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  • Martinsson, ILund University,Lunds universitet,Experimentell demensforskning,Forskargrupper vid Lunds universitet,Experimental Dementia Research,Lund University Research Groups (author)

Aβ/APP-induced hyperexcitability and dysregulation of homeostatic synaptic plasticity in models of Alzheimer’s disease

  • BookEnglish2022

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  • Cold Spring Harbor Laboratory,2022

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  • LIBRIS-ID:oai:lup.lub.lu.se:6f8d1cdd-7fe4-4531-8065-fd0a7ac27482
  • https://lup.lub.lu.se/record/6f8d1cdd-7fe4-4531-8065-fd0a7ac27482URI
  • https://doi.org/10.1101/2022.01.25.477711DOI

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  • Language:English
  • Summary in:English

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  • Subject category:ovr swepub-publicationtype
  • Subject category:vet swepub-contenttype

Notes

  • The proper function of the nervous system is dependent on the appropriate timing of neuronal firing. Synapses continually undergo rapid activity-dependent modifications that require feedback mechanisms to maintain network activity within a window in which communication is energy efficient and meaningful. Homeostatic synaptic plasticity (HSP) and homeostatic intrinsic plasticity (HIP) are such negative feedback mechanisms. Accumulating evidence implicates that Alzheimer’s disease (AD)-related amyloid precursor protein (APP) and its cleavage product amyloid-beta (Aβ) play a role in the regulation of neuronal network activity, and in particular HSP. AD features impaired neuronal activity with regional early hyper-activity and Aβ-dependent hyperexcitability has also been demonstrated in AD transgenic mice. We demonstrate similar hyper-activity in AD transgenic neurons in culture that have elevated levels of both human APP and Aβ. To examine the individual roles of APP and Aβ in promoting hyperexcitability we used an APP construct that does not generate Aβ, or elevated Aβ levels independently of APP. Increasing either APP or Aβ in wild type (WT) neurons leads to increased frequency and amplitude of calcium transients. Since HSP/HIP mechanisms normally maintain a setpoint of activity, we examined whether homeostatic synaptic/intrinsic plasticity was altered in AD transgenic neurons. Using methods known to induce HSP/HIP, we demonstrate that APP protein levels are regulated by chronic modulation of activity and show that AD transgenic neurons have an impaired response 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 present evidence that both APP and Aβ influence neuronal activity and that mechanisms of HSP/HIP are disrupted in neuronal models of AD.Competing Interest StatementThe authors have declared no competing interest.

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  • Quintino, LLund University,Lunds universitet,CNS Genterapi,Forskargrupper vid Lunds universitet,CNS Gene Therapy,Lund University Research Groups(Swepub:lu)med-lsq (author)
  • Garcia, MGLund University,Lunds universitet,Neuroinflammation,Forskargrupper vid Lunds universitet,Lund University Research Groups(Swepub:lu)me5408ga (author)
  • Konings, SCLund University,Lunds universitet,Experimentell demensforskning,Forskargrupper vid Lunds universitet,Experimental Dementia Research,Lund University Research Groups(Swepub:lu)sa8051ko (author)
  • Torres-Garcia, LLund University,Lunds universitet,Experimentell demensforskning,Forskargrupper vid Lunds universitet,Experimental Dementia Research,Lund University Research Groups(Swepub:lu)la6204to (author)
  • Svanbergsson, AlexanderLund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups(Swepub:lu)med-as29 (author)
  • Stange, OliverLund University (author)
  • England, Rebecca (author)
  • Deierborg, TLund University,Lunds universitet,Institutionen för experimentell medicinsk vetenskap,Medicinska fakulteten,Neuroinflammation,Forskargrupper vid Lunds universitet,Department of Experimental Medical Science,Faculty of Medicine,Lund University Research Groups(Swepub:lu)expb-tol (author)
  • Li, Jia-YiLund University,Lunds universitet,Neural plasticitet och reparation,Forskargrupper vid Lunds universitet,Neural Plasticity and Repair,Lund University Research Groups(Swepub:lu)mphy-jli (author)
  • Lundberg, CLund University,Lunds universitet,CNS Genterapi,Forskargrupper vid Lunds universitet,CNS Gene Therapy,Lund University Research Groups(Swepub:lu)mphy-clu (author)
  • Gouras, GKLund University,Lunds universitet,Experimentell demensforskning,Forskargrupper vid Lunds universitet,Experimental Dementia Research,Lund University Research Groups(Swepub:lu)med-grg (author)
  • Experimentell demensforskningForskargrupper vid Lunds universitet (creator_code:org_t)

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