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Cited by 149Neuroscience and Neuropharmacology ResearchAlzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration Mechanisms

PSD-95 protects synapses from β-amyloid

Open access
Dore, Kim, Carrico, Zachary, Alfonso, Stephanie, Marino, Marc, Koymans, Karin, Kessels, Helmut W., Malinow, Roberto·2021·Cell Reports
DOI 10.1016/j.celrep.2021.109194PMC PMC8237704
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Abstract

Beta-amyloid (Aβ) depresses excitatory synapses by a poorly understood mechanism requiring NMDA receptor (NMDAR) function. Here, we show that increased PSD-95, a major synaptic scaffolding molecule, blocks the effects of Aβ on synapses. The protective effect persists in tissue lacking the AMPA receptor subunit GluA1, which prevents the confounding synaptic potentiation by increased PSD-95. Aβ modifies the conformation of the NMDAR C-terminal domain (CTD) and its interaction with protein phosphatase 1 (PP1), producing synaptic weakening. Higher endogenous levels or overexpression of PSD-95 block Aβ-induced effects on the NMDAR CTD conformation, its interaction with PP1, and synaptic weakening. Our results indicate that increased PSD-95 protects synapses from Aβ toxicity, suggesting that low levels of synaptic PSD-95 may be a molecular sign indicating synapse vulnerability to Aβ. Importantly, pharmacological inhibition of its depalmitoylation increases PSD-95 at synapses and rescues deficits caused by Aβ, possibly opening a therapeutic avenue against Alzheimer's disease.

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  • It has been suggested that synaptophysin may be reduced before observable PSD95 reductions occur.

    “it has been suggested that synaptophysin may be reduced before observable PSD95 reductions occur. 37 , 38”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [38]

    The Introduction (page unavailable) reports reduced PSD-95 in Alzheimer’s disease tissue and in neural tissue exposed to β-amyloid. The paper does not report that synaptophysin falls before PSD-95; a search for synaptophysin found no relevant passage in our copy. (LLM, conf=0.84)

    Experimental — accuracy not yet measured

  • PSD95 has protective effects against Aβ-induced synaptic changes.

    “Another study demonstrated that PSD95 has protective effects against Aβ‐induced synaptic changes. 38”

    From The MR1/MAIT cell axis enhances dystrophic neurite development in Alzheimer's disease (2025) · cites this paper as [38]

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Authors
Dore, K., Carrico, Z., Alfonso, S., Marino, M., Koymans, K., Kessels, H. W., & Malinow, R.
Affiliations
  • University of California San Diego (US)
  • University of Amsterdam (NL)
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2021-06
Volume
35
Issue
9
Pages
109194
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2021.109194
PMC
PMC8237704
OpenAlex
W3164819280
Cited by
149
References
66
Citations by year
2026: 31 · 2025: 32 · 2024: 34 · 2023: 28 · 2022: 18 · 2021: 6
FWCI
9.91
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (acceptedVersion, cc-by-nc-nd)
  • eScholarship (California Digital Library) (submittedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
Funders
  • Alzheimer's Disease Research Foundation
  • Cure Alzheimer's Fund (20192193)
  • University of California, San Diego
  • National Institutes of Health (P30 NS047101, R01MH049159)
Topics
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
PSD-95, amyloid-beta, NMDA receptor, protein phosphatase 1, synaptic plasticity, synaptic depression, GluR1, depalmitoylation, Alzheimer's disease, excitatory synapses, synaptic scaffolding
MeSH terms
Neuroprotection, Protein Domains, Disks Large Homolog 4 Protein, Animals, Mice, Inbred C57BL, Phosphoprotein Phosphatases, Synapses, Receptors, N-Methyl-D-Aspartate, Amyloid beta-Peptides, Rats, Sprague-Dawley, Mice, Knockout, Palmitic Acid, Fluorescence Resonance Energy Transfer, Dendritic Spines, Mice, Rats

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