Loss of the Presynaptic Vesicle Protein Synaptophysin in Hippocampus Correlates with Cognitive Decline in Alzheimer Disease
Open accessAbstract
We tested the hypothesis that synaptic defects in the hippocampus of individuals with Alzheimer disease (AD) correlate with the severity of cognitive impairment. Three postmortem groups were studied: controls with normal and stable cognition; cognitively intact subjects with senile plaque densities diagnostic for possible AD (p-AD) and neurofibrillary changes characteristic of early AD (Braak stage III); and individuals with definite AD and neurofibrillary changes typical of incipient to severe AD (Braak stage III, V, or VI). Synaptophysin (a presynaptic vesicle protein) levels were quantified by immunoblotting of synaptic membrane fractions isolated from hippocampus, entorhinal cortex, caudate nucleus, and occipital cortex. Average synaptophysin levels were reduced in hippocampus when comparing definite AD to controls (55%, p < 0.0001), p-AD to control (25%, p < 0.005), and definite AD to p-AD (30%, p < 0.05), but levels in entorhinal cortex, occipital cortex, and caudate nucleus were either unchanged or less significantly altered than in hippocampus. By univariate analysis, hippocampal synaptophysin levels correlated with neuropsychological measurements, including Mini-mental state examination scores (r = 0.83, p < 0.0001) and Blessed scores (r = 0.74, P < 0.001), and with senile plaque densities (r = 0.89, p < 0.0001). We conclude that synaptic abnormalities in the hippocampus correlate with the severity of neuropathology and memory deficit in individuals with AD, and that this defect may predate neuropsychological evidence for cognitive impairment early in AD.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Loss of synaptic markers, specifically the pre-synaptic protein synaptophysin, is the best brain correlate of cognitive decline in AD.
“research studies have reported that loss of synaptic markers, specifically of the pre-synaptic protein synaptophysin, is the best brain correlate of cognitive decline in AD [40, 42, 168, 184, 192].”
From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [184]
Cited by
Sorted by citations
Alzheimer's Disease Is a Synaptic Failure
Selkoe, D. J. (2002) · Science · doi:10.1126/science.1074069 · Cited by 4,420 · 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
“Another presynaptic marker synaptophysin, correlates better with cognitive deficits than either plaques or tangles critical finding is that the deficits in synaptic plasticity appear to be triggered by APP overexpression, most (DeKosky and Scheff, 1990; Dickson et al., 1995; Sze et al., 1997; Terry et al., 1991).”
Nelson, P. T., Alafuzoff, I., Bigio, E. H., Bouras, C., Braak, H., Cairns, N. J., Castellani, R. J., Crain, B. J., Davies, P., Tredici, K. D., et al. (2012) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e31825018f7 · Cited by 2,050 · see citing works
Self-citationMucke, L., Masliah, E., Yu, G.-Q., Mallory, M., Rockenstein, E. M., Tatsuno, G., Hu, K., Kholodenko, D., Johnson-Wood, K., & McConlogue, L. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-11-04050.2000 · Cited by 1,856 · see citing works
“…mutations Decreases in synaptophysin immunoreactivity in specific brain regions correlate well with the severity of cognitive deficits in AD (Terry et al., 1991; Honer et al., 1992; Masliah et al., 1994; Dickson et al., 1995; Sze et al., 1997), highlighting the clinical relevance of this marker.”
BackgroundAlzheimer's disease: Targeting the Cholinergic System
H. Ferreira-Vieira, T., M. Guimaraes, I., R. Silva, F., & M. Ribeiro, F. (2016) · Current Neuropharmacology · doi:10.2174/1570159x13666150716165726 · Cited by 1,551 · see citing works
“In fact, the memory deficit and neuropathology severity observed in patients exhibiting AD highly correlate with changes in hippocampal synaptic transmission, especially with changes in synaptophysin expression, a presynaptic vesicle protein [220-222].”
