Presenilin 1 Increases Association with Synaptotagmin 1 During Normal Aging

Abstract Presenilin 1 (PS1), the catalytic component of gamma secretase, associates with Synaptotagmin 1 (Syt-1). This interaction is decreased in the brains of sporadic Alzheimer’s disease (AD) patients. However, it remains unclear how this interaction changes during normal aging. Because aging is a risk factor for AD, we sought to identify changes in PS1 and Syt-1 association during aging in primary neurons in vitro and mouse brain sections ex vivo. We also tested the effect of aging on the calcium dependence of the interaction by treating neurons aged in vitro with KCl. We found that PS1 and Syt-1 increase their association with age, an effect that is more robust in neuronal processes than cell bodies. Treatment with KCl triggered the interaction in both young and old neurons. Baseline calcium levels as well as calcium influx in response to KCl treatment were significantly higher in older neurons, which can partially explain the increase in PS1/Syt-1 binding with age. These results suggest a compensatory mechanism during normal aging to offset detrimental age-associated effects.