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Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease

Martinsson, Isak LU ; Quintino, Luis LU orcid ; Garcia, Megg G. LU orcid ; Konings, Sabine C. LU orcid ; Torres-Garcia, Laura LU ; Svanbergsson, Alexander LU orcid ; Stange, Oliver ; England, Rebecca ; Deierborg, Tomas LU and Li, Jia-yi LU , et al. (2022) In Frontiers in Aging Neuroscience 14. p.1-16
Abstract
Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of... (More)
Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of activity, we examined whether HSP was altered in AD transgenic neurons. Using methods known to induce HSP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and that AD transgenic neurons have an impaired adaptation of calcium transients to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we show that both APP and Aβ influence neuronal activity and that mechanisms of HSP are disrupted in primary neuron models of AD. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Frontiers in Aging Neuroscience
volume
14
article number
946297
pages
1 - 16
publisher
Frontiers Media S. A.
external identifiers
  • pmid:35928998
  • scopus:85135270710
ISSN
1663-4365
DOI
10.3389/fnagi.2022.946297
language
English
LU publication?
yes
id
6caf3cf2-ed9d-4448-bf2b-49b0e1a0575d
date added to LUP
2022-07-21 12:55:54
date last changed
2022-10-08 04:26:40
@article{6caf3cf2-ed9d-4448-bf2b-49b0e1a0575d,
  abstract     = {{Alzheimer’s disease (AD) is increasingly seen as a disease of synapses and diverse evidence has implicated the amyloid-β peptide (Aβ) in synapse damage. The molecular and cellular mechanism(s) by which Aβ and/or its precursor protein, the amyloid precursor protein (APP) can affect synapses remains unclear. Interestingly, early hyperexcitability has been described in human AD and mouse models of AD, which precedes later hypoactivity. Here we show that neurons in culture with either elevated levels of Aβ or with human APP mutated to prevent Aβ generation can both induce hyperactivity as detected by elevated calcium transient frequency and amplitude. Since homeostatic synaptic plasticity (HSP) mechanisms normally maintain a setpoint of activity, we examined whether HSP was altered in AD transgenic neurons. Using methods known to induce HSP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and that AD transgenic neurons have an impaired adaptation of calcium transients to global changes in activity. Further, AD transgenic compared to WT neurons failed to adjust the length of their axon initial segments (AIS), an adaptation known to alter excitability. Thus, we show that both APP and Aβ influence neuronal activity and that mechanisms of HSP are disrupted in primary neuron models of AD.}},
  author       = {{Martinsson, Isak and Quintino, Luis and Garcia, Megg G. and Konings, Sabine C. and Torres-Garcia, Laura and Svanbergsson, Alexander and Stange, Oliver and England, Rebecca and Deierborg, Tomas and Li, Jia-yi and Lundberg, Cecilia and Gouras, Gunnar K.}},
  issn         = {{1663-4365}},
  language     = {{eng}},
  pages        = {{1--16}},
  publisher    = {{Frontiers Media S. A.}},
  series       = {{Frontiers in Aging Neuroscience}},
  title        = {{Aβ/Amyloid Precursor Protein-Induced Hyperexcitability and Dysregulation of Homeostatic Synaptic Plasticity in Neuron Models of Alzheimer’s Disease}},
  url          = {{http://dx.doi.org/10.3389/fnagi.2022.946297}},
  doi          = {{10.3389/fnagi.2022.946297}},
  volume       = {{14}},
  year         = {{2022}},
}