Disruption of neuronal signaling in Alzheimer’s disease and rescue by manipulating the innate immune receptor PirB

项目总结

Project Summary Alzheimer’s disease (AD) is becoming more prevalent as our population ages and is characterized by devastating memory loss and cognitive impairment. The pruning of neuronal synapses contributes to the pathology of AD and is the best correlate of cognitive decline. Both oligomeric amyloid beta and neuroinflammatory mechanisms can lead to synapse pruning in AD. While neurons and immune cells have been shown to interact to drive pruning, the neuronal signaling downstream of this interaction is not well understood. A major goal of this proposal is to determine neuronal signaling mechanisms driving synapse pruning in mouse models of autosomal dominant AD at two ages and under varying conditions of both aggregated amyloid beta and immune activation. Synapse pruning occurs naturally throughout development, and one hypothesis is that developmental pruning mechanisms are dysregulated in AD. The Shatz lab made the surprising discovery that the innate immune receptor, PirB, is expressed in neurons and has roles in synapse pruning over development. In addition, PirB knockout in adult mice, either globally or in excitatory neurons alone, facilitates the rapid growth of new synapses and re-opens critical period-like synaptic plasticity. PirB and its human homologue, LilrB2, have both been shown to bind amyloid beta at high affinities, and germline global PirB knockout was shown to protect against memory loss in the APP/PS1 mouse model of AD. While global germline knockout was protective, in a therapeutic context, it is also important to determine the effect of PirB blockade in normally reared adult mice at various stages of disease progression. In addition, while the Shatz lab identified a signaling pathway linking PirB to synapse pruning, via the dephosphorylation of cofilin, no other signaling pathways have been examined downstream of PirB in APP/PS1 mice. Here, I propose to test the hypothesis that neuronal gene expression is dysregulated in AD model mice and can be restored with PirB KO, protecting against synapse loss. The experiments proposed should identify new signaling pathways in neurons and at synapses downstream of PirB in AD model mice. I also propose to block PirB in normally reared adult APP/PS1 mice to determine the therapeutic potential of PirB/LilrB2 blockade in AD. I focus on two stages of disease progression: 1) early, before plaque formation but when synaptic and memory deficits have been reported, and 2) late, after plaque formation and heightened immune activation. The central goal of this proposal is to use transcriptomic, biochemical, electrophysiological, and behavioral techniques to elucidate signaling pathways downstream of PirB/LilrB2 in AD and demonstrate the therapeutic potential of PirB blockade to ‘treat’ memory loss in APP/PS1 model mice. The long-term aim of this research is to contribute to our understanding of the signaling mechanisms leading to synaptic pruning in Alzheimer’s disease, as a first step toward finding potential therapies and therapeutic targets.