β-Amyloid Causes Depletion of Synaptic Vesicles Leading to Neurotransmission Failure

Abstract

Alzheimer disease is a progressive neurodegenerative brain disorder that leads to major debilitating cognitive deficits. It is believed that the alterations capable of causing brain circuitry dysfunctions have a slow onset and that the full blown disease may take several years to develop. Therefore, it is important to understand the early, asymptomatic, and possible reversible states of the disease with the aim of proposing preventive and disease-modifying therapeutic strategies. It is largely unknown how amyloid ␤-peptide (A␤), a principal agent in Alzheimer disease, affects synapses in brain neurons. In this study, we found that similar to other pore-forming neurotoxins, A␤ induced a rapid increase in intracellular calcium and miniature currents, indicating an enhancement in vesicular transmitter release. Significantly, blockade of these effects by low extracellular calcium and a peptide known to act as an inhibitor of the A␤-induced pore prevented the delayed failure, indicating that A␤ blocks neurotransmission by causing vesicular depletion. This new mechanism for A␤ synaptic toxicity should provide an alternative pathway to search for small molecules that can antagonize these effects of A␤.

Dysfunctional synapse in Alzheimer's disease – A focus on NMDA receptors

“…In addition, it was also demonstrated that Aβ reduced the magnitude of exocytosis and that the remaining synaptic vesicles displayed a much slower speed of endocytosis, thus inhibiting presynaptic function (Parodi et al, 2010). By using electron microscopy, these authors also reported that Aβ-treated neurons displayed reduced number of synaptic vesicles, especially those near the presynaptic active zones and a reduction in several presynaptic proteins (Parodi et al, 2010).…”

“…In addition, it was also demonstrated that Aβ reduced the magnitude of exocytosis and that the remaining synaptic vesicles displayed a much slower speed of endocytosis, thus inhibiting presynaptic function (Parodi et al, 2010). By using electron microscopy, these authors also reported that Aβ-treated neurons displayed reduced number of synaptic vesicles, especially those near the presynaptic active zones and a reduction in several presynaptic proteins (Parodi et al, 2010). Accordingly, presynaptic proteins such as SNAP-25, synaptophysin, and synaptotagmin were reduced in brains of patients with AD (Reddy et al, 2005) and in the hippocampus of Tg2576 mice 1 month after injection of Aβ into the third ventricle (Chauhan and Siegel, 2002 (Russell et al, 2012).…”

The Level of NMDA Receptor in the Membrane Modulates Amyloid-β Association and Perforation

“…A common hypothesis used to explain the toxicity induced by A␤ is the formation of amyloid pores in the plasma membrane. Regarding this, several studies from our and other laboratories support the notion that membrane disruptions are induced by A␤ [6][7][8][9][10][11][12][13]. Furthermore, A␤ perforation allows the entry of small molecules and ions, such as calcium, into the cells [6,7,12].…”

“…Regarding this, several studies from our and other laboratories support the notion that membrane disruptions are induced by A␤ [6][7][8][9][10][11][12][13]. Furthermore, A␤ perforation allows the entry of small molecules and ions, such as calcium, into the cells [6,7,12]. This sustained calcium influx increases the release in synaptic vesicles, leading to a delayed synaptic failure produced by vesicle depletion [6][7][8].…”

CALHM1 and its polymorphism P86L differentially control Ca2+ homeostasis, mitogen‐activated protein kinase signaling, and cell vulnerability upon exposure to amyloid β

“…Aggregation of Aβ 1–42 at 5 μ m was achieved as previously described (Parodi et al ., 2010). Briefly, human Aβ 1–42 was dissolved with dimethylsulfoxide (DMSO) at 2.3 m m ; an aliquot of the 2.3‐m m solution was then dissolved in PBS to a final concentration of 80 μ m .…”