Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives
Abstract
beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.
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Altering levels of APP and of sAPPα may impact AD more than altering Aβ levels.
“Altering levels of APP and of sAPPα, a growth factor [262], may impact AD more than altering Aβ levels.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [262]
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Xia, M., & Hyman, B. T. (1999) · Journal of NeuroVirology · doi:10.3109/13550289909029743 · Cited by 269 · see citing works
“…- ques ( at least a substantial proportion ) are believed to represent aberrant regenerating neurites ( Geddes et al , 1986 ; Masliah et al , 1991 ; 1992 ) and APP has been shown to play a role in promoting neurite outgrowth and neuronal survival in vitro ( Mattson , 1997 ; Milward et al , 1992 ) .”
BackgroundHeme oxygenase-1: role in brain aging and neurodegeneration
Schipper, H. M. (2000) · Experimental Gerontology · doi:10.1016/s0531-5565(00)00148-0 · Cited by 269 · see citing works
“Oxidative stress has been amply documented in AD-affected brain tissues (Mattson , 1997) and may be responsible for induction of HO-1 and other stress proteins in these patients (Schipper et al., 1995).”
BackgroundTorroja, L., Packard, M. C., Gorczyca, M. G., White, K., & Budnik, V. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-18-07793.1999 · Cited by 268 · see citing works
“The effects of APP on neuronal development and function have been extensively studied because of their implication in Alzheimer’s disease (for review, see Mattson, 1997; Small, 1998).”
BackgroundPar-4 is a mediator of neuronal degeneration associated with the pathogenesis of Alzheimer disease
Guo, Q., Fu, W., Xie, J., Luo, H., Sells, S. F., Geddes, J. W., Bondada, V., Rangnekar, V. M., & Mattson, M. P. (1998) · Nature Medicine · doi:10.1038/nm0898-957 · Cited by 264 · see citing works
Self-citationVerdier, Y., Zarándi, M., & Penke, B. (2004) · Journal of Peptide Science · doi:10.1002/psc.573 · Cited by 261 · see citing works
Amyloid β-peptide induces apoptosis-related events in synapses and dendrites
Mattson, M. P., Partin, J. V., & Begley, J. G. (1998) · Brain Research · doi:10.1016/s0006-8993(98)00763-x · Cited by 260 · see citing works
Self-citationGenetic Neurodegenerative Diseases: The Human Illness and Transgenic Models
Price, D. L., Sisodia, S. S., & Borchelt, D. (1998) · Science · doi:10.1126/science.282.5391.1079 · Cited by 258 · see citing works
Xie, Z., Wei, M., Morgan, T. E., Fabrizio, P., Han, D., Finch, C. E., & Longo, V. D. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-09-03484.2002 · Cited by 272 · see citing works
“AD brains show widespread oxidative damage (Mattson, 1997; Smith et al., 2000).”
