Semaphorin 4D is upregulated in neurons of diseased brains and triggers astrocyte reactivity

Abstract

Background The close interaction and interdependence of astrocytes and neurons allows for the possibility that astrocyte dysfunction contributes to and amplifies neurodegenerative pathology. Molecular pathways that trigger reactive astrocytes may represent important targets to preserve normal homeostatic maintenance and modify disease progression. Methods Semaphorin 4D (SEMA4D) expression in the context of disease-associated neuropathology was assessed in postmortem brain sections of patients with Huntington’s (HD) and Alzheimer’s disease (AD), as well as in mouse models of HD (zQ175) and AD (CVN; APPSwDI/NOS2−/−) by immunohistochemistry. Effects of SEMA4D antibody blockade were assessed in purified astrocyte cultures and in the CVN mouse AD model. CVN mice were treated weekly from 26 to 38 weeks of age; thereafter mice underwent cognitive assessment and brains were collected for histopathology. Results We report here that SEMA4D is upregulated in neurons during progression of neurodegenerative diseases and is a trigger of reactive astrocytes. Evidence of reactive astrocytes in close proximity to neurons expressing SEMA4D is detected in brain sections of patients and mouse models of HD and AD. We further report that SEMA4D-blockade prevents characteristic loss of GABAergic synapses and restores spatial memory and learning in CVN mice, a disease model that appears to reproduce many features of AD-like pathology including neuroinflammation. In vitro mechanistic studies demonstrate that astrocytes express cognate receptors for SEMA4D and that ligand binding triggers morphological variations, and changes in expression of key membrane receptors and enzymes characteristic of reactive astrocytes. These changes include reductions in EAAT-2 glutamate transporter and glutamine synthetase, key enzymes in neurotransmitter recycling, as well as reduced GLUT-1 glucose and MCT-4 lactate transporters, that allow astrocytes to couple energy metabolism with synaptic activity. Antibody blockade of SEMA4D prevented these changes and reversed functional deficits in glucose uptake. Conclusions Collectively, these results suggest that SEMA4D blockade may ameliorate disease pathology by preserving normal astrocyte function and reducing the negative consequences of reactive astrogliosis.

Systematic analysis of cellular crosstalk reveals a role for SEMA6D-TREM2 regulating microglial function in Alzheimer’s disease

“…Importantly, this study found that TREM2, PLXNA1, and DAP12 co-immunoprecipitate in a TREM2-dependent manner, consistent with the formation of a complex ( 30 , 31 ). Furthermore, additional studies also linked plexin-semaphorin signaling to immune activation and neurodegeneration ( 5 , 22 – 24 , 32 ). Given this role for SEMA6D in the immune activation of myeloid cells, we aimed to test the potential role of the SEMA6D-TREM2/PLXNA1 signaling axis in AD.…”

Sema7A and Sema4D Heterodimerization is Essential for Membrane Targeting and Neocortical Wiring

“…Similarly, neurons express higher levels of Sema4D in Alzheimer's and Huntington's disease, and its blockade can reduce astrocyte reactivity 70 .…”

Conclusions of the SIGNAL study in Huntington and implications for treatment of other slowly progressive neurodegenerative diseases

“… 5 We, therefore, investigated expression of SEMA4D and its receptors under disease conditions in neurons and astrocytes. 4 We made the following observations: SEMA4D staining of post‐mortem sections from normal human control and from people with HD and AD demonstrated significantly increased SEMA4D expression in neurons during disease progression in brain regions of three different patients at each of HD pathological stages 0, 1, and 2 as well as in advanced AD. plexin‐B1 and plexin‐B2 receptors are highly expressed on astrocytes intimately associated with neurons in brain.…”

“…In two recent publications, 3 . 4 we investigated the signals that trigger the striking morphological transformation of astrocytes. Based on the previous work of our own and others, we were aware of the important role of the semaphorin 4D:plexin‐B1/B2 pathway in triggering collapse of the actin cytoskeleton.…”

“…SEMA4D blocking‐antibody prevents these effects. 4 Because of the important role of astrocytes in glucose transport, we investigated the effect of treatment with our humanised anti‐SEMA4D antibody, pepinemab, on Fluorodeoxyglucose–positron‐emission tomography (FDG‐PET) in different brain regions of patients with early manifest HD, based on diagnostic confidence level and total functional capacity score of 11–13 (top of the scale). As previously reported for HD and other slowly progressive neurodegenerative diseases, FDG‐PET SUVR declines over 18 months progression across almost all brain regions of patients treated with placebo.…”