BackgroundDeciphering the Molecular Basis of Memory Failure in Alzheimer's Disease
Walsh, D. M., & Selkoe, D. J. (2004) · Neuron · doi:10.1016/j.neuron.2004.09.010 · Cited by 1,207 · see citing works
Lacor, P. N., Buniel, M. C., Furlow, P. W., Sanz Clemente, A., Velasco, P. T., Wood, M., Viola, K. L., & Klein, W. L. (2007) · The Journal of Neuroscience · doi:10.1523/jneurosci.3501-06.2007 · Cited by 1,188 · see citing works
“, 2004), and synapse loss is considered to be the best correlate of AD dementia (DeKosky and Scheff, 1990; Terry et al., 1991; Sze et al., 1997).”
BackgroundInfluentialPlaque-independent disruption of neural circuits in Alzheimer’s disease mouse models
Hsia, A. Y., Masliah, E., McConlogue, L., Yu, G.-Q., Tatsuno, G., Hu, K., Kholodenko, D., Malenka, R. C., Nicoll, R. A., & Mucke, L. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.6.3228 · Cited by 1,123 · see citing works
Blalock, E. M., Geddes, J. W., Chen, K. C., Porter, N. M., Markesbery, W. R., & Landfield, P. W. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0308512100 · Cited by 1,025 · see citing works
Hippocampal synaptic loss in early Alzheimer's disease and mild cognitive impairment
Scheff, S. W., Price, D. A., Schmitt, F. A., & Mufson, E. J. (2006) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2005.09.012 · Cited by 1,017 · see citing works
Self-citationBiomarkers for Alzheimer's disease: current status and prospects for the future
Blennow, K., & Zetterberg, H. (2018) · Journal of Internal Medicine · doi:10.1111/joim.12816 · Cited by 1,000 · see citing works
Hartley, D. M., Walsh, D. M., Ye, C., Diehl, T. S., Vasquez, S., Vassilev, P., Teplow, D. B., & Selkoe, D. J. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-20-08876.1999 · Cited by 965 · see citing works
“, 1998), followed by more severe neuronal changes that include increased synaptic loss, widespread neuritic dystrophy, neurofibrillary tangles, and frank neuronal death (Terry et al., 1991; Gómez-Isla et al., 1996; Sze et al., 1997; Anderton et al., 1998).”
BackgroundAdlard, P. A., Cherny, R. A., Finkelstein, D. I., Gautier, E., Robb, E., Cortes, M., Volitakis, I., Liu, X., Smith, J. P., Perez, K., et al. (2008) · Neuron · doi:10.1016/j.neuron.2008.06.018 · Cited by 672 · see citing works
“Synaptophysin is a presynaptic marker that shows a regional decrease of up to 50% in AD (Callahan et al., 1999; Sze et al., 1997 ), which may be related to the accumulation of synaptotoxic As species.”
Synaptic degeneration in Alzheimer's disease
Arendt, T. (2009) · Acta Neuropathologica · doi:10.1007/s00401-009-0536-x · Cited by 517 · see citing works
“severity of cognitive impairment and synaptic pathology in AD agree on the correlation between lower synaptic protein levels and some aspect of cognitive dysfunction [22, 79, 106, 131, 132, 133, 149, 180, 181, 206, 207, 211, 221], although in several studies, correlations between synaptic proteins and cognitive functi…”
ResultInfluentialAlzheimer's disease: synaptic dysfunction and Aβ
Shankar, G. M., & Walsh, D. M. (2009) · Molecular Neurodegeneration · doi:10.1186/1750-1326-4-48 · Cited by 522 · see citing works
Deletion of aquaporin-4 in APP/PS1 mice exacerbates brain Aβ accumulation and memory deficits
Xu, Z., Xiao, N., Chen, Y., Huang, H., Marshall, C., Gao, J., Cai, Z., Wu, T., Hu, G., & Xiao, M. (2015) · Molecular Neurodegeneration · doi:10.1186/s13024-015-0056-1 · Cited by 500 · see citing works
“Both synaptophysin (SYP) and post-synaptic density protein-95 (PSD-95) are particularly vulnerable to the toxic effects of Αβ , and their loss correlates with cognitive decline in AD [34 – 36].”