BackgroundSharples, R. A., Vella, L. J., Nisbet, R. M., Naylor, R., Perez, K. A., Barnham, K. J., Masters, C. L., & Hill, A. F. (2008) · The FASEB Journal · doi:10.1096/fj.07-9357com · Cited by 253 · see citing works
Conformational transition of amyloid β-peptide
Xu, Y., Shen, J., Luo, X., Zhu, W., Chen, K., Ma, J., & Jiang, H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0501218102 · Cited by 247 · see citing works
Parker, M. W., Rossjohn, J., Cappai, R., Feil, S. C., Henry, A., McKinstry, W. J., Galatis, D., Hesse, L., Multhaup, G., Beyreuther, K. T., et al. (1999) · Nature Structural Biology · doi:10.1038/7562 · Cited by 242 · see citing works
Aβ1–40-related reduction in functional hyperemia in mouse neocortex during somatosensory activation
Niwa, K., Younkin, L. H., Ebeling, C., Turner, S. K., Westaway, D. A., Younkin, S. G., Ashe, K. H., Carlson, G. A., & Iadecola, C. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.17.9735 · Cited by 244 · see citing works
Puzzo, D., Vitolo, O. V., Trinchese, F., Jacob, J. P., Palmeri, A., & Arancio, O. (2005) · Journal of Neuroscience · doi:10.1523/jneurosci.5291-04.2005 · Cited by 243 · see citing works
Energetics and Oxidative Stress in Synaptic Plasticity and Neurodegenerative Disorders
Mattson, M. P., & Liu, D. (2002) · NeuroMolecular Medicine · doi:10.1385/nmm:2:2:215 · Cited by 242 · see citing works
Self-citationMattson, M. P. (2000) · Brain Research · doi:10.1016/s0006-8993(00)02790-6 · Cited by 239 · see citing works
Self-citationHaughey, N. J., Liu, D., Nath, A., Borchard, A. C., & Mattson, M. P. (2002) · NeuroMolecular Medicine · doi:10.1385/nmm:1:2:125 · Cited by 236 · see citing works
Self-citationKremer, J. J., Pallitto, M. M., Sklansky, D. J., & Murphy, R. M. (2000) · Biochemistry · doi:10.1021/bi0001980 · Cited by 237 · see citing works
Rouch, L., Cestac, P., Hanon, O., Cool, C., Helmer, C., Bouhanick, B., Chamontin, B., Dartigues, J.-F., Vellas, B. J., & Andrieu, S. (2015) · CNS Drugs · doi:10.1007/s40263-015-0230-6 · Cited by 237 · see citing works
“Reactive oxygen species (ROS) caused by Ab accumulation may have an effect on NMDA receptors and L-VGCCs, leading to a greater influx of calcium [72, 73].”
Sabo, S. L., Ikin, A. F., Buxbaum, J. D., & Greengard, P. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.7.1403 · Cited by 237 · see citing works
“APP and FE65 Regulate Cell Movement 1405 where r is the correlation and v is the covariance of two scalars, x and y .”
BackgroundThe channel hypothesis of Alzheimer’s disease: current status
Kagan, B. L., Hirakura, Y., Azimov, R., Azimova, R., & Lin, M. (2002) · Peptides · doi:10.1016/s0196-9781(02)00067-0 · Cited by 230 · see citing works
- Authors
- Mattson, M. P.
- Affiliations
- University of Kentucky (US)
- Corresponding author
- Mattson, M. P.
- ORCID
- Mattson, M. P.
- Venue
- Physiological Reviews
- Publisher
- American Physiological Society
- Published
- 1997-10-01
- Volume
- 77
- Issue
- 4
- Pages
- 1081-1132
- ISSN
- 0031-9333 (ISSN-L)
- 1522-1210
- OpenAlex
- W1762207349
- Cited by
- 1,006
- References
- 0
- Citations by year
- 2026: 1 · 2025: 8 · 2024: 13 · 2023: 22 · 2022: 12 · 2021: 17 · 2020: 20 · 2019: 14 · 2018: 26 · 2017: 23 · 2016: 27 · 2015: 30 · 2014: 38 · 2013: 31 · 2012: 43
- FWCI
- 29.37
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Physiological Reviews (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ns029001-07, 5r01ns030583-04)
- National Institute of Neurological Disorders and Stroke (NS29001, NS30583)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- amyloid precursor protein, soluble APP alpha, amyloid-beta, Alzheimer's disease, axonal transport, presynaptic terminals, neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, cAMP signaling, potassium channels, NMDA receptor, NF-κB, cell adhesion, excitotoxicity, neurodegeneration
- MeSH terms
- Alzheimer Disease, Animals, Apolipoproteins E, Humans, Membrane Proteins, Mutation, Nervous System, Neurons, Protein Processing, Post-Translational, Synapses, Amyloid beta-Peptides, Neurites, Amyloid beta-Protein Precursor, Presenilin-1, Presenilin-2
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