Accumulation of intraneuronal Aβ correlates with ApoE4 genotype
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In contrast to extracellular plaque and intracellular tangle pathology, the presence and relevance of intraneuronal Abeta in Alzheimer's disease (AD) is still a matter of debate. Human brain tissue offers technical challenges such as post-mortem delay and uneven or prolonged tissue fixation that might affect immunohistochemical staining. In addition, previous studies on intracellular Abeta accumulation in human brain often used antibodies targeting the C-terminus of Abeta and differed strongly in the pretreatments used. To overcome these inconsistencies, we performed extensive parametrical testing using a highly specific N-terminal Abeta antibody detecting the aspartate at position 1, before developing an optimal staining protocol for intraneuronal Abeta detection in paraffin-embedded sections from AD patients. To rule out that this antibody also detects the beta-cleaved APP C-terminal fragment (beta-CTF, C99) bearing the same epitope, paraffin-sections of transgenic mice overexpressing the C99-fragment were stained without any evidence for cross-reactivity in our staining protocol. The staining intensity of intraneuronal Abeta in cortex and hippocampal tissue of 10 controls and 20 sporadic AD cases was then correlated to patient data including sex, Braak stage, plaque load, and apolipoprotein E (ApoE) genotype. In particular, the presence of one or two ApoE4 alleles strongly correlated with an increased accumulation of intraneuronal Abeta peptides. Given that ApoE4 is a major genetic risk factor for AD and is involved in neuronal cholesterol transport, it is tempting to speculate that perturbed intracellular trafficking is involved in the increased intraneuronal Abeta aggregation in AD.
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The human study measured Aβ40.
“However, this human study measured A40”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [63]
A single human study reports an increase in intraneuronal Aβ with one or two alleles of APOE4.
“These data are in apparent contrast with data from a single study in humans that reports an increase in intraneuronal A with one or two alleles of APOE4 (63).”
From APOE4-specific Changes in Aβ Accumulation in a New Transgenic Mouse Model of Alzheimer Disease (2012) · cites this paper as [63]
APOE ε4 has been linked to intraneuronal Aβ accumulation in the human AD brain, and its fragments seem to promote cellular Aβ uptake.
“It has also been linked to intraneuronal Aβ accumulation in the human AD brain [142] and its fragments seem to promote cellular Aβ uptake [143].”
From Neuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models (2020) · cites this paper as [142]
Intraneuronal Aβ correlates with the apolipoprotein E4 (ApoE4) genotype, which has been described to downregulate autophagy.
“Another piece of evidence for the role of autophagy in intraneuronal Aβ accumulation is the finding that intraneuronal Aβ correlates with the apolipoprotein E4 (ApoE4) genotype [21], the main known genetic risk factor for AD, which has been described to downregulate autophagy [108].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [21]
Intraneuronal Aβ accumulation has been found in the brains of patients presenting AD or mild cognitive impairment and is suggested to represent an early step in AD neuropathology.
“Intraneuronal Aβ accumulation has been found in the brains of patients presenting AD or mild cognitive impairment [3, 21, 41, 47, 78], and studies suggest that this phenomenon represents an early step in AD neuropathology [40].”
From Senescence-related impairment of autophagy induces toxic intraneuronal amyloid-β accumulation in a mouse model of amyloid pathology (2023) · cites this paper as [21]
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ResultBossers, K., Wirz, K. T. S., Meerhoff, G. F., Essing, A. H. W., van Dongen, J. W., Houba, P., Kruse, C. G., Verhaagen, J., & Swaab, D. F. (2010) · Brain · doi:10.1093/brain/awq258 · Cited by 230 · see citing works
Intraneuronal Aβ detection in 5xFAD mice by a new Aβ-specific antibody
Youmans, K. L., Tai, L. M., Kanekiyo, T., Stine Jr, W. B., Michon, S.-C., Nwabuisi-Heath, E., Manelli, A. M., Fu, Y., Riordan, S., Eimer, W. A., et al. (2012) · Molecular Neurodegeneration · doi:10.1186/1750-1326-7-8 · Cited by 164 · see citing works
The informed road map to prevention of Alzheimer Disease: a call to arms
McDade, E., Llibre-Guerra, J. J., Holtzman, D. M., Morris, J. C., & Bateman, R. J. (2021) · Molecular Neurodegeneration · doi:10.1186/s13024-021-00467-y · Cited by 89 · see citing works
Thal, D. R., Papassotiropoulos, A., Saido, T. C., Griffin, W. S. T., Mrak, R. E., Kölsch, H., Tredici, K. D., Attems, J., & Ghebremedhin, E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0707-9 · Cited by 103 · see citing works
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Self-citationNeuron Loss in Alzheimer’s Disease: Translation in Transgenic Mouse Models
Wirths, O., & Zampar, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218144 · Cited by 75 · see citing works
“It has also been linked to intraneuronal Aβ accumulation in the human AD brain [142] and its fragments seem to promote cellular Aβ uptake [143].”
BackgroundSelf-citationMathur, R., Ince, P. G., Minett, T., Garwood, C. J., Shaw, P. J., Matthews, F. E., Brayne, C., Simpson, J. E., Wharton, S. B., & on behalf of the MRC Cognitive Function and Ageing Neuropathology Study Group (2015) · PLOS ONE · doi:10.1371/journal.pone.0118463 · Cited by 52 · see citing works
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AβPP Accumulation and/or Intraneuronal Amyloid-β Accumulation? The 3xTg-AD Mouse Model Revisited
Wirths, O., Dins, A., & Bayer, T. A. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2011-111529 · Cited by 26 · see citing works
Self-citation
- Authors
- Christensen, D. Z., Schneider-Axmann, T., Lucassen, P. J., Bayer, T. A., & Wirths, O.
- Affiliations
- University of Göttingen (DE)
- University of Amsterdam (NL)
- Corresponding author
- Wirths, Oliver
- Venue
- Acta Neuropathologica
- Published
- 2010-03-10
- Volume
- 119
- Issue
- 5
- Pages
- 555-566
- ISSN
- 0001-6322 (ISSN-L)
- 1432-0533
- PMC
- PMC2849938
- OpenAlex
- W2095510744
- Cited by
- 120
- References
- 74
- Citations by year
- 2026: 8 · 2025: 7 · 2024: 10 · 2023: 12 · 2022: 13 · 2021: 7 · 2020: 7 · 2019: 6 · 2018: 1 · 2017: 5 · 2016: 9 · 2015: 2 · 2014: 4 · 2013: 7 · 2012: 9
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc
- Locations
- Acta Neuropathologica (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- UvA-DARE (University of Amsterdam) (publishedVersion, other-oa)
- GoeScholar The Publication Server of the Georg-August-Universität Göttingen (Georg-August-Universität Göttingen) (submittedVersion, cc-by)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- Funders
- Alzheimer Forschung Initiative
- European Commission (MEST-CT-2005-020013)
- Fritz Thyssen Stiftung
- Internationale Stichting Alzheimer Onderzoek (MEST-CT-2005-020013)
- 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
- intraneuronal amyloid-beta, Alzheimer's disease, APOE ε4, APOE genotype, Braak stages, amyloid plaques, hippocampus, cerebral cortex, intracellular trafficking, genetic risk factors
- MeSH terms
- Aged, Aged, 80 and over, Alleles, Alzheimer Disease, Cerebral Cortex, Female, Genotype, Humans, Immunohistochemistry, Male, Neurons, Amyloid beta-Peptides, Statistics, Nonparametric, Genetic Predisposition to Disease, Apolipoprotein E4
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
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