Microglia and complement mediate early corticostriatal synapse loss and cognitive dysfunction in Huntington’s disease

Abstract

Huntington’s disease (HD) is a devastating monogenic neurodegenerative disease characterized by early, selective pathology in the basal ganglia despite the ubiquitous expression of mutant huntingtin. The molecular mechanisms underlying this region-specific neuronal degeneration and how these relate to the development of early cognitive phenotypes are poorly understood. Here we show that there is selective loss of synaptic connections between the cortex and striatum in postmortem tissue from patients with HD that is associated with the increased activation and localization of complement proteins, innate immune molecules, to these synaptic elements. We also found that levels of these secreted innate immune molecules are elevated in the cerebrospinal fluid of premanifest HD patients and correlate with established measures of disease burden.In preclinical genetic models of HD, we show that complement proteins mediate the selective elimination of corticostriatal synapses at an early stage in disease pathogenesis, marking them for removal by microglia, the brain’s resident macrophage population. This process requires mutant huntingtin to be expressed in both cortical and striatal neurons. Inhibition of this complement-dependent elimination mechanism through administration of a therapeutically relevant C1q function-blocking antibody or genetic ablation of a complement receptor on microglia prevented synapse loss, increased excitatory input to the striatum and rescued the early development of visual discrimination learning and cognitive flexibility deficits in these models. Together, our findings implicate microglia and the complement cascade in the selective, early degeneration of corticostriatal synapses and the development of cognitive deficits in presymptomatic HD; they also provide new preclinical data to support complement as a therapeutic target for early intervention.

A Fast-Binding, Functionally Reversible, COX-2 Radiotracer for CNS PET Imaging

“…To determine whether COX-2 levels might be elevated in neurodegenerative contexts, we decided to interrogate the zQ175 mouse model of Huntington’s disease. This mouse is thought to capture some of the earliest pathological events occurring in the presymptomatic phase of HD with synaptic dysfunction and the selective loss of corticostriatal synapses beginning at three months of agea time point that also coincides with the appearance of visual discrimination learning deficits . Both phenotypes have also recently been observed in presymptomatic HD patients. − We initially performed immunoblotting using extracts from this mouse from a disease-affected brain region (striatum) and a region that is relatively spared (cerebellum).…”

“…Translation of [ 11 C]BRD1158, which is a highly specific, brain penetrant COX-2 PET radiotracer, and parallel studies characterizing the mechanism through which COX-2 influences synaptic pathology will (i) enable the study of COX-2 expression changes and distribution in the living brain to monitor and characterize key pathophysiological events in HD and potentially any microglial dynamics that might be important in synaptic elimination mechanisms; 55 (ii) allow for patient stratification in novel brain-permeable COX-2 inhibitor clinical trials; (iii) provide a therapeutic imaging biomarker for monitoring response to new treatment strategies; and (iv) generate a translatable tool to evaluate the role of COX-2 in HD and potentially other neurodegenerative diseases in the living human brain.…”

Spatial and temporal profiling of the complement system uncovered novel functions of the alternative complement pathway in brain development

“…Although a role of the CP activation in normal brain development (Presumey et al, 2017;Schafer et al, 2012;Stephan et al, 2012;Stevens et al, 2007) and neurological diseases (Dalakas et al, 2020;Hong et al, 2016;Kjaeldgaard et al, 2018;Krance et al, 2021;Sekar et al, 2016;Shi et al, 2017;Watkins et al, 2016;Wilton et al, 2023;Yilmaz et al, 2021) have been widely reported, little is known about the LP and AP in the brain. Here, we provided transcriptional evidence arguing for an absence of the LP in the brain at steady state, another brain-specific aspect, based on the lack of expression LP serine proteases Masp1 and Masp2, and high-level expression of LP inhibitor, MAp44.…”

“…Cell type, temporal and spatial expression patterns of genes involved indicate non-redundant functions of the CP and AP. In addition, deficiency in Masp3-driven AP resulted in developmental and cognitive defects, indicating essential functions of the AP, an observation that highlights the necessity to disentangle differential involvement of the three complement activation pathways in development and diseases.Huntington's disease (Wilton et al, 2023), amyotrophic lateral sclerosis (ALS) (Kjaeldgaard et al, 2018), and multiple sclerosis (Watkins et al, 2016;Werneburg et al, 2020). However, unlike in the periphery, our understanding of the complement system in the brain remains incomplete.…”

“…Huntington's disease (Wilton et al, 2023), amyotrophic lateral sclerosis (ALS) (Kjaeldgaard et al, 2018), and multiple sclerosis (Watkins et al, 2016;Werneburg et al, 2020). However, unlike in the periphery, our understanding of the complement system in the brain remains incomplete.…”