Purkinje cell loss in experimental autoimmune encephalomyelitis
Introduction
Gray matter atrophy is a common feature of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS). Atrophy has been linked to disability in all of these diseases (Camicioli et al., 2003, Chard et al., 2002, Firbank et al., 2007), underscoring its importance and the need to understand the mechanisms that drive it.
Multiple sclerosis has traditionally been viewed as an inflammatory, demyelinating disease of the central nervous system (CNS). Most patients begin with a relapsing–remitting form of the disease, characterized by inflammation and demyelination, which gradually transitions over several years to a secondary progressive form, characterized by progressive disability and tissue degeneration. A growing body of literature has documented the neurodegenerative aspect of MS (Evangelou et al., 2000, Peterson et al., 2001, Trapp et al., 1999). Whole brain atrophy was initially described in MS (Rudick et al., 1999) and several studies have since demonstrated a strong relationship between gray matter atrophy and disability (Ge et al., 2000, Rudick et al., 1999, Stevenson et al., 2000), including infratentorial and cerebellar atrophy (Edwards et al., 1999, Iannucci et al., 1999, Liu et al., 1999). Indeed, gray matter atrophy is now considered to be one of the most clinically relevant markers of MS disease progression (Fisher et al., 2002).
The primary function of the cerebellum is the modulation of movement; it plays a crucial role in coordination and balance. Clinical MS studies have found that fully one third of subjects have functionally relevant cerebellar deficits (Alusi et al., 2001, Weinshenker et al., 1996) and have demonstrated up to 19% decreases in cerebellar volume in MS patients (Edwards et al., 1999, Liu et al., 1999). Also, cerebellar atrophy in MS is closely correlated with disability on cerebellar functional subscales (Edwards et al., 1999, Liu et al., 1999). Thus, while cerebellar atrophy in MS has clinically relevant consequences, its underlying etiology remains poorly understood.
We have previously demonstrated gray matter atrophy in the cerebella of mice with experimental autoimmune encephalomyelitis (EAE), the most widely used model of MS, and found a correlation between this atrophy and disease duration (MacKenzie-Graham et al., 2006). Here, we have used neuroimaging to localize cerebellar atrophy within the cortical molecular layer and neuropathology to determine that Purkinje cell loss correlates with this atrophy. We examine the cellular etiology of the gray matter atrophy visualized by magnetic resonance imaging (MRI) and report that Purkinje cell loss is associated with it.
Section snippets
Mice
Female C57BL/6 mice, 8–12 weeks old, were purchased from the Jackson Laboratory. All studies were performed in accordance with approval from the UCLA Office of Protection of Research Subjects.
Antigen
Myelin oligodendrocyte glycoprotein (MOG) peptide 35–55 was purchased at greater than 98% purity (Chiron Mimotopes, Emeryville, CA).
EAE
Mice were immunized with MOG peptide 35–55 (300 μg/mouse) and Mycobacterium tuberculosis (500 μg/mouse) emulsified in Complete Freund's Adjuvant subcutaneously, in a volume of
Results
MOG-induced EAE in C57BL/6 mice has a chronic progressive disease course. The literature focuses primarily on disease in the spinal cord, but inflammation and focal lesions have been demonstrated in the cerebellum and forebrain as well (Black et al., 2006, Carter et al., 2007, Kuerten et al., 2007, Lees et al., 2008, MacKenzie-Graham et al., 2006, Melzer et al., 2008, Selvaraj and Geiger, 2008, Uemura et al., 2008). Mice with this form of EAE develop focal lesions that are easily identifiable
Discussion
MS is an inflammatory, demyelinating disease of the central nervous system (CNS) that results in damage to myelin, oligodendrocytes, axons, and neurons. Inflammation, demyelination, and neurodegeneration are intimately tied together (Geurts and Barkhof, 2008), and although MRI cannot establish the mechanisms of neurodegeneration, increasingly sophisticated imaging and analysis techniques are making it possible to determine precisely where and when it occurs. Here we have determined that, in the
Acknowledgments
This work was generously supported by a research grant from NMSS FG 1759A1/1 (AMG), NCRR U24 RR021760 (AWT), NIH U54 RR 021813 (AWT), NMSS CA 1028 (RRV), NMSS RG 3593 (RRV), NMSS PP 1098 (RRV), NIH P41 05959 (GAJ), and NIH R24 CA092656 (GAJ). The authors wish to acknowledge their deep appreciation to the members of the Laboratory of Neuro Imaging (LONI) and the Mouse Biomedical Informatics Research Network (Mouse BIRN). We would also like to acknowledge the late Michael D. Fehnel, who made this
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Both authors contributed equally and should both be considered first authors.