Hippocampal Neuron Loss Exceeds Amyloid Plaque Load in a Transgenic Mouse Model of Alzheimer's Disease
Open accessAbstract
According to the "amyloid hypothesis of Alzheimer's disease," beta-amyloid is the primary driving force in Alzheimer's disease pathogenesis. Despite the development of many transgenic mouse lines developing abundant beta-amyloid-containing plaques in the brain, the actual link between amyloid plaques and neuron loss has not been clearly established, as reports on neuron loss in these models have remained controversial. We investigated transgenic mice expressing human mutant amyloid precursor protein APP751 (KM670/671NL and V717I) and human mutant presenilin-1 (PS-1 M146L). Stereologic and image analyses revealed substantial age-related neuron loss in the hippocampal pyramidal cell layer of APP/PS-1 double-transgenic mice. The loss of neurons was observed at sites of Abeta aggregation and surrounding astrocytes but, most importantly, was also clearly observed in areas of the parenchyma distant from plaques. These findings point to the potential involvement of more than one mechanism in hippocampal neuron loss in this APP/PS-1 double-transgenic mouse model of Alzheimer's disease.
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The level of hippocampal pyramidal cell loss in APP751SL/PS1M146L mice exceeded the amount explainable by pure extracellular plaque deposition by approximately 10%, indicating involvement of more than one mechanism in hippocampal neuron loss.
“Interestingly, the level of hippocampal pyramidal cell loss exceeded the amount explainable by the pure presence of extracellular plaque deposition by approximately 10%, indicating the involvement of more than one mechanism in hippocampal neuron loss in this mouse model [50].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [50]
Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measuredIn APP SL PS1KI mice, intraneuronal Aβ does not appear to cause amyloid plaque formation.
“Like 5XFADmice,theneuronloss in APP SL PS1KI mice is preceded by intraneuronal A 𝛃 , although intraneuronal A 𝛃 does not appear to cause amyloid plaque formation in this model.”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Schmitz et al., 2004
The Discussion (page not provided) says intraneuronal Aβ was observed before plaque formation in this APP/PS-1 model, supporting the sentence’s timing claim. It suggests intraneuronal Aβ may contribute to neuron loss independently of extracellular aggregates, but does not say whether intraneuronal Aβ causes plaque formation. (LLM, conf=0.83)
Experimental — accuracy not yet measuredThe APP SL PS1KI line exhibits significant neuron death in CA1/2 of the hippocampus.
“However, a recent APP/PS1 line coexpressing APP K670N/M671L plus V717I and PS1 M233T plus L235P (APP SL PS1KI) exhibits significant neuron death in CA1/2 of the hippocampus (Casas et al., 2004; Schmitz et al., 2004).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Schmitz et al., 2004
The Results report significant hippocampal pyramidal-neuron loss in APP/PS-1 mice, and the figure description shows neuron loss in CA2. However, the Transgenic Mice section identifies this paper’s line as carrying PS-1 M146L, not the PS1 M233T/L235P knock-in named in the citing sentence; its quantitative result also covers CA1–CA3 together, rather than CA1/2 specifically. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIn 17-month-old APP751SL/PS1M146L mice, a loss of CA1-3 neurons of ~30% compared to age-matched PS1 control animals was demonstrated by unbiased stereological counting methods.
“In 17-month-old APP751SL/PS1M146L mice, a loss of CA1–3 neurons of ~30% compared to age-matched PS1 control animals was demonstrated by unbiased stereological counting methods.”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [50]
Some AD transgenic mice also display intraneuronal Aβ.
“Some AD transgenic mice also display intraneuronal A 𝛃 (Takahashi et al., 2002; Oddo et al., 2003; Schmitz et al., 2004).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Schmitz et al., 2004
In APP SL PS1KI mice, neuron loss is preceded by intraneuronal Aβ.
“Like 5XFADmice,theneuronloss in APP SL PS1KI mice is preceded by intraneuronal A 𝛃 , although intraneuronal A 𝛃 does not appear to cause amyloid plaque formation in this model.”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Schmitz et al., 2004
PS1/APP mutant transgenic mice have prominent intraneuronal Aβ accumulation associated with neuron cell death.
“PS1/APP mutant transgenic mice were shown to have prominent intraneuronal Aβ accumulation associated with neuron cell death [23, 35, 167].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [167]
Emerging data, such as FAD mutations and the direct association of intraneuronal Aβ42 with subcellular pathology, cell death, and behavioral and physiological abnormalities prior to plaques in AD transgenic mouse models, provide increasing evidence for the importance of intraneuronal Aβ.
“Emerging data, such as FAD mutations noted above, and the direct association of intraneuronal Aβ42 with subcellular pathology [187, 188], cell death [23, 167], and behavioral and physiological abnormalities, even prior to plaques, in AD transgenic mouse models [140], are providing increasing evidence for the importance of intraneuronal Aβ.”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [167]
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- Authors
- Schmitz, C., Rutten, B. P. F., Pielen, A., Schäfer, S., Wirths, O., Tremp, G., Czech, C., Blanchard, V., Multhaup, G., Rezaie, P., Korr, H., Steinbusch, H. W. M., Pradier, L., & Bayer, T. A.
- Affiliations
- Maastricht University (NL)
- RWTH Aachen University (DE)
- Universitätsklinikum des Saarlandes (DE)
- Sanofi (France) (FR)
- Freie Universität Berlin (DE)
- King's College London (GB)
- European Graduate School of Neuroscience (NL)
- Corresponding author
- Schmitz, Christoph
- Rutten, Bart P.F.
- ORCID
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2004-04
- Volume
- 164
- Issue
- 4
- Pages
- 1495-1502
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1615337
- OpenAlex
- W1976128767
- Cited by
- 281
- References
- 32
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 5 · 2023: 7 · 2022: 4 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 8 · 2017: 16 · 2016: 10 · 2015: 16 · 2014: 21 · 2013: 12 · 2012: 17
- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- Fritz Thyssen Stiftung
- Deutsche Forschungsgemeinschaft (Mu901)
- Internationale Stichting Alzheimer Onderzoek
- Alzheimer Forschung Initiative
- European Commission
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- Alzheimer's disease, hippocampal neuronal loss, amyloid plaques, amyloid hypothesis, presenilin 1, amyloid precursor protein, pyramidal neurons, astrocytes, age-related neurodegeneration, transgenic mouse model
- MeSH terms
- Aging, Alzheimer Disease, Animals, Disease Models, Animal, Female, Gliosis, Hippocampus, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Mice, Transgenic, Nerve Degeneration, Amyloid beta-Protein Precursor, Mice, Plaque, Amyloid
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