Evidence that Alzheimer's Disease Is a Disease of Competitive Synaptic Plasticity Gone Awry

Mounting evidence indicates that a physiological function of amyloid-beta (A beta) is to mediate neural activity-dependent homeostatic and competitive synaptic plasticity in the brain. I have previously summarized the lines of evidence supporting this hypothesis and highlighted the similarities between A beta and anti-microbial peptides in mediating cell/synapse competition. In cell competition, anti-microbial peptides deploy a multitude of mechanisms to ensure both self-protection and competitor elimination. Here I review recent studies showing that similar mechanisms are at play in A beta-mediated synapse competition and perturbations in these mechanisms underpin Alzheimer's disease (AD). Specifically, I discuss evidence that A beta and ApoE, two crucial players in AD, co-operate in the regulation of synapse competition. Glial ApoE promotes self-protection by increasing the production of trophic monomeric A beta and inhibiting its assembly into toxic oligomers. Conversely, A beta oligomers, once assembled, promote the elimination of competitor synapses via direct toxic activity and amplification of "eat-me" signals promoting the elimination of weak synapses. I further summarize evidence that neuronal ApoE may be part of a gene regulatory network that normally promotes competitive plasticity, explaining the selective vulnerability of ApoE expressing neurons in AD brains. Lastly, I discuss evidence that sleep may be key to A beta-orchestrated plasticity, in which sleep is not only induced by A beta but is also required for A beta-mediated plasticity, underlining the link between sleep and AD. Together, these results strongly argue that AD is a disease of competitive synaptic plasticity gone awry, a novel perspective that may promote AD research.