Cited by 161Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchDementia and Cognitive Impairment Research

Tipping the Scales: Peptide-Dependent Dysregulation of Neural Circuit Dynamics in Alzheimer’s Disease

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Harris, Samuel S., Wolf, Fred, De Strooper, Bart, Busche, Marc Aurel·2020·Neuron

Abstract

Identifying effective treatments for Alzheimer's disease (AD) has proven challenging and has instigated a shift in AD research focus toward the earliest disease-initiating cellular mechanisms. A key insight has been an increase in soluble Aβ oligomers in early AD that is causally linked to neuronal and circuit hyperexcitability. However, other accumulating AD-related peptides and proteins, including those derived from the same amyloid precursor protein, such as Aη or sAPPα, and autonomously, such as tau, exhibit surprising opposing effects on circuit dynamics. We propose that the effects of these on neuronal circuits have profound implications for our understanding of disease complexity and heterogeneity and for the development of personalized diagnostic and therapeutic strategies in AD. Here, we highlight important peptide-specific mechanisms of dynamic pathological disequilibrium of cellular and circuit activity in AD and discuss approaches in which these may be further understood, and theoretically and experimentally leveraged, to elucidate AD pathophysiology.

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Crossref · 10.1016/j.neuron.2020.06.005

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  • Oligodendrocyte-derived amyloid beta plays a pivotal role in the early impairment of neuronal circuits in Alzheimer's disease.

    “Together with our data showing an increased number of Aβ-producing oligodendrocytes in deeper cortical layers of the brains of individuals with AD, these results indicate that oligodendrocyte-derived Aβ plays a pivotal role in the early impairment of neuronal circuits in AD [52]”

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Authors
Harris, S. S., Wolf, F., De Strooper, B., & Busche, M. A.
Affiliations
  • Bernstein Center for Computational Neuroscience Göttingen (DE)
  • UK Dementia Research Institute (GB)
Corresponding author
Busche, Marc Aurel
Venue
Neuron
Publisher
Elsevier BV
Published
2020-08
Volume
107
Issue
3
Pages
417-435
ISSN
0896-6273 (ISSN-L)
OpenAlex
W3037412948
Cited by
161
References
198
Citations by year
2026: 15 · 2025: 25 · 2024: 35 · 2023: 26 · 2022: 27 · 2021: 28 · 2020: 5
FWCI
2.75
Type
journal article
Language
en
Open access
Locations
  • Neuron (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
  • Lirias (submittedVersion)
  • GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, other-oa)
Funders
  • Bernstein Center for Computational Neuroscience Tübingen (01GQ1005B)
  • Medical Research Council (MR/S017003/1)
  • Deutsche Forschungsgemeinschaft (CRC889, CRC1286)
  • UK Research and Innovation
  • VWR Foundation
  • UK Dementia Research Institute
  • Max-Planck-Gesellschaft
  • Alzheimer’s Research UK
  • Alzheimer's Society
  • Global Innovation Fund
  • German-Israeli Foundation for Scientific Research and Development (906-17.1/2006)
  • BrightFocus Foundation (A2019112S)
  • Volkswagen Foundation (ZN2632)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
Alzheimer's disease, neural circuit dynamics, amyloid-beta oligomers, amyloid precursor protein, neuropeptides, soluble APP alpha, tau protein, neuronal hyperexcitability, disease heterogeneity, personalized treatment
MeSH terms
Axon Initial Segment, Alzheimer Disease, Animals, Astrocytes, Brain, Humans, Neural Pathways, Neurons, Peptide Fragments, Seizures, Synapses, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, tau Proteins, Receptors, Glutamate, Microglia, Amyloid Precursor Protein Secretases, NAV1.1 Voltage-Gated Sodium Channel

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