Phenolic anti-inflammatory antioxidant reversal of Aβ-induced cognitive deficits and neuropathology
Frautschy, S. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00300-1 · Cited by 514 · see citing works
Neocortical neuronal, synaptic, and glial loss in multiple sclerosis
Wegner, C., Esiri, M., Chance, S., Palace, J. A., & Matthews, P. M. (2006) · Neurology · doi:10.1212/01.wnl.0000237551.26858.39 · Cited by 447 · see citing works
ALZHEIMER'S DISEASE: Genetic Studies and Transgenic Models
Price, D. L., Tanzi, R. E., Borchelt, D. R., & Sisodia, S. S. (1998) · Annual Review of Genetics · doi:10.1146/annurev.genet.32.1.461 · Cited by 406 · see citing works
Self-citationBeta-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
“synaptophysin immunoreactive pre-synaptic terminals (Mucke et al., 2000; Sze et al., 1997), occurs early in AD and is considered the best pathological correlate of cognitive decline (Masliah et al.”
BackgroundResultSynaptic pathology in Alzheimer's disease: a review of ultrastructural studies
Scheff, S. (2003) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2003.08.002 · Cited by 391 · see citing works
“Several studies have now shown that the strongest correlation with cognitive decline is with synaptic number and regional neuronal loss [22,52,53,93,94].”
BackgroundRegional hippocampal atrophy in multiple sclerosis.
Sicotte, N., Kern, K. C., Giesser, B., Arshanapalli, A., Schultz, A., Montag, M. J., Wang, H., & Bookheimer, S. (2008) · Brain : a journal of neurology · doi:10.1093/brain/awn030 · Cited by 376 · see citing works
“Interestingly, a loss of hippocampal synaptic density has been associated with worsening cognitive function in Alzheimer’s disease (Terry et al., 1991; Sze et al., 1997).”
BackgroundWu, H.-Y., Hudry, E., Hashimoto, T., Kuchibhotla, K., Rozkalne, A., Fan, Z., Spires-Jones, T., Xie, H., Arbel-Ornath, M., Grosskreutz, C. L., et al. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.4456-09.2010 · Cited by 367 · see citing works
“Memory loss in AD patients is correlated strongly with synaptic dysfunction (DeKosky and Scheff, 1990; Terry et al., 1991; Sze et al., 1997).”
Differential loss of synaptic proteins in Alzheimer's disease: Implications for synaptic dysfunction
Reddy, P. H., Mani, G., Park, B. S., Jacques, J., MURDOCH, G. H., Whetsell, W. O., Kaye, J. A., & Mańczak, M. (2005) · Journal of Alzheimer s Disease · doi:10.3233/jad-2005-7203 · Cited by 372 · see citing works
“The degree of cognitive decline in patients with AD has been correlated with changes in the presynaptic vesicle protein synaptophysin in the hippocampus and the associated cortices [20,63,65].”
InfluentialIntraneuronal 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
“Although not routinely analyzed in clinical neuropathological examination of AD brains, research studies have reported that loss of synaptic markers, specifically of the pre-synaptic protein synaptophysin, is the best brain correlate of cognitive decline in AD [40, 42, 168, 184, 192].”
Buttini, M., Orth, M., Bellosta, S., Akeefe, H., Pitas, R. E., Wyss‐Coray, T., Mucke, L., & Mahley, R. W. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-12-04867.1999 · Cited by 355 · see citing works
“, 1997), and this loss correlated well with the extent of cognitive impairments (Terry et al., 1991; Sze et al., 1997).”
BackgroundKvartsberg, H., Duits, F. H., Ingelsson, M., Andreasen, N., Öhrfelt, A., Andersson, K., Brinkmalm, G., Lannfelt, L., Minthon, L., Hansson, O., et al. (2014) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2014.10.009 · Cited by 339 · see citing works
“Thus, fluid biomarkers for synaptic dysfunction would be desirable, because they may be useful for early diagnosis, as tools to monitor synaptic dysfunction during disease progression [9], and to identify drug effects on synaptic function and degeneration in clinical trials.”
