Synaptic Transmission Dynamically Modulates Interstitial Fluid Amyloid-β Levels

Abstract

Aggregation of amyloid-β (Aβ)within the extracellular space of the brain into soluble and insoluble forms is central to the pathogenesis of Alzheimer’s disease. Aβ is produced in neurons by cleavage of the amyloid precursor protein (APP) subsequent to release into the brain interstitial fluid (ISF). While a substantial amount is known about APP processing, the mechanisms that regulateAβrelease andthatmodulate soluble ISFAβlevels are less clear. Several studies have suggested that postsynaptic receptor activation can alter APP processing. In vitro studies have demonstrated that synaptic activity canmodulateAβ levels in themedia of cultured neurons as well.We used in vivo microdialysis to assess ISF Aβ levels in awake, behaving mice while altering hippocampal synaptic activity both pharmacologically and electrically. Electrical stimulation increased neuronal activity and rapidly increased ISF Aβ levels. In contrast, when hippocampal synaptic activity was inhibited with agents such as TTX and tetanus toxin, ISF Aβ levels were significantly reduced within hours of treatment. Using acute brain slices, we demonstrate that synaptic vesicle cycling alone, in the absence of presynaptic or postsynaptic depolarization, drives the release ofAβ fromneurons.BecauseAβ is not localizedwithin synaptic vesicles, it is likely that an event closely associated with vesicle fusion and exocytosis is the key link between synaptic transmission and Aβ release.We propose that synaptic vesicle membrane endocytosis results in more APP endocytosis, thereby increasing Aβ generation and subsequent Aβ release into the extracellular space.These data have important implications for understanding the relationship between synaptic activity and Aβ levels. This relationship will likely also inform our understanding of the pathogenesis and treatment of Alzheimer’s disease.