Oligomeric amyloid β associates with postsynaptic densities and correlates with excitatory synapse loss near senile plaques
Open accessAbstract
Synapse loss correlates with a cognitive decline in Alzheimer's disease (AD), but whether this is caused by fibrillar deposits known as senile plaques or soluble oligomeric forms of amyloid beta (Abeta) is controversial. By using array tomography, a technique that combines ultrathin sectioning of tissue with immunofluorescence, allowing precise quantification of small structures, such as synapses, we have tested the hypothesis that oligomeric Abeta surrounding plaques contributes to synapse loss in a mouse model of AD. We find that senile plaques are surrounded by a halo of oligomeric Abeta. Analysis of >14,000 synapses (represented by PSD95-stained excitatory synapses) shows that there is a 60% loss of excitatory synapses in the halo of oligomeric Abeta surrounding plaques and that the density increases to reach almost control levels in volumes further than 50 microm from a plaque in an approximately linear fashion (linear regression, r(2) = 0.9; P < 0.0001). Further, in transgenic cortex, microdeposits of oligomeric Abeta associate with a subset of excitatory synapses, which are significantly smaller than those not in contact with oligomeric Abeta. The proportion of excitatory synapses associated with Abeta correlates with decreasing density (correlation, -0.588; P < 0.0001). These data show that senile plaques are a potential reservoir of oligomeric Abeta, which colocalizes with the postsynaptic density and is associated with spine collapse, reconciling the apparently competing schools of thought of "plaque" vs. "oligomeric Abeta" as the synaptotoxic species in the brain of AD patients.
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oAβ species accumulate at the periphery of dense-cored plaques and compact plaques enhance Aβ toxicity indirectly by creating a platform on which toxic oAβ species can accumulate or stabilize.
“A renewed interest in the pathological role of plaques has suggested that oA species accumulate at the periphery of densecored plaques (60,61) and that compact plaques enhance A toxicity indirectly by creating a platform on which toxic oA species can accumulate or stabilize.”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [60]
The reduced steady-state PSD95 detected within XO4+ microglia by immunofluorescence may be reflective of loss of synapses around plaques.
“The reduced steady-state PSD95 detected within XO4+ microglia by immunofluorescence may be reflective of loss of synapses around plaques”
From Transcriptional signature in microglia associated with Aβ plaque phagocytosis (2021) · cites this paper as [48]
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- Authors
- Koffie, R. M., Meyer-Luehmann, M., Hashimoto, T., Adams, K. W., Mielke, M. L., Garcia-Alloza, M., Micheva, K. D., Smith, S. J., Kim, M. L., Lee, V. M., Hyman, B. T., & Spires-Jones, T. L.
- Affiliations
- Massachusetts General Hospital (US)
- Neurology Department, Massachusetts General Hospital, Charlestown, MA 02129;
- Stanford Medicine (US)
- University of Pennsylvania (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-03-10
- Volume
- 106
- Issue
- 10
- Pages
- 4012-4017
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2656196
- OpenAlex
- W2132154794
- Cited by
- 850
- References
- 31
- Citations by year
- 2026: 38 · 2025: 29 · 2024: 41 · 2023: 47 · 2022: 55 · 2021: 56 · 2020: 75 · 2019: 57 · 2018: 57 · 2017: 47 · 2016: 60 · 2015: 25 · 2014: 56 · 2013: 60 · 2012: 44
- FWCI
- 32.47
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Brigham and Women's Hospital
- National Institutes of Health (AG08487, AG05134)
- National Institute on Aging (AG-08487, 2 P50 AG05134-24, R01AG008487, P50AG005134, P30AG062421)
- National Institute of General Medical Sciences (T32GM007753)
- 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
- Alzheimer's disease, amyloid-beta oligomers, amyloid plaques, synaptic loss, postsynaptic density, PSD-95, excitatory synapses, synaptotoxicity, transgenic mouse model, array tomography
- MeSH terms
- Animals, Synapses, Tomography, Amyloid beta-Peptides, Excitatory Postsynaptic Potentials, Protein Structure, Quaternary, Mice, Plaque, Amyloid
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