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β-Secretase Activity Increases with Aging in Human, Monkey, and Mouse Brain
Open accessAbstract
Amyloid beta protein (A beta) accumulates in the brains of aging humans, amyloid precursor protein (APP) transgenic mouse lines, and rhesus monkeys. We tested the hypothesis that aging was associated with increased activity of the beta-site amyloid precursor protein cleaving enzyme (beta-secretase, BACE) in brain. We evaluated BACE activity, BACE protein, and formic acid-extractable A beta levels in cohorts of young (4 months old) and old (14 to 18 months old) nontransgenic mice (n = 16) and Tg2576 APP transgenic mice (n = 17), young (4.4 to 12.7 years old) and old (20.9 to 30.4 years old) rhesus monkeys (n = 17), and a wide age range (18 to 92 years old) of nondemented human brains (n = 25). Aging was associated with increased brain A beta levels in each cohort. Furthermore BACE activity increased significantly with age in mouse, monkey, and human brains, independent of brain region. BACE protein levels, however, were unchanged with age. BACE activity correlated with formic acid-extractable A beta levels in transgenic mouse, nontransgenic mouse, and human cortex, but not in monkey brain. These data suggest that an age-related increase of BACE activity contributes to the increased production and accumulation of brain A beta, and potentially predisposes to Alzheimer's disease in humans.
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“Previous studies consistently reported that expression and activity of BACE1 are increased during aging in the brains mice, rats and humans (Boissonneault et al. 2009, Che et al. 2014, Fukumoto et al. 2004, Rossner et al. 2006), raising the possibility of a link between aging-associated alterations in BACE1 and the increased risk for AD.”
From miR‐186 is decreased in aged brain and suppresses BACE 1 expression (2016) · cites this paper as Fukumoto et al. 2004
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Cites
Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G. (1996) · Science · doi:10.1126/science.274.5284.99 · Cited by 4,210
Vassar, R., Bennett, B. D., Babu-Khan, S., Kahn, S., Mendiaz, E. A., Denis, P., Teplow, D. B., Ross, S., Amarante, P., Loeloff, R., et al. (1999) · Science · doi:10.1126/science.286.5440.735 · Cited by 3,876
Scheuner, D., Eckman, C., Jensen, M., Song, X., Citron, M., Suzuki, N., Bird, T. D., Hardy, J., Hutton, M., Kukull, W., et al. (1996) · Nature Medicine · doi:10.1038/nm0896-864 · Cited by 2,599
Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein
Games, D., Adams, D., Alessandrini, R., Barbour, R., Borthelette, P., Blackwell, C., Carr, T., Clemens, J., Donaldson, T., Gillespie, F., et al. (1995) · Nature · doi:10.1038/373523a0 · Cited by 2,516
HYMAN, B. T., & TROJANOWSKI, J. Q. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199710000-00002 · Cited by 1,542
Self-citationTwo amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology
Sturchler-Pierrat, C., Abramowski, D., Duke, M., Wiederhold, K.-H., Mistl, C., Rothacher, S., Ledermann, B., Bürki, K., Frey, P., Paganetti, P. A., et al. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.24.13287 · Cited by 1,507
Suzuki, N., Cheung, T. T., Cai, X.-D., Odaka, A., Otvos, L., Eckman, C., Golde, T. E., & Younkin, S. G. (1994) · Science · doi:10.1126/science.8191290 · Cited by 1,471
The prevalence of dementia: A quantitative integration of the literature
