Microglia Mediate Early Corticostriatal Synapse Loss and Cognitive Dysfunction in Huntington’s Disease Through Complement-Dependent Mechanisms

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 HD patients that is associated with the increased activation and localization of complement proteins, innate immune molecules, to markers of these synaptic elements. We also find that levels of these secreted innate immune molecules are elevated in the CSF 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 and 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, and also provide new preclinical data to support complement as a therapeutic target for early intervention.

The neuronal pentraxin Nptx2 regulates complement activity and restrains microglia-mediated synapse loss in neurodegeneration

“…This process is overactivated in several central nervous system (CNS) diseases, including AD, virus-induced synapse loss, frontotemporal dementia (FTD), Huntington's disease, and perhaps schizophrenia, leading to synapse loss and subsequent cognitive decline (6)(7)(8)(9)(10)(11)(12). Blocking C1q binding to neurons is sufficient to attenuate synapse loss in mouse models of AD, FTD, and Huntington's disease (7,11,13).…”

Deletion of the microglial transmembrane immune signaling adaptor TYROBP ameliorates Huntington’s disease mouse phenotype

“…Increased CD68 content in Q175 may point to an aberrant excess of phagocytosis or, in contrast, a reflection of an overwhelmed phagolysosome system incapable of processing the phagocytosed material. In many neurodegenerative diseases, including HD, aberrant microglia engulf and eliminate synapses in a non-physiological manner, leading to synaptic deficits [33,34]. Here, we evaluated post-synaptic density 95 (PSD-95) protein levels and estimated the density of PSD-95 immunopositive puncta in striatum in our four groups of mice.…”

Early whole-body mutant huntingtin lowering averts changes in proteins and lipids important for synapse function and white matter maintenance in the LacQ140 mouse model

“…Normally found on the inner leaflet of the plasma membrane, PS can be externalized by apoptotic cells to signal for removal (Williamson and Schlegel, 2002) and in neuronal synapses externalized PS signals to microglia for synaptic pruning (Scott-Hewitt et al, 2020). Microglial activation occurs in HD post-mortem brain (Sapp et al, 2001) and increased pruning by microglia may contribute to synaptic loss in R6/2 HD striatum (Savage et al, 2020) and in zQ175 and BACHD mice as well as HD brain (Wilton et al, 2021). An overall increase in PS could inadvertently mark synapses for engulfment by microglia.…”