The University of Southampton
University of Southampton Institutional Repository

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

Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons
Elevated amyloid beta disrupts the nanoscale organization and function of synaptic vesicle pools in hippocampal neurons
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.
amyloid beta, transmission, vesicle, hippocampus, synapse
1047-3211
1-14
Biasetti, Luca
77d7fcd8-50e7-4203-8428-4028e69200e2
Rey, Stephanie
1d258a2b-2f78-4f2b-8c7b-a2c600765aa3
Fowler, Milena
5bc395fb-7976-4f73-9aa7-d9595a1c875b
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Fennell, Kate
dc18bc87-0720-4474-8a2d-bb79e9a3aa84
Smith, Catherine
4a66eb67-368d-485e-b994-b6f66b213b23
Marshall, Karen
8f8cc1d2-a44f-4035-a614-cd146cee1e10
Hall, Catherine
528687d4-5980-432d-ae82-1eaa1b752ed5
Vargas-Caballero, Mariana
24126c8f-4885-4d2e-bd04-10f3b546fa37
Serpell, Louise
39a7dcac-d7b6-450e-8213-7af38f38e9b3
Staras, Kevin
5466b89b-0827-4c3d-a9ac-1059cc3924d4
Biasetti, Luca
77d7fcd8-50e7-4203-8428-4028e69200e2
Rey, Stephanie
1d258a2b-2f78-4f2b-8c7b-a2c600765aa3
Fowler, Milena
5bc395fb-7976-4f73-9aa7-d9595a1c875b
Ratnayaka, J. Arjuna
002499b8-1a9f-45b6-9539-5ac145799dfd
Fennell, Kate
dc18bc87-0720-4474-8a2d-bb79e9a3aa84
Smith, Catherine
4a66eb67-368d-485e-b994-b6f66b213b23
Marshall, Karen
8f8cc1d2-a44f-4035-a614-cd146cee1e10
Hall, Catherine
528687d4-5980-432d-ae82-1eaa1b752ed5
Vargas-Caballero, Mariana
24126c8f-4885-4d2e-bd04-10f3b546fa37
Serpell, Louise
39a7dcac-d7b6-450e-8213-7af38f38e9b3
Staras, Kevin
5466b89b-0827-4c3d-a9ac-1059cc3924d4

Biasetti, Luca, Rey, Stephanie, Fowler, Milena, Ratnayaka, J. 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, 1-14, [bhac134]. (doi:10.1093/cercor/bhac134).

Record type: Article

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.

Text
bhac134 - Version of Record
Available under License Creative Commons Attribution.
Download (2MB)
Text
Author manuscript
Restricted to Repository staff only
Available under License Creative Commons Attribution.
Request a copy

More information

Submitted date: 21 October 2021
Accepted/In Press date: 7 March 2022
e-pub ahead of print date: 3 April 2022
Published date: 3 April 2022
Keywords: amyloid beta, transmission, vesicle, hippocampus, synapse

Identifiers

Local EPrints ID: 457169
URI: http://eprints.soton.ac.uk/id/eprint/457169
ISSN: 1047-3211
PURE UUID: 8b9daed5-f9b1-43c4-b7a8-f8ed2c92684f
ORCID for J. Arjuna Ratnayaka: ORCID iD orcid.org/0000-0002-1027-6938

Catalogue record

Date deposited: 25 May 2022 16:55
Last modified: 26 May 2022 01:44

Export record

Altmetrics

Contributors

Author: Luca Biasetti
Author: Stephanie Rey
Author: Milena Fowler
Author: Kate Fennell
Author: Catherine Smith
Author: Karen Marshall
Author: Catherine Hall
Author: Mariana Vargas-Caballero
Author: Louise Serpell
Author: Kevin Staras

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of http://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×