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Alexander disease (AxD) is a primary disorder of astrocytes caused by dominant mutations in the gene for glial fibrillary acidic protein (GFAP). These mutations lead to protein aggregation and formation of Rosenthal fibers, complex astrocytic inclusions that contain GFAP, vimentin, plectin, ubiquitin, Hsp27 and alphaB-crystallin. The small heat shock protein alphaB-crystallin (Cryab) regulates GFAP assembly, and elevation of Cryab is a consistent feature of AxD; however, its role in Rosenthal fibers and AxD pathology is not known. Here, we show in AxD mouse models that loss of Cryab results in increased mortality, whereas elevation of Cryab rescues animals from terminal seizures. When mice with Rosenthal fibers induced by over-expression of GFAP are crossed into a Cryab-null background, over half die at 1 month of age. Restoration of Cryab expression through the GFAP promoter reverses this outcome, showing the effect is astrocyte-specific. Conversely, in mice engineered to express both AxD-associated mutations and elevated GFAP, which despite natural induction of Cryab also die at 1 month, transgenic over-expression of Cryab results in a markedly reduced CNS stress response, restores expression of the glutamate transporter Glt1 (EAAT2) and protects these animals from death. In its most common form, AxD is a devastating neurodegenerative disease, with early onset, characterized by seizures, spasticity and developmental delays, ultimately leading to death. Cryab plays a critical role in tempering AxD pathology and should be investigated as a therapeutic target for this and other diseases with astropathology.

To study the involvement of TNF in cerebral pathology in vivo and to define cellular interactions within the central nervous system (CNS) that promote TNF signaling, we have expressed this cytokine either as a wild-type or a mutant transmembrane form in astrocytes or neurons of transgenic mice. Mice expressing wild-type human TNF in either of these cell types spontaneously develop a neurologic disorder manifested by ataxia, seizures, and paralysis and bear histologic evidence of chronic CNS inflammation and degeneration. Moreover, astrocyte-specific expression of transmembrane TNF triggers a similar neurologic phenotype. Interestingly, transgenic mice producing a high level of transmembrane TNF in their neurons develop no apparent phenotypic abnormalities, suggesting that appropriate cellular interactions should form to allow for contact-dependent TNF signals to induce CNS pathology. These results demonstrate that target cells mediating the neuroinflammatory activities of TNF localize in the vicinity of astrocytes rather than neurons.