Cited by 1,000Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction

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Mucke, L., Selkoe, D. J.·2012·Cold Spring Harbor Perspectives in Medicine

Abstract

Evidence for an ever-expanding variety of molecular mediators of amyloid β-protein neurotoxicity (membrane lipids, receptor proteins, channel proteins, second messengers and related signaling cascades, cytoskeletal proteins, inflammatory mediators, etc.) has led to the notion that the binding of hydrophobic Aβ assemblies to cellular membranes triggers multiple effects affecting diverse pathways. It appears unlikely that there are only one or two cognate receptors for neurotoxic forms of Aβ and also that there are just one or two assembly forms of the peptide that induce neuronal dysfunction. Rather, various soluble (diffusible) oligomers of Aβ that may be in dynamic equilibrium with insoluble, fibrillar deposits (amyloid plaques) and that can bind to different components of neuronal and non-neuronal plasma membranes appear to induce complex patterns of synaptic dysfunction and network disorganization that underlie the intermittent but gradually progressive cognitive manifestations of the clinical disorder. Modern analyses of this problem utilize electrophysiology coupled with synaptic biochemistry and behavioral phenotyping of animal models to elucidate the affected circuits and assess the effects of potential therapeutic interventions.

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Crossref · 10.1101/cshperspect.a006338

Cites

109 of 109 references verified0 citation errors · 0 not checkable

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  • Synaptic deficits occur in early Alzheimer's disease and mild cognitively impaired patients before onset of plaques and are some of the first signs of the neuronal degenerative process.

    “Synaptic deficits occur in early AD and mild cognitively impaired patients before onset of plaques and are some of the first signs of the neuronal degenerative process (4, 23-25).”

    From Complement and microglia mediate early synapse loss in Alzheimer mouse models (2016) · cites this paper as [4]

    The “Early versus Late” section links synaptic alterations with cognitive impairment in AD subjects and reports that synaptic deficits precede plaques and substantial neuronal loss in hAPP mice. It does not establish that deficits precede plaques in human patients with early AD or mild cognitive impairment, so the claim extends the mouse finding to those patients. No page number is available in our copy. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • In Alzheimer's disease, plaque deposits, fibrils, and oligomers of Aβ are considered essential mediators in the pathophysiological cascade leading to cognitive decline.

    “In AD, plaque deposits, fibrils, and oligomers of A␤ are considered essential mediators in the pathophysiological cascade leading to cognitive decline (Mucke and Selkoe, 2012).”

    From Early Alterations in Functional Connectivity and White Matter Structure in a Transgenic Mouse Model of Cerebral Amyloidosis (2014) · cites this paper as Mucke and Selkoe, 2012

    In the section on monomers, oligomers, and fibrils (page not provided), the paper links Aβ accumulation and soluble oligomers to neuronal dysfunction relevant to cognitive decline, and allows that plaques may have local neurotoxic effects. It does not treat plaques, fibrils, and oligomers alike as essential mediators: it describes insoluble fibrils as potentially relatively inactive reservoirs and reports that washed plaque cores did not block synaptic plasticity unless dissolved to release oligomers. (LLM, conf=0.88)

    Experimental — accuracy not yet measured
  • Synapse loss in Alzheimer's disease correlates with cognitive decline.

    “Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline.”
  • Oligomeric Aβ, but not monomeric Aβ or vehicle, induced C1q deposition in wild-type mice.

    “Oligomeric Aβ (oAβ), which is prefibrillar in nature and acts as a mediator of synapse loss and dysfunction in AD (4), but not the relatively innocuous monomeric Aβ or vehicle, induced C1q deposition (Fig. 2A and fig. S5).”
  • Aβ can deteriorate synaptic functions and block LTP.

    “Numerous in vitro and in vivo studies have demonstrated that Aβ can deteriorate synaptic functions and block long-term potentiation (LTP), which is the cellular basis of learning and memory (35).”

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Authors
Mucke, L., & Selkoe, D. J.
Affiliations
  • University of California, San Francisco (US)
  • Brigham and Women's Hospital (US)
Corresponding author
Mucke, L.
Venue
Cold Spring Harbor Perspectives in Medicine
Published
2012-03-13
Volume
2
Issue
7
Pages
a006338-a006338
ISSN
2157-1422 (ISSN-L)
OpenAlex
W2126402425
Cited by
1,000
References
109
Citations by year
2026: 41 · 2025: 44 · 2024: 53 · 2023: 81 · 2022: 91 · 2021: 103 · 2020: 74 · 2019: 57 · 2018: 82 · 2017: 75 · 2016: 71 · 2015: 87 · 2014: 91 · 2013: 37 · 2012: 11
Type
posted content
Language
en
Open access
Locations
  • Cold Spring Harbor Perspectives in Medicine (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
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 › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
amyloid-beta, neurotoxicity, synaptic dysfunction, neuronal network dysfunction, membrane binding, amyloid plaques, receptor binding, cognitive impairment, animal models of Alzheimer's disease, therapeutic interventions
MeSH terms
Alzheimer Disease, Animals, Extracellular Space, Humans, Nerve Net, Synaptic Transmission, Neurons, Synapses, Amyloid beta-Peptides

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