Intraneuronal amyloid β and reduced brain volume in a novel APP T714I mouse model for Alzheimer's disease
Abstract
Transgenic mouse models of Alzheimer's disease (AD) expressing high levels of amyloid precursor protein (APP) with familial AD (FAD) mutations have proven to be extremely useful in understanding pathogenic processes of AD especially those that involve amyloidogenesis. We earlier described Austrian APP T714I pathology that leads to one of the earliest AD age-at-onsets with abundant intracellular and extracellular amyloid deposits in brain. The latter strikingly was non-fibrillar diffuse amyloid, composed of N-truncated A beta 42 in absence of A beta 40. In vitro, this mutation leads to one of the highest A beta 42/A beta 40 ratios among all FAD mutations. We generated an APP T714I transgenic mouse model that despite having 10 times lower transgene than endogenous murine APP deposited intraneuronal A beta in brain by 6 months of age. Accumulations increased with age, and this was paralleled by decreased brain sizes on volumetric MRI, compared to age-matched and similar transgene-expressing APP wild-type mice, although, with these levels of transgenic expression we did not detect neuronal loss or significant memory impairment. Immunohistochemical studies revealed that the majority of the intraneuronal A beta deposits colocalized with late endosomal markers, although some A beta inclusions were also positive for lysosomal and Golgi markers. These data support earlier observations of A beta accumulation in the endosomal-lysosomal pathway and the hypothesis that intraneuronal accumulation of A beta could be an important factor in the AD pathogenesis.
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FAD transgenic mouse models with the highest level of amyloidogenic Aβ display particularly prominent early intraneuronal Aβ accumulation.
“FAD transgenic mouse models with the highest level of amyloidogenic Aβ display particularly prominent early intraneuronal Aβ accumulation [89, 106, 196].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [196]
Cites
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864 · see citing works
The Mouse Brain in Stereotaxic Coordinates
Paxinos, G. (2001) · Cited by 12,859 · see citing works
Triple-Transgenic Model of Alzheimer’s Disease with Plaques and Tangles
Oddo, S., Caccamo, A., Shepherd, J. D., Murphy, M. P., Golde, T. E., Kayed, R., Metherate, R., Mattson, M. P., Akbari, Y., & LaFerla, F. M. (2003) · Neuron · doi:10.1016/s0896-6273(03)00434-3 · Cited by 4,126 · see citing works
Billings, L. M., Oddo, S., Green, K. N., McGaugh, J. L., & LaFerla, F. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.01.040 · Cited by 1,294 · see citing works
Differences in the pattern of hippocampal neuronal loss in normal ageing and Alzheimer's disease
West, M. J., Coleman, P. D., Flood, D. G., & Troncoso, J. C. (1994) · The Lancet · doi:10.1016/s0140-6736(94)92338-8 · Cited by 1,267 · cited 1× · see citing works
“Initially, the CA1 region was chosen because it showed the most significant intraneuronal A deposition in this study (see later) and a region-specific neuronal loss for CA1 has been described in the APP23 transgenic mouse model (Calhoun et al., 1998) as well as in human AD ( West et al., 1994 ).”
