Increased Plp1 gene expression leads to massive microglial cell activation and inflammation throughout the brain

• Published in: ASN neuro Vol. 2; no. 4; p. e00043
• Main Authors: Tatar, Carrie L, Appikatla, Sunita, Bessert, Denise A, Paintlia, Ajaib S, Singh, Inderjit, Skoff, Robert P
• Format: Journal Article
• Language: English
• Published: United States American Society for Neurochemistry 27-09-2010
• Subjects: Animals; Brain Chemistry - genetics; Female; Gene Dosage; Gene Expression Regulation; Humans; Inflammation Mediators - physiology; Male; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Jimpy; Mice, Neurologic Mutants; Mice, Transgenic; Microglia - metabolism; Microglia - pathology; Myelin Proteolipid Protein - biosynthesis; Myelin Proteolipid Protein - genetics; Myelin Proteolipid Protein - physiology; Up-Regulation - genetics; DAB, diaminobenzidine; CD8, cluster of differentiation 8; Pelizaeus–Merzbacher disease; qRT–PCR, quantitative reverse transcription–PCR; CCR1, CC chemokine receptor 1; EAE, experimental allergic encephalomyelitis; CCL3, CC chemokine ligand 3; IL-1β, interleukin-1β; CXCL, CXC chemokine ligand; jp, jimpy; HRP, horseradish peroxidase; MOG, myelin oligodendrocyte glycoprotein; inflammation; Iba1, ionized calcium-binding adaptor molecule 1; DPN, day postnatal; microglia; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; myelin; CD11b, cluster of differentiation molecule 11B; BrdU, bromodeoxyuridine; proteolipid protein; TNF-α, tumour necrosis factor-α; oligodendrocyte; Ta, Tabby; PLP1, proteolipid protein 1 gene (human); CNS, central nervous system; Plp1, proteolipid protein 1 gene (non-human); QPCR, quantitative PCR; iNOS, inducible nitric oxide synthase; CRP, C-reactive protein; PMD, Pelizaeus–Merzbacher disease
• ISSN: 1759-0914; 1759-0914
• DOI: 10.1042/an20100016

PMD (Pelizaeus-Merzbacher disease) is a rare neurodegenerative disorder that impairs motor and cognitive functions and is associated with a shortened lifespan. The cause of PMD is mutations of the PLP1 [proteolipid protein 1 gene (human)] gene. Transgenic mice with increased Plp1 [proteolipid protein 1 gene (non-human)] copy number model most aspects of PMD patients with duplications. Hypomyelination and demyelination are believed to cause the neurological abnormalities in mammals with PLP1 duplications. We show, for the first time, intense microglial reactivity throughout the grey and white matter of a transgenic mouse line with increased copy number of the native Plp1 gene. Activated microglia in the white and grey matter of transgenic mice are found as early as postnatal day 7, before myelin commences in normal cerebra. This finding indicates that degeneration of myelin does not cause the microglial response. Microglial numbers are doubled due to in situ proliferation. Compared with the jp (jimpy) mouse, which has much more oligodendrocyte death and hardly any myelin, microglia in the overexpressors show a more dramatic microglial reactivity than jp, especially in the grey matter. Predictably, many classical markers of an inflammatory response, including TNF-α (tumour necrosis factor-α) and IL-6, are significantly up-regulated manyfold. Because inflammation is believed to contribute to axonal degeneration in multiple sclerosis and other neurodegenerative diseases, inflammation in mammals with increased Plp1 gene dosage may also contribute to axonal degeneration described in patients and rodents with PLP1 increased gene dosage.