APP Processing and Synaptic Function

Kamenetz, Flavio; Tomita, Taisuke; Hsieh, Helen; Seabrook, Guy; Borchelt, David; Iwatsubo, Takeshi; Sisodia, Sangram; Malinow, Roberto

doi:10.1016/s0896-6273(03)00124-7

Cited by 1,644Alzheimer's disease research and treatmentsNeuroscience and Neuropharmacology ResearchNeuroinflammation and Neurodegeneration Mechanisms

APP Processing and Synaptic Function

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Kamenetz, Flavio, Tomita, Taisuke, Hsieh, Helen, Seabrook, Guy, Borchelt, David, Iwatsubo, Takeshi, Sisodia, Sangram, Malinow, Roberto·2003·Neuron

DOI 10.1016/s0896-6273(03)00124-7

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Abstract

A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.

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Toxic Ab decreases synaptic NMDARs, a change that contributes to the impaired LTP.
“Furthermore, the toxic Ab also decreases synaptic NMDARs, a change that contributes to the impaired LTP (Kamenetz et al. 2003).”
From NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD). (2012) · cites this paper as Kamenetz et al. 2003
Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracellular fluid or interstitial fluid (ISF).
“Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracellular fluid or interstitial fluid (ISF) (4–6).”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [6]
Synaptic activity is one key regulator of brain Aβ production.
“Synaptic activity is one key regulator of brain Aβ production.”
From Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans (2011) · cites this paper as [6]
Excess Aβ causes impaired synaptic function.
“APP is likely important for synapse formation in the developing brain [1], while excess Aβ causes impaired synaptic function [2].”
From FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein (2007) · cites this paper as [2]
One explanation for Aβ aggregation within the DMN is that deposition of Aβ fibrils could be caused by high neuronal activity within the DMN, supported by animal studies showing Aβ secretion and deposition is enhanced by neuronal activity.
“One explanation is that the deposition of Aβ fibrils could be caused by the high neuronal activity within the DMN, which is supported by animal studies showing that Aβ secretion and deposition is enhanced by neuronal activity27–29.”
From Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity (2017) · cites this paper as [28]

Soluble oligomers isolated from AD brain inhibit long-term potentiation, enhance long-term depression, and reduce dendritic spine density in rodent hippocampal slice cultures.
“Soluble oligomers isolated from AD brain have been shown to potently inhibit long-term potentiation (LTP), enhance long-term depression (LTD) and reduce dendritic spine density in rodent hippocampal slice cultures”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Kamenetz et al., 2003
APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.
“Overall, we feel we can confidently state APP and Aβ homeostasis are exquisitely regulated processes, and bioenergetic metabolism regulates these processes.”
From The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives (2014) · cites this paper as [180]
Aβ monomers stimulated astrocytes to increase clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.
“Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.377,378”
From Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future (2023) · cites this paper as [377]
APP is transported down both axons and dendrites.
“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [85]
Aβ appears to be generated preferentially at synapses.
“APP is transported down both axons and dendrites and Aβ appears to be generated preferentially at synapses [25, 54, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [85]
Synaptic activity increases secretion of Aβ in hippocampal slices and living rodent brain.