BackgroundCano, A., Ettcheto, M., Chang, J.-H., Barroso, E., Espina, M., Kühne, B. A., Barenys, M., Auladell, C., Folch, J., Souto, E. B., et al. (2019) · Journal of Controlled Release · doi:10.1016/j.jconrel.2019.03.010 · Cited by 337 · see citing works
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
miR-206 regulates brain-derived neurotrophic factor in Alzheimer disease model
Lee, S., Chu, K., Jung, K., Kim, J. H., Huh, J., Yoon, H., Park, D., Lim, J., Kim, J., Jeon, D., et al. (2012) · Annals of Neurology · doi:10.1002/ana.23588 · Cited by 275 · see citing works
Antoine, J.-C. G., Cinotti, L., Tilikete, C., Bouhour, F., Camdessanch�, J. P., Confavreux, C., Vighetto, A., Renault‐Mannel, V., Michel, D., & Honnorat, J. (2000) · Annals of Neurology · doi:10.1002/1531-8249(200007)48:1 · Cited by 86 · see citing works
Enrichment enhances spatial memory and increases synaptophysin levels in aged female mice
Frick, K. M., & Fernandez, S. M. (2003) · Neurobiology of Aging · doi:10.1016/s0197-4580(02)00138-0 · Cited by 303 · see citing works
“In patients with Alzheimer’s disease, synaptophysin immunoreactivity is significantly reduced in frontal cortex and hippocampus, and is correlated with impaired cognitive abilities [51,72,74,82] .”
Cerebrospinal fluid neurogranin: relation to cognition and neurodegeneration in Alzheimer’s disease
Portelius, E., Zetterberg, H., Skillbäck, T., Törnqvist, U., Andreasson, U., Trojanowski, J. Q., Weiner, M. W., Shaw, L. M., & Mattsson, N. (2015) · Brain · doi:10.1093/brain/awv267 · Cited by 279 · see citing works
“…and tau pathology, synaptic pathology is not only a very early change, but is probably also the direct substrate of cognitive decline, showing a tight correlation with degree of cognitive symptoms and dementia (Davies et al. , 1987; Blennow et al. , 1996; Masliah et al. , 2001; Sze et al. , 1997).”
InfluentialAlzheimer’s disease-related alterations in synaptic density: neocortex and hippocampus.
Scheff, S. W., & Price, D. A. (2006) · Journal of Alzheimer's Disease · doi:10.3233/jad-2006-9s312 · Cited by 284 · see citing works
“The loss of such brain connectivity is important since several studies have now demonstrated a good correlation be-tween synaptic numbers and cognitive ability [19,96, 97].”
Self-citationde Wilde, M. C., Overk, C., Sijben, J., & Masliah, E. (2016) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2015.12.005 · Cited by 273 · see citing works
Eastwood, S. L., & Harrison, P. J. (2001) · Brain Research Bulletin · doi:10.1016/s0361-9230(01)00530-5 · Cited by 262 · see citing works
Diabetes and Alzheimer’s disease crosstalk
Baglietto‐Vargas, D., Shi, J. J., Yaeger, D. M., Ager, R. R., & LaFerla, F. M. (2016) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2016.03.005 · Cited by 254 · see citing works
Iwata, N., Mizukami, H., Shirotani, K., Takaki, Y., Muramatsu, S., Lu, B., Gerard, N. P., Gerard, C. J., Ozawa, K., & Saido, T. C. (2004) · Journal of Neuroscience · doi:10.1523/jneurosci.4792-03.2004 · Cited by 258 · see citing works
“An aberrant increase in A at presynaptic sites has been suggested to give rise to synaptic dysfunction (Terry et al., 1991; Sze et al., 1997; Selkoe, 2002).”
BackgroundInfluentialZhang, Z., Liu, X., Schroeder, J. P., Chan, C.-B., Song, M., Yu, S. P., Weinshenker, D., & Ye, K. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2013.243 · Cited by 242 · see citing works
“Furthermore, synaptic loss appears to be the best pathologic correlate of dementia in AD (Sze et al, 1997; Terry et al, 1991).”
