Abstract
The innate immune system plays an integral role in the brain. Synaptic pruning, a fundamental process in developmental circuit refinement, is partially mediated by neuroimmune signalling at the synapse. In particular, microglia, the major tissue-resident macrophages of the brain, and the classical complement cascade, an innate immune pathway that aids in the clearance of unwanted material, have been implicated in mediating synapse elimination. Emerging data suggest that improper signalling of the innate immune pathway at the synapse leads to pathological synapse loss in age-related neurodegenerative diseases, including Alzheimer’s disease. Now the key questions are whether synapses are targeted by complement and, if so, which synapses are vulnerable to elimination. Here, we review recent work implicating C1q, the initiator of the classical complement cascade, and surrounding glia as mediators of synapse loss. We examine how synapses could undergo apoptosis-like pathways in the Alzheimer brain, which may lead to the externalisation of phosphatidylserine on synapses. Finally, we discuss potential roles for microglia and astrocytes in this ‘synaptic apoptosis’. Critical insight into neuroimmune regulatory pathways on synapses will be key to developing effective targets against pathological synapse loss in dementia.
Highlights
Genetic studies in Alzheimer’s disease (AD) implicate microglia, the major resident immune cells of the brain, as modulators for the risk of dementia[1,2,3,4,5]
Emerging data suggest that immune mechanisms involving classical complement cascade are critical for synaptic homeostasis, raising the key question of whether certain synapses are targeted for elimination by glia
We postulate several pathways, including caspase-3 activation and mitochondrial dysfunction, that may lead to the externalisation of PtdSer on synapses (Figure 1)
Summary
Genetic studies in Alzheimer’s disease (AD) implicate microglia, the major resident immune cells of the brain, as modulators for the risk of dementia[1,2,3,4,5]. One proposed mechanism for the microglia-mediated synapse loss involves a region-specific reactivation of an innate immune pathway called the classical complement cascade, which has been shown to play a critical role in developmental synaptic pruning[12,13]. Cleaved caspase-3 levels are increased in post-synaptic densities from post-mortem AD human brains[72] and in hippocampal synaptosomes of pre-plaque Tg2576 hAPP mice at the onset of memory decline and spine loss[15] These findings collectively suggest that caspase-3 activity contributes to the loss and dysfunction of dendritic spines in AD models and support the notion of focal apoptotic cascades at synapses (that is, ‘synaptosis’)[73,74]. Some intriguing questions are whether the changes of expression of these molecules involved in PtdSer recognition impair the ability of microglia or astrocytes to effectively respond to damaged synapses and neurons and whether they trigger the aberrant removal of otherwise healthy synapses
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