“Synaptic activity has been shown to increase the secretion of Aβ in hippocampal slices and living rodent brain [26, 85].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [85]

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Soluble protein oligomers in neurodegeneration: lessons from the Alzheimer's amyloid β-peptide
Haass, C., & Selkoe, D. J. (2007) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2101 · Cited by 4,744 · see citing works
Alzheimer’s disease
Querfurth, H. W., & LaFerla, F. M. (2010) · New England Journal of Medicine · doi:10.1056/nejmra0909142 · Cited by 4,569 · 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
Alzheimer Disease: An Update on Pathobiology and Treatment Strategies
Long, J. M., & Holtzman, D. M. (2019) · Cell · doi:10.1016/j.cell.2019.09.001 · Cited by 3,204 · see citing works
Pathways towards and Away from Alzheimer’s Disease
Mattson, M. P. (2004) · Nature · doi:10.1038/nature02621 · Cited by 3,052 · see citing works
Cortical Hubs Revealed by Intrinsic Functional Connectivity: Mapping, Assessment of Stability, and Relation to Alzheimer's Disease
Buckner, R. L., Sepulcre, J., Talukdar, T., Krienen, F. M., Liu, H., Hedden, T., Andrews-Hanna, J. R., Sperling, R. A., & Johnson, K. A. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.5062-08.2009 · Cited by 2,862 · see citing works
Molecular, structural, and functional characterization of Alzheimer's disease: evidence for a relationship between default activity, amyloid, and memory
Buckner, R. L., Snyder, A. Z., Shannon, B. J., LaRossa, G., Sachs, R., Fotenos, A. F., Sheline, Y. I., Klunk, W. E., Mathis, C. A., Morris, J. C., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.2177-05.2005 · Cited by 2,140 · see citing works
Amyloid Precursor Protein Processing and Alzheimer's Disease
O'Brien, R. J., & Wong, P. C. (2011) · Annual Review of Neuroscience · doi:10.1146/annurev-neuro-061010-113613 · Cited by 2,061 · see citing works
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952 · see citing works
Self-citation
Enriched environments, experience-dependent plasticity and disorders of the nervous system
Nithianantharajah, J., & Hannan, A. J. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn1970 · Cited by 1,771 · see citing works
Aberrant excitatory neuronal activity and compensatory remodeling of inhibitory hippocampal circuits in mouse models of alzheimer’s disease.
Palop, J. J., Chin, J., Roberson, E. D., Wang, J., Thwin, M. T., Bien-Ly, N., Yoo, J., Ho, K. O., Yu, G.-Q., Kreitzer, A., et al. (2007) · Neuron · doi:10.1016/j.neuron.2007.07.025 · Cited by 1,653 · see citing works
Amyloid-β–induced neuronal dysfunction in Alzheimer's disease: from synapses toward neural networks
Palop, J. J., & Mucke, L. (2010) · Nature Neuroscience · doi:10.1038/nn.2583 · Cited by 1,651 · see citing works
Mutant presenilins specifically elevate the levels of the 42 residue β-amyloid peptide in vivo: evidence for augmentation of a 42-specific γ secretase
Jankowsky, J. L., Fadale, D. J., Anderson, J., Xu, G. M., Gonzales, V., Jenkins, N. A., Copeland, N. G., Lee, M. K., Younkin, L. H., Wagner, S. L., et al. (2004) · Human Molecular Genetics · doi:10.1093/hmg/ddh019 · Cited by 1,575 · see citing works
Self-citation
Amyloid-β Dynamics Are Regulated by Orexin and the Sleep-Wake Cycle
Kang, J.-E., Lim, M. M., Bateman, R. J., Lee, J. J., Smyth, L. P., Cirrito, J. R., Fujiki, N., Nishino, S., & Holtzman, D. M. (2009) · Science · doi:10.1126/science.1180962 · Cited by 1,565 · see citing works
Regulation of NMDA receptor trafficking by amyloid-β
Snyder, E. M., Nong, Y., Almeida, C. G., Paul, S., Moran, T., Choi, E. Y., Nairn, A. C., Salter, M. W., Lombroso, P. J., Gouras, G. K., et al. (2005) · Nature Neuroscience · doi:10.1038/nn1503 · Cited by 1,561 · see citing works
Inhibitory Interneuron Deficit Links Altered Network Activity and Cognitive Dysfunction in Alzheimer Model
Verret, L., Mann, E. O., Hang, G. B., Barth, A. M. I., Cobos, I., Ho, K., Devidze, N., Masliah, E., Kreitzer, A. C., Mody, I., et al. (2012) · Cell · doi:10.1016/j.cell.2012.02.046 · Cited by 1,216 · see citing works
Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo
Cirrito, J. R., Yamada, K. A., Finn, M. B., Sloviter, R. S., Bales, K. R., May, P. C., Schoepp, D. D., Paul, S. M., Mennerick, S., & Holtzman, D. M. (2005) · Neuron · doi:10.1016/j.neuron.2005.10.028 · Cited by 1,265 · see citing works
Impaired Balance of Mitochondrial Fission and Fusion in Alzheimer's Disease
Wang, X., Su, B., Lee, H.-G., Li, X., Perry, G., Smith, M. A., & Zhu, X. (2009) · Journal of Neuroscience · doi:10.1523/jneurosci.1357-09.2009 · Cited by 1,224 · see citing works
NMDA receptor-dependent long-term potentiation and long-term depression (LTP/LTD).
