechanism underlying this accelerated phenotype is a profound neuroinflammatory response within the CNS. 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