Lithium Decreases Glial Fibrillary Acidic Protein in a Mouse Model of Alexander Disease.

Alexander disease is a fatal neurodegenerative disease caused by mutations in the astrocyte intermediate filament glial fibrillary acidic protein (GFAP). The disease is characterized by elevated levels of GFAP and the formation of protein aggregates, known as Rosenthal fibers, within astrocytes. Lithium has previously been shown to decrease protein aggregates by increasing the autophagy pathway for protein degradation. In addition, lithium has also been reported to decrease activation of the transcription factor STAT3, which is a regulator of GFAP transcription and astrogliogenesis. Here we tested whether lithium treatment would decrease levels of GFAP in a mouse model of Alexander disease. Mice with the Gfap-R236H point mutation were fed lithium food pellets for 4 to 8 weeks. Four weeks of treatment with LiCl at 0.5% in food pellets decreased GFAP protein and transcripts in several brain regions, although with mild side effects and some mortality. Extending the duration of treatment to 8 weeks resulted in higher mortality, and again with a decrease in GFAP in the surviving animals. Indicators of autophagy, such as LC3, were not increased, suggesting that lithium may decrease levels of GFAP through other pathways. Lithium reduced the levels of phosphorylated STAT3, suggesting this as one pathway mediating the effects on GFAP. In conclusion, lithium has the potential to decrease GFAP levels in Alexander disease, but with a narrow therapeutic window separating efficacy and toxicity

Adult-onset Alexander disease with typical "tadpole" brainstem atrophy and unusual bilateral basal ganglia involvement: a case report and review of the literature

<p>Abstract</p> <p>Background</p> <p>Alexander disease (ALX) is a rare neurological disorder characterized by white matter degeneration and cytoplasmic inclusions in astrocytes called Rosenthal fibers, labeled by antibodies against glial fibrillary acidic protein (GFAP). Three subtypes are distinguished according to age at onset: infantile (under age 2), juvenile (age 2 to 12) and adult (over age 12). Following the identification of heterozygous mutations in <it>GFAP </it>that cause this disease, cases of adult-onset ALX have been increasingly reported.</p> <p>Case Presentation</p> <p>We present a 60-year-old Japanese man with an unremarkable past and no family history of ALX. After head trauma in a traffic accident at the age of 46, his character changed, and dementia and dysarthria developed, but he remained independent. Spastic paresis and dysphagia were observed at age 57 and 59, respectively, and worsened progressively. Neurological examination at the age of 60 revealed dementia, pseudobulbar palsy, left-side predominant spastic tetraparesis, axial rigidity, bradykinesia and gaze-evoked nystagmus. Brain MRI showed tadpole-like atrophy of the brainstem, caused by marked atrophy of the medulla oblongata, cervical spinal cord and midbrain tegmentum, with an intact pontine base. Analysis of the <it>GFAP </it>gene revealed a heterozygous missense mutation, c.827G>T, p.R276L, which was already shown to be pathogenic in a case of pathologically proven hereditary adult-onset ALX.</p> <p>Conclusion</p> <p>The typical tadpole-like appearance of the brainstem is strongly suggestive of adult-onset ALX, and should lead to a genetic investigation of the <it>GFAP </it>gene. The unusual feature of this patient is the symmetrical involvement of the basal ganglia, which is rarely observed in the adult form of the disease. More patients must be examined to confirm, clinically and neuroradiologically, extrapyramidal involvement of the basal ganglia in adult-onset ALX.</p

Astrocytes: biology and pathology

Astrocytes are specialized glial cells that outnumber neurons by over fivefold. They contiguously tile the entire central nervous system (CNS) and exert many essential complex functions in the healthy CNS. Astrocytes respond to all forms of CNS insults through a process referred to as reactive astrogliosis, which has become a pathological hallmark of CNS structural lesions. Substantial progress has been made recently in determining functions and mechanisms of reactive astrogliosis and in identifying roles of astrocytes in CNS disorders and pathologies. A vast molecular arsenal at the disposal of reactive astrocytes is being defined. Transgenic mouse models are dissecting specific aspects of reactive astrocytosis and glial scar formation in vivo. Astrocyte involvement in specific clinicopathological entities is being defined. It is now clear that reactive astrogliosis is not a simple all-or-none phenomenon but is a finely gradated continuum of changes that occur in context-dependent manners regulated by specific signaling events. These changes range from reversible alterations in gene expression and cell hypertrophy with preservation of cellular domains and tissue structure, to long-lasting scar formation with rearrangement of tissue structure. Increasing evidence points towards the potential of reactive astrogliosis to play either primary or contributing roles in CNS disorders via loss of normal astrocyte functions or gain of abnormal effects. This article reviews (1) astrocyte functions in healthy CNS, (2) mechanisms and functions of reactive astrogliosis and glial scar formation, and (3) ways in which reactive astrocytes may cause or contribute to specific CNS disorders and lesions

GFAP and its role in Alexander disease

Here we review how GFAP mutations cause Alexander disease. The current data suggest that a combination of events cause the disease. These include: (i) the accumulation of GFAP and the formation of characteristic aggregates, called Rosenthal fibers, (ii) the sequestration of the protein chaperones alpha B-crystallin and HSP27 into Rosenthal fibers, and (iii) the activation of both Jnk and the stress response. These then set in motion events that lead to Alexander disease. We discuss parallels with other intermediate filament diseases and assess potential therapies as part of this review as well as emerging trends in disease diagnosis and other aspects concerning GFAP