Luscher, C., & Malenka, R. C. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005710 · Cited by 1,110 · see citing works
Clusters of Hyperactive Neurons Near Amyloid Plaques in a Mouse Model of Alzheimer’s Disease
Busche, M. A., Eichhoff, G., Adelsberger, H., Abramowski, D., Wiederhold, K.-H., Haass, C., Staufenbiel, M., Konnerth, A., & Garaschuk, O. (2008) · Science · doi:10.1126/science.1162844 · Cited by 1,125 · see citing works
Trafficking and Proteolytic Processing of APP
Haass, C., Kaether, C., Thinakaran, G., & Sisodia, S. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006270 · Cited by 1,075 · see citing works
Self-citation
AMPAR Removal Underlies Aβ-Induced Synaptic Depression and Dendritic Spine Loss
Hsieh, H., Boehm, J., Sato, C., Iwatsubo, T., Tomita, T., Sisodia, S., & Malinow, R. (2006) · Neuron · doi:10.1016/j.neuron.2006.10.035 · Cited by 1,042 · see citing works
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Network abnormalities and interneuron dysfunction in Alzheimer disease
Palop, J. J., & Mucke, L. (2016) · Nature reviews. Neuroscience · doi:10.1038/nrn.2016.141 · Cited by 1,022 · see citing works
Neurotoxicity of Amyloid -Protein: Synaptic and Network Dysfunction
Mucke, L., & Selkoe, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006338 · Cited by 1,000 · see citing works
Earliest accumulation of β-amyloid occurs within the default-mode network and concurrently affects brain connectivity
Palmqvist, S., Schöll, M., Strandberg, O., Mattsson, N., Stomrud, E., Zetterberg, H., Blennow, K., Landau, S., Jagust, W., & Hansson, O. (2017) · Nature Communications · doi:10.1038/s41467-017-01150-x · Cited by 911 · see citing works
A critical appraisal of amyloid-β-targeting therapies for Alzheimer disease
Panza, F., Lozupone, M., Logroscino, G., & Imbimbo, B. P. (2019) · Nature Reviews Neurology · doi:10.1038/s41582-018-0116-6 · Cited by 965 · see citing works
Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future
Zhang, Y., Chen, H., Li, R., Sterling, K., & Song, W. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01484-7 · Cited by 988 · see citing works
“Aβ monomers stimulated astrocytes to increase the clearance of synaptic glutamate and therefore protect neurons from glutamate excitotoxicity.(377,378) Aβ can also be released into the synaptic cleft, where it acts on presynaptic neurons to induce the release of neurotransmitters (e.”
Environmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice
Lazarov, O., Robinson, J., Tang, Y.-P., Hairston, I. S., Korade-Mirnics, Z., Lee, V. M.-Y., Hersh, L. B., Sapolsky, R. M., Mirnics, K., & Sisodia, S. S. (2005) · Cell · doi:10.1016/j.cell.2005.01.015 · Cited by 885 · see citing works
Self-citation
Neuronal activity regulates the regional vulnerability to amyloid-β deposition
Bero, A. W., Yan, P., Roh, J. H., Cirrito, J. R., Stewart, F. R., Raichle, M. E., Lee, J.-M., & Holtzman, D. M. (2011) · Nature Neuroscience · doi:10.1038/nn.2801 · Cited by 880 · see citing works
The Alzheimer’s disease mitochondrial cascade hypothesis: progress and perspectives
Swerdlow, R. H., Burns, J. M., & Khan, S. M. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.09.010 · Cited by 786 · see citing works
Molecular mechanisms of neurodegeneration in Alzheimer's disease
Crews, L., & Masliah, E. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq160 · Cited by 772 · see citing works
Loss of Presenilin Function Causes Impairments of Memory and Synaptic Plasticity Followed by Age-Dependent Neurodegeneration
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
Picomolar Amyloid-β Positively Modulates Synaptic Plasticity and Memory in Hippocampus