BackgroundIntraneuronal Aβ42 Accumulation in Human Brain
Gouras, G. K., Tsai, J., Naslund, J., Vincent, B., Edgar, M., Checler, F., Greenfield, J. P., Haroutunian, V., Buxbaum, J. D., Xu, H., et al. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64700-1 · Cited by 991 · see citing works
Saura, C. A., Choi, S.-Y., Beglopoulos, V., Malkani, S., Zhang, D., Rao, B. S. S., Chattarji, S., Kelleher, R. J., Kandel, E. R., Duff, K., et al. (2004) · Neuron · doi:10.1016/s0896-6273(04)00182-5 · Cited by 757 · see citing works
Takahashi, R. H., Milner, T. A., Li, F., Nam, E. E., Edgar, M. A., Yamaguchi, H., Beal, M. F., Xu, H., Greengard, P., & Gouras, G. K. (2002) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64463-x · Cited by 706 · see citing works
Johnson‐Wood, K., Lee, M., Motter, R. N., Hu, K., Gordon, G., Barbour, R., Khan, K., Gordon, M. N., Tan, H. T., Games, D., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.4.1550 · Cited by 634 · see citing works
Neuron loss in APP transgenic mice
Calhoun, M. E., Wiederhold, K.-H., Abramowski, D., Phinney, A. L., Probst, A., Sturchler-Pierrat, C., Staufenbiel, M., Sommer, B., & Jucker, M. (1998) · Nature · doi:10.1038/27351 · Cited by 502 · see citing works
Irizarry, M. C., Soriano, F., McNamara, M., Page, K. J., Schenk, D., Games, D., & Hyman, B. T. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-18-07053.1997 · Cited by 497 · see citing works
Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain
Takahashi, R. H., Almeida, C. G., Kearney, P. F., Yu, F., Lin, M. T., Milner, T. A., & Gouras, G. K. (2004) · The Journal of Neuroscience · doi:10.1523/jneurosci.5167-03.2004 · Cited by 445 · see citing works
Presenilin clinical mutations can affect γ‐secretase activity by different mechanisms
Bentahir, M., Nyabi, O., Verhamme, J., Tolia, A., Horré, K., Wiltfang, J., Esselmann, H., & Strooper, B. D. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03578.x · Cited by 412 · see citing works
Casas, C., Sergeant, N., Itier, J.-M., Blanchard, V., Wirths, O., van der Kolk, N., Vingtdeux, V., van de Steeg, E., Ret, G., Canton, T., et al. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63388-3 · Cited by 400 · see citing works
D'Andrea, M. R., Nagele, R. G., Wang, H., Peterson, P. A., & Lee, D. H. S. (2001) · Histopathology · doi:10.1046/j.1365-2559.2001.01082.x · Cited by 390 · see citing works
Chui, D.-H., Tanahashi, H., Ozawa, K., Ikeda, S., Checler, F., Ueda, O., Suzuki, H., Araki, W., Inoue, H., Shirotani, K., et al. (1999) · Nature Medicine · doi:10.1038/8438 · Cited by 364 · see citing works
Cataldo, A. M., Petanceska, S., Terio, N. B., Peterhoff, C. M., Durham, R., Mercken, M., Mehta, P. D., Buxbaum, J., Haroutunian, V., & Nixon, R. A. (2004) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.02.027 · Cited by 363 · see citing works
Intraneuronal Aβ accumulation and origin of plaques in Alzheimer's disease
Gouras, G. K., Almeida, C. G., & Takahashi, R. H. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.05.022 · Cited by 338 · see citing works
Kumar‐Singh, S., Theuns, J., Broeck, B. V., Pirici, D. N., Vennekens, K., Corsmit, E., Cruts, M., Dermaut, B., Wang, R., & Broeckhoven, C. V. (2006) · Human Mutation · doi:10.1002/humu.20336 · Cited by 320 · see citing works
Self-citationAge‐dependent cognitive decline in the APP23 model precedes amyloid deposition
Dam, D. V., D’Hooge, R., Staufenbiel, M., Ginneken, C. J. V., Meir, F. V., & Deyn, P. P. D. (2003) · European Journal of Neuroscience · doi:10.1046/j.1460-9568.2003.02444.x · Cited by 297 · see citing works
Skovronsky, D. M., Doms, R. W., & Lee, V. M.-Y. (1998) · The Journal of Cell Biology · doi:10.1083/jcb.141.4.1031 · Cited by 290 · see citing works
Lord, A., Kalimo, H., Eckman, C., Zhang, X.-Q., Lannfelt, L., & Nilsson, L. N. G. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.12.007 · Cited by 260 · see citing works
