This talk will cover our recent progress in understanding mechanisms of neurodegeneration and how this is informing new therapeutic approaches. The central concept is the identification of common pathways across the spectrum of these disorders (which include Alzheimer ’s and related diseases) that are relevant for both mechanistic insights and therapy. These include both ‘toxic’ processes that can be targeted to prevent neuronal death, and regenerative processes that can be harnessed for repair. I will discuss our data in mouse models targeting both of these aspects to prevent neurodegeneration and their relevance for human disease. I will focus on modulating the Unfolded Protein Response pharmacolog- ically and the recent discovery of repurposed drugs ready for clinical trials. I will also discuss the strategy of harnessing pathways that drive synapse regeneration, as occurs in hibernation, for the therapy of neurodegeneration.