Puzzo, D., Privitera, L., Leznik, E., Fà, M., Staniszewski, A., Palmeri, A., & Arancio, O. (2008) · The Journal of Neuroscience · doi:10.1523/jneurosci.2692-08.2008 · Cited by 740 · see citing works
Multimodal techniques for diagnosis and prognosis of Alzheimer's disease
Perrin, R. J., Fagan, A. M., & Holtzman, D. M. (2009) · Nature · doi:10.1038/nature08538 · Cited by 702 · see citing works
The role of microglia in amyloid clearance from the AD brain
Lee, C. Y. D., & Landreth, G. E. (2010) · Journal of Neural Transmission · doi:10.1007/s00702-010-0433-4 · Cited by 701 · see citing works
Epilepsy and Cognitive Impairments in Alzheimer Disease
Palop, J. J. (2009) · Archives of Neurology · doi:10.1001/archneurol.2009.15 · Cited by 684 · see citing works
Endocytosis Is Required for Synaptic Activity-Dependent Release of Amyloid-β In Vivo
Cirrito, J. R., Kang, J.-E., Lee, J., Stewart, F. R., Verges, D. K., Silverio, L. M., Bu, G., Mennerick, S., & Holtzman, D. M. (2008) · Neuron · doi:10.1016/j.neuron.2008.02.003 · Cited by 635 · see citing works
Amyloid-β/Fyn–Induced Synaptic, Network, and Cognitive Impairments Depend on Tau Levels in Multiple Mouse Models of Alzheimer's Disease
Roberson, E. D., Halabisky, B., Yoo, J. W., Yao, J., Chin, J., Yan, F., Wu, T., Hamto, P., Devidze, N., Yu, G.-Q., et al. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.4152-10.2011 · Cited by 654 · see citing works
Imaging the evolution and pathophysiology of Alzheimer disease
Jagust, W. (2018) · Nature Reviews Neuroscience · doi:10.1038/s41583-018-0067-3 · Cited by 604 · see citing works
Group 1 mGluR-Dependent Synaptic Long-Term Depression: Mechanisms and Implications for Circuitry and Disease
Lüscher, C., & Huber, K. M. (2010) · Neuron · doi:10.1016/j.neuron.2010.01.016 · Cited by 627 · see citing works
New insights on the role of microglia in synaptic pruning in health and disease
Hong, S., Dissing-Olesen, L., & Stevens, B. (2016) · Current Opinion in Neurobiology · doi:10.1016/j.conb.2015.12.004 · Cited by 557 · see citing works
Disrupted energy metabolism and neuronal circuit dysfunction in cognitive impairment and Alzheimer's disease
Kapogiannis, D., & Mattson, M. P. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(10)70277-5 · Cited by 594 · see citing works
Disruption of the Sleep-Wake Cycle and Diurnal Fluctuation of β-Amyloid in Mice with Alzheimer’s Disease Pathology
Roh, J. H., Huang, Y., Bero, A. W., Kasten, T., Stewart, F. R., Bateman, R. J., & Holtzman, D. M. (2012) · Science Translational Medicine · doi:10.1126/scitranslmed.3004291 · Cited by 563 · see citing works
The Alzheimer's disease Beta-secretase enzyme, BACE1
Cole, S. L., & Vassar, R. (2007) · Molecular Neurodegeneration · doi:10.1186/1750-1326-2-22 · Cited by 550 · see citing works
Sleep, circadian rhythms, and the pathogenesis of Alzheimer disease
Musiek, E. S., Xiong, D. D., & Holtzman, D. M. (2015) · Experimental & Molecular Medicine · doi:10.1038/emm.2014.121 · Cited by 529 · see citing works
Reelin, lipoprotein receptors and synaptic plasticity
Herz, J., & Chen, Y. (2006) · Nature Reviews Neuroscience · doi:10.1038/nrn2009 · Cited by 524 · see citing works
The Role of NMDA Receptors in Alzheimer’s Disease
Liu, J., Chang, L., Song, Y., Li, H., & Wu, Y. (2019) · Frontiers in Neuroscience · doi:10.3389/fnins.2019.00043 · Cited by 535 · see citing works
Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease
Jankowsky, J. L., Melnikova, T., Fadale, D. J., Xu, G. M., Slunt, H. H., Gonzales, V., Younkin, L. H., Younkin, S. G., Borchelt, D. R., & Savonenko, A. V. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.5080-04.2005 · Cited by 517 · see citing works
Self-citation
Alzheimer's disease, β‐amyloid, glutamate, NMDA receptors and memantine – searching for the connections