Jorm, A. F., Korten, A. E., & Henderson, A. S. (1987) · Acta Psychiatrica Scandinavica · doi:10.1111/j.1600-0447.1987.tb02906.x · Cited by 1,301
Luo, Y., Bolon, B., Kahn, S., Bennett, B. D., Babu-Khan, S., Denis, P., Fan, W., Kha, H., Zhang, J., Gong, Y., et al. (2001) · Nature Neuroscience · doi:10.1038/85059 · Cited by 1,001
Price, J. L., Davis, P. B., Morris, J. C., & White, D. L. (1991) · Neurobiology of Aging · doi:10.1016/0197-4580(91)90006-6 · Cited by 818
The Relationship between Aβ and Memory in the Tg2576 Mouse Model of Alzheimer's Disease
Westerman, M. A., Cooper-Blacketer, D., Mariash, A., Kotilinek, L., Kawarabayashi, T., Younkin, L. H., Carlson, G. A., Younkin, S. G., & Ashe, K. H. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-05-01858.2002 · Cited by 731
Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease
Yang, L.-B., Lindholm, K., Yan, R., Citron, M., Xia, W., Yang, X.-L., Beach, T., Sue, L., Wong, P., Price, D., et al. (2003) · Nature Medicine · doi:10.1038/nm0103-3 · Cited by 729
Roberds, S. L. (2001) · Human Molecular Genetics · doi:10.1093/hmg/10.12.1317 · Cited by 705
IRIZARRY, M. C., MCNAMARA, M., FEDORCHAK, K., HSIAO, K., & HYMAN, B. T. (1997) · Journal of Neuropathology and Experimental Neurology · doi:10.1097/00005072-199709000-00002 · Cited by 649
Self-citationβ-Secretase Protein and Activity Are Increased in the Neocortex in Alzheimer Disease
Fukumoto, H. (2002) · Archives of Neurology · doi:10.1001/archneur.59.9.1381 · Cited by 575
Self-citationIncreased expression of the amyloid precursor β‐secretase in Alzheimer's disease
Holsinger, R. M. D., McLean, C. A., Beyreuther, K., Masters, C. L., & Evin, G. (2002) · Annals of Neurology · doi:10.1002/ana.10208 · Cited by 562
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
Self-citationMaturation and Endosomal Targeting of β-Site Amyloid Precursor Protein-cleaving Enzyme
Huse, J. T., Pijak, D. S., Leslie, G. J., Lee, V. M.-Y., & Doms, R. W. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m004175200 · Cited by 402
Oxidative stress increases expression and activity of BACE in NT2 neurons
Tamagno, E., Bardini, P., Obbili, A., Vitali, A., Borghi, R., Zaccheo, D., Pronzato, M. A., Danni, O., Smith, M. A., Perry, G., et al. (2002) · Neurobiology of Disease · doi:10.1006/nbdi.2002.0515 · Cited by 385
Conservation of brain amyloid proteins in aged mammals and humans with Alzheimer's disease.
Selkoe, D. J., Bell, D. S., Podlisny, M. B., Price, D. L., & Cork, L. C. (1987) · Science · doi:10.1126/science.3544219 · Cited by 377
Benjannet, S., Elagoz, A., Wickham, L., Mamarbachi, M., Munzer, J. S., Basak, A., Lazure, C., Cromlish, J. A., Sisodia, S., Checler, F., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009899200 · Cited by 301
Kinoshita, A., Fukumoto, H., Shah, T., Whelan, C. M., Irizarry, M. C., & Hyman, B. T. (2003) · Journal of Cell Science · doi:10.1242/jcs.00643 · Cited by 284
Self-citationNeuritic (Senile) Plaques and Filamentous Changes in Aged Rhesus Monkeys
Wiśniewski, H. M., Ghetti, B., & Terry, R. D. (1973) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-197310000-00007 · Cited by 272
Compartmentalization of β-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts
Riddell, D. R., Christie, G., Hussain, I., & Dingwall, C. (2001) · Current Biology · doi:10.1016/s0960-9822(01)00394-3 · Cited by 253
Deciphering the genesis and fate of amyloid β-protein yields novel therapies for Alzheimer disease
