Cited by 396Alzheimer's disease research and treatmentsNeuroinflammation and Neurodegeneration MechanismsDementia and Cognitive Impairment Research

A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss In Vivo

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Tomiyama, Takami, Matsuyama, Shogo, Iso, Hiroyuki, Umeda, Tomohiro, Takuma, Hiroshi, Ohnishi, Kiyouhisa, Ishibashi, Kenichi, Teraoka, Rie +8 more·2010·The Journal of Neuroscience

Abstract

Although amyloid β (Aβ) oligomers are presumed to cause synaptic and cognitive dysfunction in Alzheimer's disease (AD), their contribution to other pathological features of AD remains unclear. To address the latter, we generated APP transgenic mice expressing the E693Δ mutation, which causes AD by enhanced Aβ oligomerization without fibrillization. The mice displayed age-dependent accumulation of intraneuronal Aβ oligomers from 8 months but no extracellular amyloid deposits even at 24 months. Hippocampal synaptic plasticity and memory were impaired at 8 months, at which time the presynaptic marker synaptophysin began to decrease. Furthermore, we detected abnormal tau phosphorylation from 8 months, microglial activation from 12 months, astrocyte activation from 18 months, and neuronal loss at 24 months. These findings suggest that Aβ oligomers cause not only synaptic alteration but also other features of AD pathology and that these mice are a useful model of Aβ oligomer-induced pathology in the absence of amyloid plaques.

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Crossref · 10.1523/jneurosci.5825-09.2010

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  • In the E693Delta APP mutation discovered in a Japanese kindred, the presence of intracellular oligomers is essentially identical in patients and in the transgenic mouse model.

    “In the E693Delta APP mutation discovered in a Japanese kindred (Nishitsuji et al., 2009), the presence of intracellular oligomers is essentially identical in patients and in the transgenic mouse model (Tomiyama et al., 2010).”
  • A transgenic mouse model bearing APP with a recently described AD-associated mutation exhibits intraneuronal Aβ accumulation in the absence of plaques and still shows signs of AD-related neurodegeneration.

    “This idea is confirmed by studies reporting a transgenic mouse model bearing APP with a recently described AD-associated mutation that exhibits intraneuronal Aβ accumulation in the absence of plaques and still shows signs of AD-related neurodegeneration [113].”
  • While some of these mouse models showed evidence of localized hyperphosphorylated tau that may represent 'pretangles', none developed neurofibrillary tangles.

    “The other major limitation of these mouse models was that while some showed evidence of localized hyperphosphylated tau that may represent “pretangles”[107, 118, 151, 159], none developed neurofibrillary tangles.”

    From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [159]

  • The APP E693Δ-Tg model expresses the Osaka (APPE693Δ) mutation, which results in significantly increased expression of Aβ oligomers, synaptic impairment and cognitive impairments from 8 months of age, but no plaque or tau pathology formation.

    “The APP E693Δ-Tg model expresses the Osaka (APPE693Δ) mutation, which results in a unique phenotype of significantly increased expression of Aβ oligomers, synaptic impairment and cognitive impairments from 8 months of age, but no plaque or tau pathology formation [159].”

    From Alzheimer's disease: experimental models and reality (2017) · cites this paper as [159]

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Authors
Tomiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., Nishitsuji, K., Ito, K., Shimada, H., Lambert, M. P., Klein, W. L., & Mori, H.
Affiliations
  • Osaka City University (JP)
  • Himeji Dokkyo University (JP)
  • Hyogo University of Health Sciences (JP)
  • Northwestern University (US)
Venue
The Journal of Neuroscience
Published
2010-04-06
Volume
30
Issue
14
Pages
4845-4856
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
OpenAlex
W2095031277
Cited by
396
References
52
Citations by year
2026: 3 · 2025: 13 · 2024: 21 · 2023: 26 · 2022: 20 · 2021: 24 · 2020: 21 · 2019: 23 · 2018: 20 · 2017: 19 · 2016: 18 · 2015: 33 · 2014: 22 · 2013: 27 · 2012: 39
FWCI
28.82
Type
journal article
Language
en
Open access
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Alzheimer's Association (IIRG-09-132098)
  • Ministry of Education, Culture, Sports, Science and Technology (18023033, 17300114, 20023026, IIRG-09-132098)
  • Ministry of Health, Labour and Welfare
  • Japan Society for the Promotion of Science (18023033, 20023026, 17300114)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
amyloid-beta oligomers, Alzheimer's disease, APP transgenic mice, synaptic plasticity, memory impairment, synaptophysin, tau phosphorylation, microglial activation, astrocyte activation, neuronal loss, mouse model
MeSH terms
Alzheimer Disease, Animals, Disease Models, Animal, Humans, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Transgenic, Neuroglia, Neurons, Phosphorylation, Synapses, Amyloid beta-Peptides, tau Proteins, Cell Death, Mice

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