Complement and microglia mediate early synapse loss in Alzheimer mouse models

Abstract

Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3 or the microglial complement receptor CR3, reduces the number of phagocytic microglia as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation (LTP). Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD.

Microglial dysfunction as a key pathological change in adrenomyeloneuropathy

“…Colocalization of C1q and synaptophysin in Abcd1 –/– mice of different ages suggests that microglia mediate synaptic pruning. During postnatal development and in the normal aging process, the complement pathway plays a critical role in the refinement of neural circuits 10, 33, 34, 35, 36. In AMN, abnormal synaptic pruning attributed to excessive microglial activation may instead promote neurodegeneration, as also observed in many neurodegenerative disease models 10, 36…”

“…ABCD1 is not uniformly expressed across different cell types 9. How can axons be affected when ABCD1 is only expressed in neurons at very low levels?9 Microglia have recently been implicated as potential cellular mediators of synapse loss 10. Specific transcriptional and functional alterations of microglia vary in each neurological disease depending on pathology and type of molecular stimuli encountered 11.…”

Glial and Neuroimmune Mechanisms as Critical Modulators of Drug Use and Abuse

“…Glial and neuroimmune mechanisms have been extensively characterized in the context of pathological pain (Grace et al, 2014a), while researchers attempting to decode the complex etiology of neurodegenerative disorders such as Alzheimer's disease have also argued for a more holistic framework, where the interactions and compensatory responses between neurons, glia, and vascular cells all contribute to the progression of the disease (De Strooper and Karran, 2016). Given their role in immune surveillance and debris clearance, it is perhaps unsurprising that microglial activation in particular has been implicated in neurodegenerative diseases beyond Alzheimer's disease, including multiple sclerosis and Parkinson's disease (Chung et al, 2015b;Heneka et al, 2015;Hong et al, 2016). As evidence accumulates positioning glia as critical for synapse maturity and elimination, many have speculated that glia and immune signaling are associated with many neuropsychiatric disorders, from stress-related conditions such as depression (Hodes et al, 2015;Miller and Raison, 2015), to neurodevelopmental disorders such as autism and schizophrenia (Gupta et al, 2014;Sekar et al, 2016;Werling et al, 2016).…”

Role of microglia in fungal infections of the central nervous system

“…For instance, C1q is expressed in microglia and abundantly found in brain tissue, playing a major role in neurodegenerative diseases such as Alzheimer's disease. 89 This is an exciting and promising area of investigation considering the predilection of C. neoformans for the CNS and the importance microglia and complement may play in preventing fungal brain colonization. 90 …”