Enis HİDİSOGLU

Short-Term Amyloid Beta Application Decreased Glutamate Release, but Increased Glutamate Spillover in Hippocampal Neurons

Aim: Synaptic dysfunction is a characteristic linked with the early stages of Alzheimer's disease (AD), but the pathological mechanisms remain elusive. It was aimed to investigate how amyloid beta 42 (Abeta42) peptide affects miniature events mediated by glutamate release in hippocampal neurons. Material and Methods: We performed all experiments in the primary cultured hippocampal neurons in control and Abeta42-treated neurons (24 h). Pharmacologically isolated miniature excitatory postsynaptic currents (mEPSCs) were obtained in whole-cell voltage-clamp configuration at – 70 mV. AMPAergic channel conductance and basic synaptic parameters were evaluated by performing peak-scaled variance analysis and cumulative event analysis and glutamate spillover is determined by application of DNQX. Results: The oligomeric Abeta42 for 24h decreased the mEPSCs frequency (***p<0.001), while it has no any measurable effect on the amplitude of mEPSCs as well as unitary current and number of receptors. In addition, the incubation of neurons with oligomeric Abeta42 for 24h increased the glutamate spillover measured as baseline shift (***p<0.001). Conclusion: The oligomeric form of the Abeta42 peptide has a significant effect on the presynaptic site of excitatory synapses in primary cultured hippocampal neurons. It lowers the release probability during short-term incubation, while it increases glutamate spillover.

Keywords:

Alzheimer’s disease, amyloid beta peptide, AMPAergic synapses glutamate spillover,

PDF

___

2020 Alzheimer's disease facts and figures. Alzheimers Dement. 2020 Mar 10. doi: 10.1002/alz.12068. [Epub ahead of print].
Yamamoto K, Yamamoto R, Kato N. Amyloid β and amyloid precursor protein synergistically suppress large-conductance calcium-activated potassium channel in cortical neurons. Front Aging Neurosci. 2021;13:660319.
Hidisoglu E, Kantar D, Ozdemir S, Yargicoglu P. Cognitive dysfunctions and spontaneous EEG alterations induced by hippocampal amyloid pathology in rats. Adv Med Sci. 2022;67:328-37.
Hidisoglu E, Chiantia G, Franchino C, et al. The ryanodine receptor-calstabin interaction stabilizer S107 protects hippocampal neurons from GABAergic synaptic alterations induced by Abeta42 oligomers. J Physiol. 2022;600:5295-309.
Rowe CC, Ng S, Ackermann U, et al. Imaging beta-amyloid burden in aging and dementia. Neurology. 2007;68:1718-25.
Ting JT, Kelley BG, Lambert TJ, et al. Amyloid precursor protein overexpression depresses excitatory transmission through both presynaptic and postsynaptic mechanisms. Proc Natl Acad Sci U S A. 2007;104:353-8.
Hidisoglu E, Kantar-Gok D, Er H, et al. Alterations in spontaneous delta and gamma activity might provide clues to detect changes induced by amyloid-beta administration. Eur J Neurosci. 2018;47:1013-23.
Shankar GM, Li S, Mehta TH, et al. Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat Med. 2008;14:837-42.
Gavello D, Rojo-Ruiz J, Marcantoni A, et al. Leptin counteracts the hypoxia-induced inhibition of spontaneously firing hippocampal neurons: a microelectrode array study. Plos One. 2012;7:e41530.
Gavello D, Calorio C, Franchino C, et al. Early alterations of hippocampal neuronal firing induced by Abeta42. Cereb Cortex. 2018;28:433-46.
Russo I, Gavello D, Menna E, et al. p140Cap regulates GABAergic synaptogenesis and development of hippocampal inhibitory circuits. Cereb Cortex. 2019;29:91-105.
He Y, Wei M, Wu Y, et al. Amyloid beta oligomers suppress excitatory transmitter release via presynaptic depletion of phosphatidylinositol-4,5-bisphosphate. Nat Commun. 2019;10:1193.
Parodi J, Sepulveda FJ, Roa J, et al. Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem. 2010;285:2506-14.
Busche MA, Eichhoff G, Adelsberger H, et al. Clusters of hyperactive neurons near amyloid plaques in a mouse model of Alzheimer's disease. Science. 2008;321:1686-9.
Ghatak S, Dolatabadi N, Trudler D, et al. Mechanisms of hyperexcitability in Alzheimer's disease hiPSC-derived neurons and cerebral organoids vs isogenic controls. Elife. 2019;8:e50333.
Lerdkrai C, Asavapanumas N, Brawek B, et al. Intracellular Ca(2+) stores control in vivo neuronal hyperactivity in a mouse model of Alzheimer's disease. Proc Natl Acad Sci U S A. 2018;115:E1279-88.
Marcantoni A, Cerullo MS, Buxeda P, et al. Amyloid Beta42 oligomers up-regulate the excitatory synapses by potentiating presynaptic release while impairing postsynaptic NMDA receptors. J Physiol-London. 2020;598:2183-97.