Selkoe, D. J. (2002) · Journal of Clinical Investigation · doi:10.1172/jci16783 · Cited by 230
Phosphorylation Regulates Intracellular Trafficking of β-Secretase
Walter, J., Fluhrer, R., Hartung, B., Willem, M., Kaether, C., Capell, A., Lammich, S., Multhaup, G., & Haass, C. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m011116200 · Cited by 229
Yasojima, K., McGeer, E. G., & McGeer, P. L. (2001) · Brain Research · doi:10.1016/s0006-8993(01)03008-6 · Cited by 224
Region‐specific reduction of Aβ‐degrading endopeptidase, neprilysin, in mouse hippocampus upon aging
Iwata, N., Takaki, Y., Fukami, S., Tsubuki, S., & Saido, T. C. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10390 · Cited by 207
Maturation and Pro-peptide Cleavage of β-Secretase
Capell, A., Steiner, H., Willem, M., Kaiser, H., Meyer, C., Walter, J., Lammich, S., Multhaup, G., & Haass, C. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003202200 · Cited by 205
Senile plaques in cortex of aged normal monkeys
Struble, R. G., Price, D. L., Cork, L. C., & Price, D. L. (1985) · Brain Research · doi:10.1016/0006-8993(85)91298-3 · Cited by 189
Astrocytic expression of the Alzheimer's disease β‐secretase (BACE1) is stimulus‐dependent
Hartlage‐Rübsamen, M., Zeitschel, U., Apelt, J., Gärtner, U., Franke, H., Stahl, T., Günther, A., Schliebs, R., Penkowa, M., Bigl, V., et al. (2002) · Glia · doi:10.1002/glia.10178 · Cited by 160
Ermolieff, J., Loy, J. A., Koelsch, G., & Tang, J. (2000) · Biochemistry · doi:10.1021/bi001494f · Cited by 127
Shi, X., Chen, E., Yin, K., Sang, N., Garsky, V. M., Lai, M., Li, Y., Platchek, M., Register, R. B., Sardana, M. K., et al. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m009200200 · Cited by 123
Expression of human β‐secretase in the mouse brain increases the steady‐state level of β‐amyloid
Bodendorf, U., Danner, S., Fischer, F., Stefani, M., Sturchler, C., Wiederhold, K., Staufenbiel, M., & Paganetti, P. (2002) · Journal of Neurochemistry · doi:10.1046/j.0022-3042.2002.00770.x · Cited by 123
The neural basis of memory decline in aged monkeys
Walker, L. C., Kitt, C. A., Struble, R. G., Wagster, M. V., Price, D. L., & Cork, L. C. (1988) · Neurobiology of Aging · doi:10.1016/s0197-4580(88)80130-1 · Cited by 122
Fukumoto, H., Asami-Odaka, A., Suzuki, N., Shimada, H., Ihara, Y., & Iwatsubo, T. (1996) · Europe PMC (PubMed Central) · Cited by 108
Self-citationKosaka, T., Imagawa, M., Seki, K., Arai, H., Sasaki, H., Tsuji, S., Asami-Odaka, A., Fukushima, T., Imai, K., & Iwatsubo, T. (1997) · Neurology · doi:10.1212/wnl.48.3.741 · Cited by 104
Lack of correlation between plaque burden and cognition in the aged monkey
Sloane, J. A., Pietropaolo, M., Rosene, D. L., Moss, M. B., Peters, A., Kemper, T. L., & Abraham, C. R. (1997) · Acta Neuropathologica · doi:10.1007/s004010050735 · Cited by 103
Self-citationRoßner, S., Apelt, J., Schliebs, R., Perez-Polo, J. R., & Bigl, V. (2001) · Journal of Neuroscience Research · doi:10.1002/jnr.1095 · Cited by 102
β-Site APP Cleaving Enzyme mRNA Expression in APP Transgenic Mice
Irizarry, M. C., Locascio, J. J., & Hyman, B. T. (2001) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63955-7 · Cited by 69
Self-citationDevelopmental Regulation of Presenilin mRNA Expression Parallels Notch Expression
Berezovska, O., Xia, M., Page, K. J., Wasco, W., Tanzi, R. E., & Hyman, B. T. (1997) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/00005072-199701000-00004 · Cited by 66
