Presynaptic Vesicle Pool Size is Upregulated by Amyloid Beta Mutations Mediating an Increase in Spontaneous Synaptic Vesicle Release During Disease Progression

Alzheimer's Disease (AD) is a neurodegenerative disease that encompasses a combination of different protein mutations. The commonly studied amyloid beta mutations have the hallmark of plaques and tangles during neurodegeneration. Interestingly, different studies have shown that neurons expressing amyloid beta mutation also exhibit increases in spontaneous transmission and slower protein turnover during the early stages of the disease. These early-stage molecular level changes have been proposed to lead to hyperexcitability and synaptic plasticity alterations. However, no direct mechanistic pathway has been able to explain how molecular level changes lead to observed changes in synaptic transmission such as increased spontaneous release. Here, we introduce a recent model we developed, based on experimental results, that mechanistically explains how changes in presynaptic vesicle pools mediate spontaneous release. We use this model to show how amyloid beta mutations upregulate the number of synaptic vesicles and specific presynaptic proteins leading to observed increases in spontaneous release. These combined results show how molecular level changes directly lead to synapse and neuronal level functional changes.