Investigating Mechanisms of Complement Mediated Synaptic Removal - Project Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder that culminates in neurodegeneration resulting in
cognitive decline. The pathological correlate most tightly associated with cognitive decline in AD is synapse
loss. Synaptic loss occurs in early-stage AD patients and progresses over time. The presence of pathological
tau significantly correlates with synapse loss and cognitive decline in AD, and synapse loss is present in all
models of tauopathy. It is unclear how pathological tau causes synapse loss, however neuroinflammation,
including activation of microglia and the complement cascade, may play a causative role. The complement
system, and specifically complement C1q, is used by the central nervous system to coordinate the removal of
synapses. Within the brain, complement C1q coats the membrane of weak or damaged synapses, resulting in
phagocytic removal of tagged synapses by microglia. In the AD brain there is an increase in C1q-mediated
synaptic pruning resulting in synapse loss. Importantly, complement activation and synapse loss correlate with
the deposition of pathological tau. We hypothesize that a tau-induced insult initiates a synaptic profile
that attracts C1q to coat synapses for removal. The mechanisms by which C1q recognizes tau-affected
synapses are unclear. Synaptic deposition of C1q requires presentation of a C1q-binding partner in the outer
membrane of weak/damaged synapses. In addition, cells normally express complement regulatory proteins
that prevent the synaptic deposition of C1q. Thus, tau-induced synaptic changes that recruit C1q to the
synaptic membrane could include 1) the presentation of disease-specific C1q binding partners, and/or 2) a
decrease in the expression of complement inhibitory regulators. We will investigate both possibilities in the
PS19 mouse model of tauopathy. To identify potential C1q interacting partners, synaptosomes will be isolated
from the hippocampus of PS19 or wild type (WT) mice and C1q will be immunoprecipitated from
synaptosomes. Mass spectrometry will be used to identify protein and lipid interacting partners that co-
immunoprecipitate with C1q. C1q interacting partners identified by mass spec will be verified biochemically and
histologically in PS19 mice and early-stage post-mortem human AD tissue. To determine the effect of
tauopathy on synaptic complement regulatory proteins, we will isolate C1q+ synaptosomes from PS19 or WT
mice at 1, 3 and 6 months of age and quantify complement regulators. Changes in complement regulators will
be correlated to changes in pathological tau. Changes in complement regulators in PS19 mice will be
confirmed in early-stage post-mortem human AD tissue. Successful completion of these aims will identify the
molecular mechanisms of complement mediated synaptic pruning in response to tauopathy. Preventing
synaptic loss in early-stage AD patients could preserve cognitive function and improve quality of life.