Intraneuronal Aβ42 accumulation in Down syndrome brain: Original Articles
Mori, C., Spooner, E. T., Wisniewski, K. E., Wisniewski, T. M., Yamaguchi, H., Saido, T. C., Tolan, D. R., Selkoe, D. J., & Lemere, C. A. (2002) · Amyloid · doi:10.3109/13506120208995241 · Cited by 255 · see citing works
Intraneuronal Aβ-Amyloid Precedes Development of Amyloid Plaques in Down Syndrome
Gyure, K. A., Durham, R., Stewart, W. F., Smialek, J. E., & Troncoso, J. C. (2001) · Archives of Pathology & Laboratory Medicine · doi:10.5858/2001-125-0489-iaapdo · Cited by 248 · see citing works
De Jonghe, C. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.16.1665 · Cited by 223 · see citing works
Intracellular Mechanisms of Amyloid Accumulation and Pathogenesis in Alzheimer's Disease
Glabe, C. (2001) · Journal of Molecular Neuroscience · doi:10.1385/jmn:17:2:137 · Cited by 222 · see citing works
Redwine, J. M., Kosofsky, B. E., Jacobs, R. E., Games, D., Reilly, J. F., Morrison, J. H., Young, W. G., & Bloom, F. E. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.242746599 · Cited by 201 · see citing works
Kumar‐Singh, S., Pirici, D. N., McGowan, E. M., Serneels, S., Ceuterick, C., Hardy, J., Duff, K., Dickson, D. W., & Broeckhoven, C. V. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62995-1 · Cited by 179 · see citing works
Self-citationAncolio, K., Dumanchin‐Njock, C., Barelli, H., Warter, J., Brice, A., Campion, D., Frébourg, T., & Checler, F. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.4119 · Cited by 179 · see citing works
Subcellular Topography of Neuronal Aβ Peptide in APPxPS1 Transgenic Mice
Langui, D., Girardot, N., El Hachimi, K. H., Allinquant, B., Blanchard, V., Pradier, L., & Duyckaerts, C. (2004) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)63405-0 · Cited by 165 · see citing works
Kumar-Singh, S. (2000) · Human Molecular Genetics · doi:10.1093/hmg/9.18.2589 · Cited by 158 · see citing works
Self-citationGeneration and Regulation of β‐Amyloid Peptide Variants by Neurons
Gouras, G., Xu, H.-X., Jovanovic, J., Buxbaum, J. D., Wang, R., Greengard, P., Relkin, N., & Gandy, S. (1998) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.1998.71051920.x · Cited by 124 · see citing works
Soler‐Botija, C. (2002) · Brain · doi:10.1093/brain/awf155 · Cited by 109 · see citing works
Echeverrı́a, V., Ducatenzeiler, A., Dowd, E., Jänne, J., Grant, S. M., Szyf, M., Wandosell, F. G., Ávila, J., Grimm, H. S., Dunnett, S. B., et al. (2004) · Neuroscience · doi:10.1016/j.neuroscience.2004.07.036 · Cited by 101 · see citing works
Zhang, S., Zhou, Y., Trusa, S., Xiao, M., Lee, E. Y. C., & Lee, M. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m610356200 · Cited by 84 · see citing works
Early intraneuronal Aβ deposition in the hippocampus of APP transgenic mice
Shie, F., LeBoeur, R. C., & Jin, L. (2003) · Neuroreport · doi:10.1097/00001756-200301200-00023 · Cited by 83 · see citing works
Wild-type Presenilin 1 Protects against Alzheimer Disease Mutation-induced Amyloid Pathology
Wang, R., Wang, B., He, W., & Zheng, H. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m512574200 · Cited by 73 · see citing works
Presenilins in Memory, Alzheimer's Disease, and Therapy
Marjaux, E., Hartmann, D., & Strooper, B. D. (2004) · Neuron · doi:10.1016/s0896-6273(04)00218-1 · Cited by 63 · see citing works
Pirici, D. N., Vandenberghe, R. R., Rademakers, R., Dermaut, B., Cruts, M., Vennekens, K., Cuijt, I., Lübke, U., Ceuterick, C., Martin, J., et al. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000205147.39210.c7 · Cited by 46 · see citing works
Self-citationAn African American family with early-onset Alzheimer disease and an APP (T714I) mutation
Edwards-Lee, T. A., Ringman, J. M., Chung, J. A., Werner, J. S., Morgan, A. R., George‐Hyslop, P. S., Thompson, P. M., Dutton, R. A., Mlikotic, A., Rogaeva, E. A., et al. (2005) · Neurology · doi:10.1212/01.wnl.0000149761.70566.3e · Cited by 43 · see citing works