Self-citationTanahashi, H., & Tabira, T. (2001) · Neuroscience Letters · doi:10.1016/s0304-3940(01)01912-7 · Cited by 51
Kametaka, S., Shibata, M., Moroe, K., Kanamori, S., Ohsawa, Y., Waguri, S., Sims, P. J., Emoto, K., Umeda, M., & Uchiyama, Y. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208611200 · Cited by 47
Huse, J. T., Byant, D., Yang, Y., Pijak, D. S., D’Souza, I., Lah, J. J., Lee, V. M. ‐., Doms, R. W., & Cook, D. G. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m213303200 · Cited by 43
Localization of β-Secretase Memapsin 2 in the Brain of Alzheimer's Patients and Normal Aged Controls
Sun, A., Koelsch, G., Tang, J., & Bing, G. (2002) · Experimental Neurology · doi:10.1006/exnr.2002.7875 · Cited by 42
Age-related changes in the localization of presenilin-1 in cynomolgus monkey brain
Kimura, N., Nakamura, S., Honda, T., Takashima, A., Nakayama, H., Ono, F., Sakakibara, I., Doi, K., Kawamura, S., & Yoshikawa, Y. (2001) · Brain Research · doi:10.1016/s0006-8993(01)03146-8 · Cited by 38
BACE1 interacts with nicastrin
Hattori, C., Asai, M., Oma, Y., Kino, Y., Sasagawa, N., Saido, T. C., Maruyama, K., & Ishiura, S. (2002) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(02)00351-0 · Cited by 35
Flood, F., Cowburn, R. F., & Johnston, J. A. (1997) · Neuroscience Letters · doi:10.1016/s0304-3940(97)00697-6 · Cited by 13
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Lim, G. P., Calon, F., Morihara, T., Yang, F., Teter, B., Ubeda, O. J., Salem, N., Frautschy, S. A., & Cole, G. M. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.4225-04.2005 · Cited by 697
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Sun, X., He, G., Qing, H., Zhou, W., Dobie, F., Cai, F., Staufenbiel, M., Huang, L. E., & Song, W. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0606298103 · Cited by 605
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Ly, P. T. T., Wu, Y., Zou, H., Wang, R., Zhou, W., Kinoshita, A., Zhang, M., Yang, Y., Cai, F., Woodgett, J., et al. (2013) · Journal of Clinical Investigation · doi:10.1172/jci64516 · Cited by 442
Metadata
- Authors
- Fukumoto, H., Rosene, D. L., Moss, M. B., Raju, S., Hyman, B. T., & Irizarry, M. C.
- Affiliations
- Massachusetts General Hospital (US)
- Boston University (US)
- Corresponding author
- Irizarry, Michael C.
- Venue
- The American Journal of Pathology
- Publisher
- Elsevier BV
- Published
- 2004-02
- Volume
- 164
- Issue
- 2
- Pages
- 719-725
- ISSN
- 0002-9440 (ISSN-L)
- PMC
- PMC1602259
- OpenAlex
- W2076868543
- Cited by
- 294
- References
- 50
- Citations by year
- 2026: 6 · 2025: 7 · 2024: 11 · 2023: 13 · 2022: 13 · 2021: 11 · 2020: 12 · 2019: 10 · 2018: 10 · 2017: 13 · 2016: 16 · 2015: 16 · 2014: 8 · 2013: 23 · 2012: 18
- FWCI
- 11.75
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- American Journal Of Pathology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Boston University (RR00165, PHS MH/NS 31862)
- National Institutes of Health (AG05134, AG15453, AG00001)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
- beta-secretase, brain aging, amyloid-beta deposition, amyloid precursor protein, Alzheimer's disease, rhesus monkeys, human brain, cerebral cortex
- MeSH terms
- Aging, Animals, Brain, Enzyme-Linked Immunosorbent Assay, Humans, Macaca mulatta, Mice, Transgenic, Blotting, Western, Amyloid beta-Peptides, Aspartic Acid Endopeptidases, Mice
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