For Alzheimer?s disease (AD), a range of pathological, genetic and biomarker data supports the hypothesis that Amyloid beta (A?) peptide triggers the disease process. As AD progresses over decades, subsequent Tau pathology and inflammatory reaction occur during progressive cognitive decline to dementia and death. Symptoms are tightly linked to the loss of neuronal synapses in the brain, but the mechanisms causing synapses to be removed are less clear. Recent data implicate innate immunity, microglia cells and complement proteins in synaptic engulfment. However, the molecular mechanism by which complement proteins accumulate focally and tag specific synapses for removal in AD remains unknown. In addition, the misfolded aggregated peptides, A? and Tau, are known to interact with synapses and cause dysfunction. We hypothesize that the tagging of synapses with microglia-derived complement components for subsequent engulfment is coupled with synapse-specific derangements driven by neuronal interaction with misfolded protein accumulation. We will examine the connection between synaptic damage signals and complement recruitment. Preliminary studies show that interruption of synaptic signaling by PrPC or mGluR5 prevents both C1q tagging and loss of synapses in AD mice, despite persistent microgliosis and complement overproduction. We will examine the specificity, timing and genetic necessity of a link between complement and the A?o/PrPC/mGluR5 complex for synapse tagging and engulfment. Mechanistically, we find that C1q and C1qBP physically associate with hydrogels composed of A?o/PrPC/mGluR5, and this may provide a direct means for C1q selectivity. We will test this possibility by biochemical and cellular analysis, and by genetic studies in mice. Alternatively, synaptic signaling triggered by A? or Tau may regulate other molecules, which in turn recruit C1q. An arrayed expression cloning screen for C1q binding sites revealed a novel high affinity neuronal protein binding C1q. We will test the role of this binding site in C1q tagging of synapses, and in the loss of synapses in neurodegenerative and developmental models.
Disease-modifying therapy for Alzheimer?s disease (AD) is a massive and urgent unmet medical need. Cognitive failure stems most directly from neuronal synapse loss during mild cognitive impairment and mild AD. Innate immune mechanisms release complement proteins, which then tag specific neuronal synapses for removal. Here, we seek to define the molecular mechanisms at specific neuronal synapses which instruct the recruitment of complement proteins to trigger synapse loss. By understanding synaptic clearance mechanisms, we aim to develop the means to preserve synaptic number and function in AD.