Synaptic vesicle cycle and amyloid β: Biting the hand that feeds

The synaptic vesicle cycle (SVC) holds center stage in the biology of presynaptic terminals. Through recurrent exocytosis and endocytosis, it facilitates a sequence of events enabling chemical neurotransmission between functionally related neurons. As a fundamental process that links the interior of nerve cells with their environment, the SVC is also critical for signaling and provides an entry route for a range of pathogens and toxins, enabling detrimental effects. In Alzheimer's disease, the SVC is both the prime site of amyloid β production and toxicity. In this study, we discuss the emerging evidence for physiological and pathological effects of Aβ on various stages of the SVC, from postfusion membrane recovery to trafficking, docking, and priming of vesicles for fusion and transmitter release. Understanding of the mechanisms of Aβ interaction with the SVC within the unifying calcium hypothesis of aging and Alzheimer's disease should further elucidate the fundamental biology of the presynaptic terminal and reveal novel therapeutic targets for Alzheimer's disease and other age-related dementias.