[F4–06–02]: UPDATE OF THE AMYLOID HYPOTHESIS: COMPLEMENT MODULATES THE GLIAL RESPONSE TO Aβ PLAQUES AND MEDIATES SYNAPSE LOSS

Complement-mediated microglial synaptic pruning occurs in brain development and in response to amyloid-β (Aβ) oligomers in early pre-plaque stages of Alzheimer's disease (AD) as well as aging. We investigated whether complement mediates Aβ deposition and synapse loss at later, plaque-rich stages of AD. We crossbred APPswe/PS1dE9 transgenic mice with complement C3 knockout (C3 KO) mice and aged the males to 16 months. We compared APP/PS1;C3 KO mice with wildtype (WT), APP/PS1 and C3 KO mice in behavioral testing for cognitive flexibility (Water T Maze, WTM) and anxiety (Elevated Plus Maze, EPM). In addition, we assessed Aβ plaque load. gliosis, synaptic changes and neuron number in the hippocampus. Sixteen month-old male APP/PS1;C3 KO mice performed significantly better on a learning and memory task (WTM) than APP/PS1 mice and were less anxious (EPM), despite having more Aβ plaque deposition. In general, behavior in the APP/PS1;C3 KO mice was normalized to that of wildtype littermate control mice. Although the number of hippocampal glia did not change, microglia appeared to be less activated in the APP/PS1;C3 KO mice and fewer microglia and astrocytes moved into the plaque center. In support of the attenuation of the glial response to plaques, several pro-inflammatory cytokines were reduced in the APP/PS1;C3 KO mice. Hippocampal synapses were partially protected by C3-deficiency in APP/PS1 mice. Neuron loss was evident in the hippocampal CA3 region in 16 month-old APP/PS1 mice but spared in APP/PS1;C3 KO mice. Complement C3 or downstream complement activation fragments play a key role in the glial response to Aβ plaques and neuronal dysfunction.