PROJECT SUMMARY
Alzheimer’s disease (AD) is a major cause of dementia worldwide. Increasing age is the major risk of 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 spatially 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 Aß oligomers and whether they engulf specific synapses targeted by Aß. 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.
