Microglial activation and inflammatory reaction preceding neurodegeneration in Sandhoff disease

Abstract

Sandhoff disease is a lysosomal storage disorder characterized by the absence of β-hexosaminidase and storage of G M2 ganglioside and related glycolipids in the central nervous system. The glycolipid storage causes severe neurodegeneration and progressive decline of neurological function that leads to death at an early stage of life. The pathogenetic mechanisms of neurodegeneration in this disease are poorly understood. In Sandhoff disease model, mice apoptotic cell death was prominent in the brainstem and spinal cord during the rapid decline of neurological function. By global gene expression and histological analyses, we identified an inflammatory reaction mediated by microglia/macrophages that precedes neuronal apoptosis. When the inflammatory response was suppressed by bone marrow transplantation, neuronal apoptosis was suppressed. We suggest that the inflammatory reaction may have a direct role in the neurodegenerative process. Thus, this lysosomal storage disease may have similarities to other neurodegenerative disorders, such as Alzheimer's, HIV dementia and prion diseases, where inflammatory processes are believed to participate directly in neuronal cell death.