Premium
Microglial reduction of colony stimulating factor‐1 receptor expression is sufficient to confer adult onset leukodystrophy
Author(s) -
Biundo Fabrizio,
Chitu Violeta,
Shlager Gabriel G. L.,
Park Eun S.,
Gulinello Maria E.,
Saha Kusumika,
Ketchum Harmony C.,
Fernandes Christopher,
Gökhan Şölen,
Mehler Mark F.,
Stanley E. Richard
Publication year - 2021
Publication title -
glia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.954
H-Index - 164
eISSN - 1098-1136
pISSN - 0894-1491
DOI - 10.1002/glia.23929
Subject(s) - microglia , leukodystrophy , biology , neurodegeneration , neuroscience , neuroglia , pathology , leukoencephalopathy , central nervous system , disease , immunology , inflammation , medicine
Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is a dementia resulting from dominantly inherited CSF1R inactivating mutations. The Csf1r +/− mouse mimics ALSP symptoms and pathology. Csf1r is mainly expressed in microglia, but also in cortical layer V neurons that are gradually lost in Csf1r+/− mice with age. We therefore examined whether microglial or neuronal Csf1r loss caused neurodegeneration in Csf1r+/− mice. The behavioral deficits, pathologies and elevation of Csf2 expression contributing to disease, previously described in the Csf1r +/− ALSP mouse, were reproduced by microglial deletion ( MCsf1r het mice), but not by neural deletion. Furthermore, increased Csf2 expression by callosal astrocytes, oligodendrocytes, and microglia was observed in Csf1r +/− mice and, in MCsf1r het mice, the densities of these three cell types were increased in supraventricular patches displaying activated microglia, an early site of disease pathology. These data confirm that ALSP is a primary microgliopathy and inform future therapeutic and experimental approaches.