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

Author:

Biasetti Luca1ORCID,Rey Stephanie12,Fowler Milena1,Ratnayaka Arjuna13ORCID,Fennell Kate1ORCID,Smith Catherine1,Marshall Karen1,Hall Catherine4ORCID,Vargas-Caballero Mariana5ORCID,Serpell Louise1ORCID,Staras Kevin1ORCID

Affiliation:

1. Sussex Neuroscience , School of Life Sciences, University of Sussex, Brighton, BN1 9QG , United Kingdom

2. National Physical Laboratory , Middlesex, TW11 0LW , United Kingdom

3. Faculty of Medicine, University of Southampton , SO17 1BJ , United Kingdom

4. Sussex Neuroscience , School of Psychology, University of Sussex, Brighton, BN1 9QH , United Kingdom

5. School of Biological Sciences , University of Southampton, Highfield Campus, Southampton SO17 1BJ , United Kingdom

Abstract

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.

Funder

R.M. Phillips Trust

Wellcome Trust

Biotechnology and Biological Sciences Research Council

Medical Research Council

Publisher

Oxford University Press (OUP)

Subject

Cellular and Molecular Neuroscience,Cognitive Neuroscience

Reference90 articles.

1. Amyloid-beta as a positive endogenous regulator of release probability at hippocampal synapses;Abramov;Nat Neurosci,2009

2. Synaptic vesicle pools and dynamics;Alabi;Cold Spring Harb Perspect Biol,2012

3. Aβ1-16 controls synaptic vesicle pools at excitatory synapses via cholinergic modulation of synapsin phosphorylation;Anni;Cell Mol Life Sci,2021

4. Response of the medial temporal lobe network in amnestic mild cognitive impairment to therapeutic intervention assessed by fMRI and memory task performance;Bakker;NeuroImage: Clinical,2015

5. Slow presynaptic and fast postsynaptic components of compound long-term potentiation;Bayazitov;J Neurosci,2007

Cited by 7 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3