Convergence of signals for pruning at a synaptic receptor implicated in Alzheimer's disease

Memories are stored at synapses and circuits, which tragically are pruned and deconstructed in Alzheimer's disease (AD). Genetic mutations including APP generate high levels of soluble oligomeric beta amyloid (oAbeta42), leading to insoluble beta amyloid plaques - hallmarks of late-stage disease. Clinical trials have designed "plaque-busting" drugs assuming that plaques cause disease. However, disappointing outcomes demand new approaches. Inflammation is also an AD risk factor, including complement cascade molecules. This team has discovered that complement C4 cleavage generates a fragment that binds with high affinity to human LilrB2/mouse PirB, a receptor in brain needed for pruning. Human genetic studies identify LilrB2 as a significant AD risk locus. PirB/LilrB2 is also a known receptor for oAbeta42. Here the team proposes that PirB/LilrB2 receptor is a convergence point for binding both oAbeta42 and C4 fragment, and that these 3 molecules are located at synapses to drive excessive synapse loss. Our work implies that treatments targeting just amyloid plaques not only happen too late but also do not recognize the possibility that even if oAbeta is targeted, a known pruning receptor for complement remains: the receptor should be targeted. This research can illuminate new ways of thinking about AD mechanisms, leading to new therapeutic approaches.