Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons

Biasetti, Luca, Rey, Stephanie, Fowler, Milena, Ratnayaka, Arjuna, Fennell, Kate, Smith, Catherine, Marshall, Karen, Hall, Catherine, Vargas-Caballero, Mariana, Serpell, Louise and Staras, Kevin (2022) Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons. Cerebral Cortex. pp. 1-14. ISSN 1047-3211

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Abstract

Alzheimer’s disease is linked to increased levels of amyloid beta (Aβ) in the brain, but the mechanisms underlying neuronal dysfunction and neurodegeneration remain enigmatic. Here, we investigate whether organizational characteristics of functional presynaptic vesicle pools, key determinants of information transmission in the central nervous system, are targets for elevated Aβ. Using an optical readout method in cultured hippocampal neurons, we show that acute Aβ42 treatment significantly enlarges the fraction of functional vesicles at individual terminals. We observe the same effect in a chronically elevated Aβ transgenic model (APPSw,Ind) using an ultrastructure-function approach that provides detailed information on nanoscale vesicle pool positioning. Strikingly, elevated Aβ is correlated with excessive accumulation of recycled vesicles near putative endocytic sites, which is consistent with deficits in vesicle retrieval pathways. Using the glutamate reporter, iGluSnFR, we show that there are parallel functional consequences, where ongoing information signaling capacity is constrained. Treatment with levetiracetam, an antiepileptic that dampens synaptic hyperactivity, partially rescues these transmission defects. Our findings implicate organizational and dynamic features of functional vesicle pools as targets in Aβ-driven synaptic impairment, suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value.

Item Type: Article
Keywords: amyloid beta, transmission, vesicle, hippocampus, synapse
Schools and Departments: School of Psychology > Psychology
Research Centres and Groups: Sussex Neuroscience
Subjects: Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0361 Nervous system > QP0364 Synapses
Q Science > QP Physiology > QP0351 Neurophysiology and neuropsychology > QP0361 Nervous system > QP0364.5 Neural transmission
Depositing User: Kevin Staras
Date Deposited: 06 Apr 2022 11:10
Last Modified: 06 Apr 2022 11:15
URI: http://sro.sussex.ac.uk/id/eprint/105205

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Project NameSussex Project NumberFunderFunder Ref
Abeta-mediated toxicity in Alzheimer's disease: delineating mechanisms of internalisation, cell-cell transmission and synaptic dysfunction.G1106MRC-MEDICAL RESEARCH COUNCILMR/K022105/1
Ultrastructure-function properties of recycling vesicle pools in native central synapsesG1150BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/K019015/1
Functional synaptic vesicle pool remodelling as a basis for plasticity and control of complex behaviourG2521BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCILBB/S00310X/1
Alzheimer's Society Doctoral Training CentreG1708ALZHEIMERS SOCIETY230 (AS-DTC-2014-003