Danysz, W., & Parsons, C. G. (2012) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2012.02057.x · Cited by 500 · see citing works
Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses
Abramov, E., Dolev, I., Fogel, H., Ciccotosto, G. D., Ruff, E., & Slutsky, I. (2009) · Nature Neuroscience · doi:10.1038/nn.2433 · Cited by 499 · see citing works
<scp>CSF</scp> Aβ42/Aβ40 and Aβ42/Aβ38 ratios: better diagnostic markers of Alzheimer disease
Janelidze, S., Zetterberg, H., Mattsson, N., Palmqvist, S., Vanderstichele, H., Lindberg, O., van Westen, D., Stomrud, E., Minthon, L., Blennow, K., et al. (2016) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.274 · Cited by 456 · see citing works
Synapses and Alzheimer's Disease
Sheng, M., Sabatini, B. L., & Sudhof, T. C. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a005777 · Cited by 436 · see citing works
Effect of 1 Night of Total Sleep Deprivation on Cerebrospinal Fluid β-Amyloid 42 in Healthy Middle-Aged Men: A Randomized Clinical Trial
Ooms, S., Overeem, S., Besse, K., Rikkert, M. O., Verbeek, M., & Claassen, J. A. H. R. (2014) · JAMA Neurology · doi:10.1001/jamaneurol.2014.1173 · Cited by 438 · see citing works
Human LilrB2 Is a β-Amyloid Receptor and Its Murine Homolog PirB Regulates Synaptic Plasticity in an Alzheimer’s Model
Kim, T., Vidal, G. S., Djurisic, M., William, C. M., Birnbaum, M. E., Garcia, K. C., Hyman, B. T., & Shatz, C. J. (2013) · Science · doi:10.1126/science.1242077 · Cited by 410 · see citing works
Reversing EphB2 depletion rescues cognitive functions in Alzheimer model
Cissé, M., Halabisky, B., Harris, J., Devidze, N., Dubal, D. B., Sun, B., Orr, A., Lotz, G., Kim, D. H., Hamto, P., et al. (2011) · Nature · doi:10.1038/nature09635 · Cited by 433 · see citing works
Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector
Wang, C., Najm, R., Xu, Q., Jeong, D.-E., Walker, D., Balestra, M. E., Yoon, S. Y., Yuan, H., Li, G., Miller, Z. A., et al. (2018) · Nature Medicine · doi:10.1038/s41591-018-0004-z · Cited by 428 · see citing works
β-Amyloid Monomers Are Neuroprotective
Giuffrida, M. L., Caraci, F., Pignataro, B., Cataldo, S., De Bona, P., Bruno, V., Molinaro, G., Pappalardo, G., Messina, A., Palmigiano, A., et al. (2009) · The Journal of Neuroscience · doi:10.1523/jneurosci.1736-09.2009 · Cited by 421 · see citing works
Spatial correlation between brain aerobic glycolysis and amyloid-β (Aβ) deposition
Vlassenko, A. G., Vaishnavi, S. N., Couture, L., Sacco, D., Shannon, B. J., Mach, R. H., Morris, J. C., Raichle, M. E., & Mintun, M. A. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1010461107 · Cited by 404 · see citing works
The Secreted β-Amyloid Precursor Protein Ectodomain APPsα Is Sufficient to Rescue the Anatomical, Behavioral, and Electrophysiological Abnormalities of APP-Deficient Mice
Ring, S., Weyer, S. W., Kilian, S. B., Waldron, E., Pietrzik, C. U., Filippov, M. A., Herms, J., Buchholz, C., Eckman, C. B., Korte, M., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.1026-07.2007 · Cited by 390 · see citing works
Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses
Almeida, C. G., Tampellini, D., Takahashi, R. H., Greengard, P., Lin, M. T., Snyder, E. M., & Gouras, G. K. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2005.02.008 · Cited by 397 · see citing works
A Mouse Model of Amyloid β Oligomers: Their Contribution to Synaptic Alteration, Abnormal Tau Phosphorylation, Glial Activation, and Neuronal Loss In Vivo
Tomiyama, T., Matsuyama, S., Iso, H., Umeda, T., Takuma, H., Ohnishi, K., Ishibashi, K., Teraoka, R., Sakama, N., Yamashita, T., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5825-09.2010 · Cited by 396 · see citing works
