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Cited by 216Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchMemory and Neural Mechanisms

Early restoration of parvalbumin interneuron activity prevents memory loss and network hyperexcitability in a mouse model of Alzheimer’s disease

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Hijazi, Sara, Heistek, Tim S., Scheltens, Philip, Neumann, Ulf, Shimshek, Derya R., Mansvelder, Huibert D., Smit, August B., van Kesteren, Ronald E.·2020·Molecular Psychiatry
DOI 10.1038/s41380-019-0483-4PMC PMC7714697
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Abstract

Neuronal network dysfunction is increasingly recognized as an early symptom in Alzheimer’s disease (AD) and may provide new entry points for diagnosis and intervention. Here, we show that amyloid-beta-induced hyperexcitability of hippocampal inhibitory parvalbumin (PV) interneurons importantly contributes to neuronal network dysfunction and memory impairment in APP/PS1 mice, a mouse model of increased amyloidosis. We demonstrate that hippocampal PV interneurons become hyperexcitable at ~16 weeks of age, when no changes are observed yet in the intrinsic properties of pyramidal cells. This hyperexcitable state of PV interneurons coincides with increased inhibitory transmission onto hippocampal pyramidal neurons and deficits in spatial learning and memory. We show that treatment aimed at preventing PV interneurons from becoming hyperexcitable is sufficient to restore PV interneuron properties to wild-type levels, reduce inhibitory input onto pyramidal cells, and rescue memory deficits in APP/PS1 mice. Importantly, we demonstrate that early intervention aimed at restoring PV interneuron activity has long-term beneficial effects on memory and hippocampal network activity, and reduces amyloid plaque deposition, a hallmark of AD pathology. Taken together, these findings suggest that early treatment of PV interneuron hyperactivity might be clinically relevant in preventing memory decline and delaying AD progression.

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  • Evidence that FTD tau pathology leads to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies.

    “Evidence that FTD tau pathology leads to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies51–53.”

    From The R136S mutation in the APOE3 gene confers resilience against tau pathology via inhibition of the cGAS-STING-IFN pathway (2025) · cites this paper as [51]

    The Introduction describes neuronal network dysfunction in AD, and the Discussion reports early network alterations in APP/PS1 mice. The paper does not report that FTD tau pathology causes similar dysfunction or establish convergence between AD and primary tauopathies. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • FTD tau pathology leads to network dysfunction similar to that in AD, suggesting converging network dysfunction in AD and primary tauopathies.

    “The revelation that frontotemporal dementia (FTD) tau pathology led to similar network dysfunction suggests converging network dysfunction in AD and primary tauopathies49–51”

    From <i>APOE3</i> - <i>R136S</i> mutation confers resilience against tau pathology via cGAS-STING-IFN inhibition (2024) · cites this paper as [49]

    The Introduction describes neuronal network dysfunction in AD, and the Discussion reports impaired inhibitory transmission in APP/PS1 mice. The cited paper does not report FTD tau pathology causing similar dysfunction or compare AD with primary tauopathies (searched: FTD tau pathology; primary tauopathies). (LLM, conf=0.82)

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Cited by

Sorted by citations

Authors
Hijazi, S., Heistek, T. S., Scheltens, P., Neumann, U., Shimshek, D. R., Mansvelder, H. D., Smit, A. B., & van Kesteren, R. E.
Affiliations
  • Amsterdam Neuroscience (NL)
  • Novartis (Switzerland) (CH)
ORCID
Venue
Molecular Psychiatry
Publisher
Springer Science and Business Media LLC
Published
2019-08-20
Volume
25
Issue
12
Pages
3380-3398
ISSN
  • 1359-4184 (ISSN-L)
  • 1476-5578
DOI
10.1038/s41380-019-0483-4
PMC
PMC7714697
OpenAlex
W2969899571
Cited by
216
References
9
Citations by year
2026: 25 · 2025: 37 · 2024: 41 · 2023: 31 · 2022: 32 · 2021: 30 · 2020: 20
FWCI
14.05
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Psychiatry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion, other-oa)
  • VU Research Portal (publishedVersion, other-oa)
  • The Novartis Repository (Novartis) (submittedVersion)
  • Pure Amsterdam UMC (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
EU-FP7-PEOPLE program; CognitionNet
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
Keywords
Alzheimer's disease, parvalbumin interneurons, amyloid-beta, APP/PS1 mice, hippocampus, spatial learning and memory, amyloid plaques, early intervention, synaptic inhibition, pyramidal neurons
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Interneurons, Memory Disorders, Mice, Transgenic, Parvalbumins, Mice

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