Affiliations: [a] Department of Drug Sciences, Pharmacology Section, University of Pavia, Italy
| [b]
Scuola Universitaria Superiore IUSS, Pavia, Italy
Correspondence:
[*]
Correspondence to: Elizabeth M. Rhea, Veterans Affairs Puget Sound Health Care System, 1660S. Columbian Way, Seattle, WA 98106, USA. Correspondence to: Stefano Govoni, PhD, Department of Drug Sciences, Pharmacology Section, University of Pavia, Viale Taramelli 14 - 27100, Pavia, Italy. Tel.: +39 0382 987 394; E-mail: [email protected].
Note: [1] These authors contributed equally to this work.
Abstract: It is now more than two decades since amyloid-β (Aβ), the proteolytic product of the amyloid-β protein precursor (AβPP), was first demonstrated to be a normal and soluble product of neuronal metabolism. To date, despite a growing body of evidence suggests its regulatory role on synaptic function, the exact cellular and molecular pathways involved in Aβ-driven synaptic effects remain elusive. This review provides an overview of the mounting evidence showing Aβ-mediated effects on presynaptic functions and neurotransmitter release from axon terminals, focusing on its interaction with synaptic vesicle cycle. Indeed, Aβ peptides have been found to interact with key presynaptic scaffold proteins and kinases affecting the consequential steps of the synaptic vesicle dynamics (e.g., synaptic vesicles exocytosis, endocytosis, and trafficking). Defects in the fine-tuning of synaptic vesicle cycle by Aβ and deregulation of key molecules and kinases, which orchestrate synaptic vesicle availability, may alter synaptic homeostasis, possibly contributing to synaptic loss and cognitive decline. Elucidating the presynaptic mechanisms by which Aβ regulate synaptic transmission is fundamental for a deeper comprehension of the biology of presynaptic terminals as well as of Aβ-driven early synaptic defects occurring in prodromal stage of AD. Moreover, a better understating of Aβ involvement in cellular signal pathways may allow to set up more effective therapeutic interventions by detecting relevant molecular mechanisms, whose imbalance might ultimately lead to synaptic impairment in AD.