BackgroundNelson, P. T., Abner, E. L., Schmitt, F. A., Kryscio, R. J., Jicha, G. A., Smith, C. D., Davis, D. G., Poduska, J. W., Patel, E., Mendiondo, M. S., et al. (2010) · Brain Pathology · doi:10.1111/j.1750-3639.2008.00244.x · Cited by 239 · see citing works
“For a variety of reasons, MMSE scores (1, 8, 22, 28, 31, 33, 35, 37, 51, 60, 62, 64, 68, 71, 73, 84, 87, 98, 112, 114, 115, 122), or the even less finely graded Clinical Dementia Rating scale (14, 15, 48, 57, 103, 107), have been used as metrics of dementia severity in many informative clinicopathological correlation…”
MethodReddy, P. H., Mańczak, M., Mao, P., Calkins, M. J., Reddy, A. P., & Shirendeb, U. P. (2010) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-100504 · Cited by 240 · see citing works
“…revealed decreased levels of presynaptic (synaptophysin ) and postsynaptic proteins (synaptopodin and PSD95) in AD patients compared to age-matched control subjects [113] [114] [115] [116] [117] [118], suggesting that presynaptic and postsynaptic proteins are critically involved in AD progression.”
Entorhinal Cortex β-Amyloid Load in Individuals with Mild Cognitive Impairment
Mufson, E. J., Chen, E.-Y., Cochran, E. J., Beckett, L. A., Bennett, D. A., & Kordower, J. H. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7086 · Cited by 237 · see citing works
Hongpaisan, J., Sun, M., & Alkon, D. L. (2011) · Journal of Neuroscience · doi:10.1523/jneurosci.5209-10.2011 · Cited by 231 · see citing works
“…neurons before amyloid plaque deposition in Tg2576 mice Because memory loss in vivo is closely associated with synaptic loss in the AD brain (Sze et al., 1997) at autopsy, we quantified synaptic numbers and structures in the hippocampal CA1 stratum radiatum, which contains mainly proximal…”
BackgroundMethodGiménez‐Llort, L., Blázquez, G., Cañete, T., Johansson, B. A., Oddo, S., Tobeña, A., LaFerla, F. M., & Fernández‐Teruel, A. (2006) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2006.07.007 · Cited by 232 · see citing works
“, 1991; Roses, 1994), and synaptic dysfunction stands as the most significant factor contributing to the initial stages of memory loss in AD (Flood and Coleman, 1990; Dickson et al., 1995; Sze et al., 1997; Masliah et al., 2001), although the trigger underlying the synaptic pathology is unknown.”
BackgroundSanchez-Varo, R., Trujillo-Estrada, L., Sanchez-Mejias, E., Torres, M., Baglietto-Vargas, D., Moreno-Gonzalez, I., De Castro, V., Jimenez, S., Ruano, D., Vizuete, M., et al. (2012) · Acta Neuropathologica · doi:10.1007/s00401-011-0896-x · Cited by 222 · see citing works
“The presence of morphologically disrupted presynaptic terminals may be one of the initial stages for synaptic loss and dysfunction, so far the best correlate for early symptoms in AD patients [3, 9, 19, 41, 45, 52, 53, 59, 61] and, therefore, a pre-clinical manifestation of progression of the disease.”
BackgroundShao, C. Y., Mirra, S. S., Sait, H. B. R., Sacktor, T. C., & Sigurdsson, E. M. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0843-x · Cited by 219 · see citing works
“level as well as reduction in synaptic markers have been well documented in early and late stages of AD [8, 10, 25, 26, 37]”
BackgroundMetabolism of amyloid-β peptide and Alzheimer's disease
Iwata, N., Higuchi, M., & Saido, T. C. (2005) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2005.03.010 · Cited by 216 · see citing works
Insulin receptor signaling in the development of neuronal structure and function
Chiu, S., & Cline, H. T. (2010) · Neural Development · doi:10.1186/1749-8104-5-7 · Cited by 217 · see citing works
“Although tangle formation and amyloid deposits are useful diagnostic markers, synapse loss is more robustly correlated with cognitive deficits than any other pathological lesion observable in Alzheimer’s patients [161-164].”
