A study published in the Journal of Neuroinflammation reports the therapeutic potential of SEMA4D antibody blockade to regulate glial cell function and reduce neuronal toxicity and dysfunction in neurodegenerative diseases.
]. However, the sources of SEMA4D ligand in brain, as well as its possible role in triggering reactive astrocytes and their contribution to neurodegenerative processes have not been fully described. Here, we characterize SEMA4D expression in neurodegenerative disease settings of HD and AD, and report SEMA4D-induced changes in cytoskeletal morphology and regulation of key receptors and enzymes required for normal astrocytic functions in glucose metabolism and neurotransmitter recycling.
We previously reported a role for SEMA4D in a preclinical model of HD. PLXN receptors are expressed in GFAP+ striatal astrocytes in YAC128 HD transgenic mice. In addition, treatment with an anti-SEMA4D antibody reduced anxiety-like behavior and cognitive deficits, as evidenced by rescue of spatial memory and learning, along with significant reduction in brain atrophy and preservation of healthy medium spiny neurons, as indicated by DARPP-32 immunoreactivity in this model [].
These studies indicate that SEMA4D is sparsely expressed in normal brain, but is upregulated in neurons during disease progression in both mouse models and human disease. Increased expression of SEMA4D ligand was associated with changes in astrocyte morphology and downregulation of GS expression, a previously described marker of reactive astrocytes [] that is associated with impairment of neurotransmitter recycling, a key astrocytic function.
Immunofluorescence staining of human tissue sections were performed for human semaphorin 4D , glutamine synthetase , HuC/HuD and GFAP in accordance with manufacturer-recommended concentrations combining host-dependent secondary Alexa Fluor antibodies.Imaging of stained tissue sections were performed on AxioObserver7 Automated Inverted Microscope System with EC Plan-Neofluar × 10/0.30 and Objective Plan-Apochromat ×20/0.8.
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