ApoE4 reduces glutamate receptor function and synaptic plasticity by selectively impairing ApoE receptor recycling
Chen, Y., Durakoglugil, M. S., Xian, X., & Herz, J. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0914984107 · Cited by 368 · see citing works
How chronic inflammation can affect the brain and support the development of Alzheimer's disease in old age: the role of microglia and astrocytes
Blasko, I., Stampfer‐Kountchev, M., Robatscher, P., Veerhuis, R., Eikelenboom, P., & Grubeck‐Loebenstein, B. (2004) · Aging Cell · doi:10.1111/j.1474-9728.2004.00101.x · Cited by 374 · see citing works
Intraneuronal 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
Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans
Cirrito, J. R., Disabato, B. M., Restivo, J. L., Verges, D. K., Goebel, W. D., Sathyan, A., Hayreh, D., D'Angelo, G., Benzinger, T., Yoon, H., et al. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1107411108 · Cited by 370 · see citing works
Amyloid beta from axons and dendrites reduces local spine number and plasticity
Wei, W., Nguyen, L. N., Kessels, H. W., Hagiwara, H., Sisodia, S., & Malinow, R. (2010) · Nature Neuroscience · doi:10.1038/nn.2476 · Cited by 357 · see citing works
Self-citation
β-Site Amyloid Precursor Protein Cleaving Enzyme 1 Levels Become Elevated in Neurons around Amyloid Plaques: Implications for Alzheimer's Disease Pathogenesis
Zhao, J., Fu, Y., Yasvoina, M., Shao, P., Hitt, B., O'Connor, T., Logan, S., Maus, E., Citron, M., Berry, R., et al. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.4396-06.2007 · Cited by 365 · 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
Causes of oxidative stress in Alzheimer disease
Zhu, X., Su, B., Wang, X., Smith, M. A., & Perry, G. (2007) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-007-7218-4 · Cited by 336 · see citing works
Transsynaptic progression of amyloid-β-induced neuronal dysfunction within the entorhinal-hippocampal network
Harris, J. A., Devidze, N., Verret, L., Ho, K., Halabisky, B., Thwin, M. T., Kim, D., Hamto, P., Lo, I., Yu, G.-Q., et al. (2010) · Neuron · doi:10.1016/j.neuron.2010.10.020 · Cited by 319 · see citing works
The Physiological Roles of Amyloid-β Peptide Hint at New Ways to Treat Alzheimer's Disease
Brothers, H. M., Gosztyla, M. L., & Robinson, S. R. (2018) · Frontiers in Aging Neuroscience · doi:10.3389/fnagi.2018.00118 · Cited by 314 · see citing works
NPTX2 and cognitive dysfunction in Alzheimer’s Disease
Xiao, M.-F., Xu, D., Craig, M. T., Pelkey, K. A., Chien, C.-C., Shi, Y., Zhang, J., Resnick, S., Pletnikova, O., Salmon, D., et al. (2017) · eLife · doi:10.7554/elife.23798 · Cited by 316 · see citing works
Role of Amyloid-β and Tau Proteins in Alzheimer’s Disease: Confuting the Amyloid Cascade
Gulisano, W., Maugeri, D., Baltrons, M. A., Fà, M., Amato, A., Palmeri, A., D’Adamio, L., Grassi, C., Devanand, D. P., Honig, L. S., et al. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179935 · Cited by 313 · see citing works
Amyloid triggers extensive cerebral angiogenesis causing blood brain barrier permeability and hypervascularity in Alzheimer's disease
Biron, K. E., Dickstein, D. L., Gopaul, R., & Jefferies, W. A. (2011) · PLoS ONE · doi:10.1371/journal.pone.0023789 · Cited by 300 · see citing works
Locus Ceruleus Degeneration Promotes Alzheimer Pathogenesis in Amyloid Precursor Protein 23 Transgenic Mice
Heneka, M. T., Ramanathan, M., Jacobs, A. H., Dumitrescu-Ozimek, L., Bilkei-Gorzo, A., Debeir, T., Sastre, M., Galldiks, N., Zimmer, A., Hoehn, M., et al. (2006) · The Journal of Neuroscience · doi:10.1523/jneurosci.4236-05.2006 · Cited by 305 · see citing works
