Alzheimer's disease (AD) is a major cause of dementia worldwide. Increasing age is the major risk factor for AD but the mechanisms are not clear. Genetic factors also contribute to increased susceptibility for AD including variations in immune-related genes including TREM2, Complement receptor 1 (CR1) and CD33; however, the role of the immune system AD has also not been determined. The complement cascade, part of innate immunity, has been strongly implicated in AD pathogenesis and inhibiting complement components has been shown to lessen AD-relevant phenotypes in multiple mouse models of AD. Our data suggests that complement-expressing myeloid cells (resident microglia and/or infiltrating macrophages) actively prune synapses and cause glia-vascular breakdown during aging and early AD. We have developed specific resources to test the role of complement in AD. We have developed the first conditional allele for C1qa to enable genetic ablation of C1qa in specific cell types. Furthermore, to achieve our goals, we have assembled a multidisciplinary team that includes neuroscientists, immunologists and computational biologists from Harvard University and The Jackson Laboratory. We will use genomic, molecular and imaging approaches to fully characterize C1QA+ myeloid cells in aging and AD mouse models. We will also use genetic and pharmacological approaches to determine whether these cells play beneficial or damaging roles in aging and AD. We have three aims:
In Aim 1 we will characterize immune cells in relation to vascular compromise and synapse loss in aging and AD. Our preliminary data suggests that vascular compromise and myeloid activation are critical age-related events that contribute to an increased susceptibility to AD. To test this, we will spatiall and temporally characterize C1QA+ myeloid cells by both transcriptional profiling and the use of transgenic reporter strains. To functional test the importance of vascular compromise and myeloid activation in AD, we will use an acute A? model in young and aged mice.
In Aim 2, we will examine whether C1QA+ myeloid cells actively prune synapses in aging and AD. Our data strongly supports a role for microglia (and other myeloid cells) in pruning synapses during very early stages of AD. We also predict this pruning occurs during aging, increasing susceptibility for developing AD. We will use 3D two-photon imaging in awake, behaving mice to test whether microglia actively engulf intact synapses when challenged with A? oligomers and whether they engulf specific synapses targeted by A?. We will also determine whether age increases the risk of aberrant synaptic pruning by microglia and whether engulfing cells are of resident or peripheral origin.
In Aim 3, we will specifically test whether myeloid or neuronal C1qa plays damaging or protective role(s) in vascular compromise and synapse loss. We will use a combination of genetic (conditional KO for C1qa) and pharmacological (complement C1q blocking antibody) in aged mice and multiple models relevant to AD to explore the potential of targeting C1q as a treatment for AD.

Public Health Relevance

Alzheimer's disease (AD) is the leading cause of dementia estimated to affect 50 million people worldwide. No treatments are clinically approved. We, and others, have established that the complement pathway plays an important role early in the disease and in aging, the major risk factor for AD. We will fully investigate the role of complement proteins in immune cells in aging and AD using genetic and genomic approaches. This work will determine exactly how the complement pathway influences AD and aging and provide new avenues for therapies.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Multi-Year Funded Research Project Grant (RF1)
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Special Emphasis Panel (ZAG1)
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Wise, Bradley C
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Jackson Laboratory
Bar Harbor
United States
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Soto, Ileana; Grabowska, Weronika A; Onos, Kristen D et al. (2016) Meox2 haploinsufficiency increases neuronal cell loss in a mouse model of Alzheimer's disease. Neurobiol Aging 42:50-60
Hong, Soyon; Beja-Glasser, Victoria F; Nfonoyim, Bianca M et al. (2016) Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science 352:712-716
Onos, Kristen D; Sukoff Rizzo, Stacey J; Howell, Gareth R et al. (2016) Toward more predictive genetic mouse models of Alzheimer's disease. Brain Res Bull 122:1-11