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.

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Within the vertebrate neocortex and other telencephalic structures, molecularly-defined neurons tend to segregate at first order into inhibitory (GABAergic) and excitatory (glutamatergic) types. We used single-nucleus RNA sequencing, analyzing over 2.4 million brain cells sampled from 16 locations in a primate (the common marmoset) to ask whether (1) neurons generally segregate by neurotransmitter status, and (2) neurons expressing the same neurotransmitters share additional molecular features in common, beyond the few genes directly responsible for neurotransmitter synthesis and release. Unexpectedly, we find the answer to both is "no": there is a surprising degree of transcriptional similarity between GABAergic and glutamatergic neurons found in the same brain structure, and there is generally little in common between glutamatergic neurons residing in phylogenetically divergent brain structures. The origin effect is permanent: we find that cell types that cross cephalic boundaries in development retain the transcriptional identities of their birthplaces. GABAergic interneurons, which migrate widely, follow highly specialized and distinct distributions in striatum and neocortex. We use interneuron-restricted AAVs to reveal the morphological diversity of molecularly defined types. Our analyses expose how lineage and functional class sculpt the transcriptional identity and biodistribution of primate neurons.