Temporal memory deficits in Alzheimer’s mouse models: Rescue by genetic deletion of BACE1
Ohno, M., Chang, L., Tseng, W., Oakley, H., Citron, M., Klein, W. L., Vassar, R., & Disterhoft, J. F. (2006) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2005.04551.x · Cited by 298 · see citing works
Amyloid-β Dynamics Correlate with Neurological Status in the Injured Human Brain
Brody, D. L., Magnoni, S., Schwetye, K. E., Spinner, M. L., Esparza, T. J., Stocchetti, N., Zipfel, G. J., & Holtzman, D. M. (2008) · Science · doi:10.1126/science.1161591 · Cited by 295 · see citing works
FMRP Mediates mGluR5-Dependent Translation of Amyloid Precursor Protein
Westmark, C. J., & Malter, J. S. (2007) · PLoS Biology · doi:10.1371/journal.pbio.0050052 · Cited by 292 · see citing works
“], while excess Aβ causes impaired synaptic function [”
BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice
Ohno, M., Cole, S. L., Yasvoina, M., Zhao, J., Citron, M., Berry, R., Disterhoft, J. F., & Vassar, R. (2007) · Neurobiology of Disease · doi:10.1016/j.nbd.2006.12.008 · Cited by 290 · see citing works
Olfactory Dysfunction Correlates with Amyloid-β Burden in an Alzheimer's Disease Mouse Model
Wesson, D. W., Levy, E., Nixon, R. A., & Wilson, D. A. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4622-09.2010 · Cited by 290 · see citing works
Physiological roles for amyloid β peptides
Pearson, H. A., & Peers, C. (2006) · The Journal of Physiology · doi:10.1113/jphysiol.2006.111203 · Cited by 286 · see citing works
Possible Implications of Insulin Resistance and Glucose Metabolism in Alzheimer's Disease Pathogenesis
Bosco, D., Fava, A., Plastino, M., Montalcini, T., & Pujia, A. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01318.x · Cited by 283 · see citing works
Secreted amyloid-β precursor protein functions as a GABA B R1a ligand to modulate synaptic transmission
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Fluctuations of CSF amyloid-β levels: Implications for a diagnostic and therapeutic biomarker
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Authors: Kamenetz, F., Tomita, T., Hsieh, H., Seabrook, G., Borchelt, D., Iwatsubo, T., Sisodia, S., & Malinow, R.
Affiliations: State University of New York (US)
The University of Tokyo (JP)
Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
Johns Hopkins University (US)
University of Chicago (US)
Corresponding author: Malinow, Roberto
ORCID: Tomita, Taisuke
Hsieh, Helen
Borchelt, David
Iwatsubo, Takeshi
Sisodia, Sangram
Malinow, Roberto
Venue: Neuron
Publisher: Elsevier BV
Published: 2003-03
Volume: 37
Issue: 6
Pages: 925-937
ISSN: 0896-6273 (ISSN-L)
DOI: 10.1016/s0896-6273(03)00124-7
OpenAlex: W1964049915
Cited by: 1,644
References: 67
Citations by year: 2026: 34 · 2025: 49 · 2024: 59 · 2023: 46 · 2022: 57 · 2021: 78 · 2020: 93 · 2019: 81 · 2018: 68 · 2017: 61 · 2016: 103 · 2015: 74 · 2014: 102 · 2013: 71 · 2012: 92
FWCI: 35.34
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 3791 d)
Locations: Neuron (publishedVersion)
PubMed (publishedVersion)
Cold Spring Harbor Laboratory Institutional Repository (Cold Spring Harbor Laboratory) (acceptedVersion)
Funders: National Institute of General Medical Sciences (T32GM008444)
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, amyloid-beta, Alzheimer's disease, synaptic depression, excitatory synaptic transmission, NMDA receptor, neuronal activity, hippocampal neurons, neuronal hyperactivity, cognitive decline
MeSH terms: Alzheimer Disease, Animals, Hippocampus, Humans, Mice, Transgenic, Synaptic Transmission, Neurons, Synapses, Gene Expression, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Feedback, Physiological, Mice, Rats

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