In Honor of Nobel Laureate Prof. M Stanley Whittingham
| ALZHEIMER DISEASE: NANOELECTROCHEMISTRY REVEALS HOW SOLUBLE Aβ42 OLIGOMERS ALTER VESICULAR STORAGE AND RELEASE OF GLUTAMATE Christian Andre Amatore1; Wei-hua Huang2; Xiao-ke Yang2; Fu-li Zhang2; Xue-ke Jin2; Yu-ting Jiao2; Yan-ling Liu2; 1CNRS & PSL, FRENCH ACADEMY OF SCIENCES, Paris, France; 2WUHAN UNIVERSITY, Wuhan, China; PAPER: 181/Oxidative/Plenary (Oral) OS SCHEDULED: 15:55/Tue. 28 Nov. 2023/Dreams 1 ABSTRACT: Glutamate (Glu) is one of the most important excitatory transmitter in the nervous system. Impairment of its vesicular release due to β-amyloid (Aβ) oligomers liberation in the brain is thought to participate in pathological processes leading to Alzheimer’s disease. However, before this work [1] it was unclear whether soluble Aβ42 oligomers affect intravesicular amounts of Glu or its release in the brain, or both. Nanoelectrochemical measurements which will be presented used amperometric nanowire Glu biosensors to test single Glu-generating neuronal varicosities. This revealed that soluble Aβ42 oligomers first caused a dramatic increase in vesicular Glu storage and stimulation-induced release, accompanied by a high level of parallel spontaneous exocytosis. This was shown to ultimately result in the depletion of intravesicular Glu content enforcing greatly reduced Glu release. Molecular biology tools and mouse models of Aβ amyloidosis have further established that the transient hyperexcitation observed during the primary pathological stage was mediated by an altered behavior of VGLUT1 responsible for transporting Glu into synaptic vesicles. Thereafter, an overexpression of Vps10p-tail-interactor-1a, a protein that maintains spontaneous release of neurotransmitters by selective interaction with t-SNAREs, resulted in a depletion of intravesicular Glu content, triggering advanced-stage neuronal malfunction. These findings are expected to open perspectives for remediating Aβ42-induced neuronal hyperactivity and neuronal degeneration in the context of initiation of Alzheimer disease. The authors would like to acknowledge support from joint sino-french CNRS IRP NanoBioCatEchem. CA thanks Xiamen University for his Distinguished Visiting Professor position. References: 1. Xiao-Ke Yang, Fu-Li Zhang, Xue-Ke Jin, Yu-Ting Jiao, Xin-Wei Zhang, Yan-Ling Liu, Christian Amatore, Wei-Hua Huang. Nanoelectrochemistry reveals how soluble Aβ42 oligomers alter vesicular storage and release of glutamate. Proc. Nat. Acad. Sci. USA 120 (2023) e2219994120. |
