Sialoadhesin promotes neuroinflammation-related disease progression in two mouse models of CLN disease

Glia
Janos GrohRudolf Martini

Abstract

CLN diseases are mostly fatal lysosomal storage diseases that lead to neurodegeneration in the CNS. We have previously shown that CD8+ T-lymphocytes contribute to axonal perturbation and neuron loss in the CNS of Ppt1(-/-) mice, a model of CLN1 disease. We now investigated the role of the inflammation-related cell adhesion molecule sialoadhesin (Sn) in Ppt1(-/-) and Cln3(-/-) mice, a model of the most frequent form, CLN3 disease. Microglia/macrophages in the CNS of both models showed an upregulation of Sn and markers for proinflammatory M1 polarization and antigen presentation. Sn+ microglia/macrophages associated with SMI32+ axonal spheroids and CD8+ T-lymphocytes. To analyze their pathogenic impact, we crossbred both models with Sn-deficient mice and scored axonal degeneration and neuronal integrity using immunohistochemistry, electron microscopy and optical coherence tomography. Degenerative alterations in the retinotectal pathway of Ppt1(-/-)Sn(-/-) and Cln3(-/-)Sn(-/-) mice were significantly reduced. Ppt1(-/-)Sn(-/-) mice also showed a substantially improved clinical phenotype and extended lifespan, attenuated numbers of M1-polarized microglia/macrophages and reduced expression levels of proinflammatory cytokines. This wa...Continue Reading

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Citations

Dec 12, 2018·The EMBO Journal·Enrique Gabandé-RodríguezMaría Dolores Ledesma
Jun 6, 2018·Frontiers in Molecular Neuroscience·Jian Jing Siew, Yijuang Chern
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Sep 16, 2019·Biochimica Et Biophysica Acta. Molecular Basis of Disease·Valerjans KaussDiego Luis Medina
Dec 15, 2019·Molecular Therapy. Nucleic Acids·Marianthi KaraliSandro Banfi

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