Dickson, D. W. (2004) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63202-6 · Cited by 23 · see citing works
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LaFerla, F. M., Green, K. N., & Oddo, S. (2007) · Nature Reviews Neuroscience · doi:10.1038/nrn2168 · Cited by 1,942 · see citing works
Jawhar, S., Trawicka, A., Jenneckens, C., Bayer, T. A., & Wirths, O. (2012) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2010.05.027 · Cited by 623 · see citing works
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BackgroundIntraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease
Gouras, G. K., Tampellini, D., Takahashi, R. H., & Capetillo-Zarate, E. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0679-9 · Cited by 372 · see citing works
Bayer (2010) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2010.00008 · Cited by 252 · see citing works
Wirths, O., Breyhan, H., Cynis, H., Schilling, S., Demuth, H.-U., & Bayer, T. A. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0557-5 · Cited by 174 · see citing works
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Takahashi, R. H., Capetillo-Zarate, E., Lin, M. T., Milner, T. A., & Gouras, G. K. (2010) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2008.07.021 · Cited by 150 · see citing works
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Takahashi, H., Brasnjevic, I., Rutten, B. P. F., Van Der Kolk, N., Perl, D. P., Bouras, C., Steinbusch, H. W. M., Schmitz, C., Hof, P. R., & Dickstein, D. L. (2010) · Brain Structure and Function · doi:10.1007/s00429-010-0242-4 · Cited by 124 · see citing works
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Christensen, D. Z., Schneider-Axmann, T., Lucassen, P. J., Bayer, T. A., & Wirths, O. (2010) · Acta Neuropathologica · doi:10.1007/s00401-010-0666-1 · Cited by 120 · see citing works
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Wirths, O., & Zampar, S. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21218144 · Cited by 75 · see citing works
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BackgroundAho, L., Pikkarainen, M., Hiltunen, M., Leinonen, V., & Alafuzoff, I. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-091681 · Cited by 71 · see citing works
Christensen, D. Z., Bayer, T. A., & Wirths, O. (2009) · Brain Research · doi:10.1016/j.brainres.2009.09.014 · Cited by 47 · see citing works
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- Authors
- Van Broeck, B., Vanhoutte, G., Pirici, D., Van Dam, D., Wils, H., Cuijt, I., Vennekens, K., Zabielski, M., Michalik, A., Theuns, J., De Deyn, P. P., Van der Linden, A., Van Broeckhoven, C., & Kumar-Singh, S.
- Affiliations
- University of Antwerp (BE)
- Venue
- Neurobiology of Aging
- Publisher
- Elsevier BV
- Published
- 2008-02
- Volume
- 29
- Issue
- 2
- Pages
- 241-252
- ISSN
- 0197-4580 (ISSN-L)
- OpenAlex
- W2033686120
- Cited by
- 60
- References
- 41
- Citations by year
- 2025: 1 · 2022: 2 · 2021: 1 · 2020: 1 · 2018: 2 · 2017: 1 · 2016: 1 · 2015: 4 · 2014: 1 · 2013: 8 · 2012: 6
- FWCI
- 3.76
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurobiology of Aging (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Universiteit Antwerpen
- 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, intraneuronal amyloid-beta, transgenic mouse model, familial Alzheimer's disease, brain atrophy, amyloid-beta 42/40 ratio, endolysosomal pathway, late endosomes, Golgi apparatus, lysosomes, amyloid precursor protein
- MeSH terms
- Alzheimer Disease, Analysis of Variance, Animals, Behavior, Animal, Brain, Disease Models, Animal, Enzyme-Linked Immunosorbent Assay, Humans, Isoleucine, Magnetic Resonance Imaging, Mice, Transgenic, Neurons, Peptide Fragments, Psychomotor Performance, Tyrosine, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Maze Learning, Mice
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