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Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons
journal contribution
posted on 2023-06-10, 03:04 authored by Luca Biasetti, Stephanie Rey, Milena Fowler, Arjuna Ratnayaka, Kate FennellKate Fennell, Catherine Smith, Karen MarshallKaren Marshall, Catherine HallCatherine Hall, Mariana Vargas-Caballero, Louise SerpellLouise Serpell, Kevin StarasKevin StarasAlzheimer’s disease is linked to increased levels of amyloid beta (Aß) 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 Aß. Using an optical readout method in cultured hippocampal neurons, we show that acute Aß42 treatment significantly enlarges the fraction of functional vesicles at individual terminals. We observe the same effect in a chronically elevated Aß transgenic model (APPSw,Ind) using an ultrastructure-function approach that provides detailed information on nanoscale vesicle pool positioning. Strikingly, elevated Aß 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 Aß-driven synaptic impairment, suggesting that interventions to relieve the overloading of vesicle retrieval pathways might have promising therapeutic value.
Funding
Alzheimer's Society Doctoral Training Centre; G1708; ALZHEIMERS SOCIETY; 230 (AS-DTC-2014-003
Ultrastructure-function properties of recycling vesicle pools in native central synapses; G1150; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/K019015/1
Abeta-mediated toxicity in Alzheimer's disease: delineating mechanisms of internalisation, cell-cell transmission and synaptic dysfunction.; G1106; MRC-MEDICAL RESEARCH COUNCIL; MR/K022105/1
Functional synaptic vesicle pool remodelling as a basis for plasticity and control of complex behaviour; G2521; BBSRC-BIOTECHNOLOGY & BIOLOGICAL SCIENCES RESEARCH COUNCIL; BB/S00310X/1
History
Publication status
- Published
File Version
- Published version
Journal
Cerebral CortexISSN
1047-3211Publisher
Oxford University PressExternal DOI
Page range
1-14Department affiliated with
- Psychology Publications
Research groups affiliated with
- Sussex Neuroscience Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2022-04-06First Open Access (FOA) Date
2022-04-06First Compliant Deposit (FCD) Date
2022-04-05Usage metrics
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