ABSTRACT Chronic short sleep (CSS) is common in developed countries and yet is likely to be a key modifier of Alzheimer disease (AD), the most prevalent tauopathy in older adults. Sleep loss acutely increases tau in humans and in mice, and we have recently shown that CSS hastens the temporal progression of tauopathy in the P301S murine model of tauopathy, increasing all aspects of tauopathy, including soluble tau oligomers, pathologic tau aggregation, gliosis, neuron loss and neurobehavioral impairment. The fact that all aspects of tauopathy are impacted by sleep loss leads us to hypothesize that CSS targets a key upstream initiating factor. Hippocampal calcium/calmodulin dependent kinase II (HC CAMKII) neurons are among some of the most vulnerable neurons in AD and show early tau accumulation. We find that CSS massively increases calcium transients in HC CAMKII neurons, activates CAMKII and calpain, and induces uncompensated endoplasmic reticulum stress with loss of molecular chaperone BiP. Our overall hypothesis is that CSS results in excessive intracellular calcium bursts in HC CAMKII neurons, leading to sustained CAMKII and calpain activation, pathogenic tau modifications, and chronic uncompensated endoplasmic reticulum stress with loss of BiP that feeds back positively to perpetuate injury. Here we propose to critically test the role of each component of our working model in the biochemical, pathological and behavioral aspects of tauopathy and CSS-hastening of tauopathy in the P301S model. In Aim 1, we will test the role of CSS-increased calcium and calpain in HC CAMKII neurons in the CSS HC tau changes by genetically suppressing local HC CAMKII calcium and calpain, while verifying suppressed calcium transients with in vivo calcium imaging of CAMKII neurons. In Aim 2, using pharmacologic inhibition and conditional HC transgenic knock down of CAMKII across CSS, we will determine to what role CAMKII induces CSS-induced HC ER stress and CSS effects on tauopathy, and in Aim 3, we will critically test the role of CSS-reduced BiP in the temporal progression of tauopathy and CSS effects on tauopathy. Collectively, the proposed studies will identify important in vivo mechanisms by which CSS hastens the temporal progression of tauopathy and will substantiate therapeutic avenues to lessen CSS exacerbation of tauopathy and tauopathy progression in general.