BackgroundDiagnostic and Prognostic Utility of the Synaptic Marker Neurogranin in Alzheimer Disease
Tarawneh, R. M., D’Angelo, G., Crimmins, D. L., Herries, E. M., Griest, T. A., Fagan, A. M., Zipfel, G. J., Ladenson, J. H., Morris, J. C., & Holtzman, D. M. (2016) · JAMA Neurology · doi:10.1001/jamaneurol.2016.0086 · Cited by 219 · see citing works
Hippocampal neuron and synaptophysin-positive bouton number in aging C57BL/6 mice
Calhoun, M. E., Kurth, D., Phinney, A. L., Long, J. M., Hengemihle, J. M., Mouton, P. R., Ingram, D. K., & Jucker, M. (1998) · Neurobiology of Aging · doi:10.1016/s0197-4580(98)00098-0 · Cited by 215 · see citing works
Ager, R. R., Davis, J. L., Agazaryan, A., Benavente, F., Poon, W. W., LaFerla, F. M., & Blurton-Jones, M. M. (2014) · Hippocampus · doi:10.1002/hipo.22405 · Cited by 212 · see citing works
“The presynaptic vesicle-associated proteins synaptophysin and synapsin are frequently used as an indicator of synaptic integrity and are significantly reduced in patients with AD (Sze et al., 1997; Qin et al., 2004).”
Backgroundβ-Amyloid Regulation of Presynaptic Nicotinic Receptors in Rat Hippocampus and Neocortex
Dougherty, J. J., Wu, J., & Nichols, R. A. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-17-06740.2003 · Cited by 213 · see citing works
Blalock, E. M., Buechel, H. M., Popovic, J., Geddes, J. W., & Landfield, P. W. (2011) · Journal of Chemical Neuroanatomy · doi:10.1016/j.jchemneu.2011.06.007 · Cited by 211 · see citing works
“…1994; Price and Sisodia, 1998; Tanzi and Bertram, 2001), neurofibrillary tangles (NFTs) (Davies and Koppel, 2009; Johnson and Bailey, 2002; Morris et al., 2011; Noble et al., 2003) and synaptic dysfunction or loss (Masliah et al., 1994; Scheff and Price, 2001; Sze et al., 1997; Yao et al., 2003).”
BackgroundMitochondrial Dysfunction and Synaptic Transmission Failure in Alzheimer’s Disease
Guo, L., Tian, J., & Du, H. (2017) · Journal of Alzheimer’s Disease · doi:10.3233/jad-160702 · Cited by 211 · see citing works
“Clinical and pathological studies have shown a strong correlation between synaptic deficits and the degree of memory loss in AD [13–16].”
Kim, H., Rapoport, S. I., & Rao, J. S. (2009) · Neurobiology of Disease · doi:10.1016/j.nbd.2009.11.010 · Cited by 210 · see citing works
“, 2007) anddecreased synapticmarkers such as synaptophysin and drebrin, also associated with cognitive defects, in Alzheimer disease brain (Sze et al., 1997; Harigaya et al., 1996).”
Neurogranin in cerebrospinal fluid as a marker of synaptic degeneration in Alzheimer's disease
Thorsell, A., Bjerke, M., Gobom, J., Brunhage, E., Vanmechelen, E., Andreasen, N., Hansson, O., Minthon, L., Zetterberg, H., & Blennow, K. (2010) · Brain Research · doi:10.1016/j.brainres.2010.09.073 · Cited by 204 · see citing works
Mitochondrial and Cell Death Mechanisms in Neurodegenerative Diseases
Martin, L. J. (2010) · Pharmaceuticals · doi:10.3390/ph3040839 · Cited by 208 · see citing works
“[266,267], defects in synapses [268–272], abnormalities in the metabolism of APP and presenilin proteins, toxic actions of Aβ protein derived from APP [273,274], and cytoskeletal pathology [275,276].”
BackgroundSelf-citationRegion‐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 202 · see citing works
“Synaptic loss is a typical and early function related event in the AD cascade (Terry et al., 1991; Sze et al., 1997) and may be caused by such locally high concentrations of A .”
BackgroundInflammatory changes parallel the early stages of Alzheimer disease
Parachikova, A., Agadjanyan, M. G., Cribbs, D. H., Blurton-Jones, M., Perreau, V., Rogers, J., Beach, T. G., & Cotman, C. W. (2007) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2006.08.014 · Cited by 203 · see citing works
“Another potential mechanism underlying dementia is synaptic loss, since synaptic markers are decreased in AD brains [16] [54] [59] [62].”
BackgroundFrick, K. M., Fernandez, S. M., & Bulinski, S. C. (2002) · Neuroscience · doi:10.1016/s0306-4522(02)00377-9 · Cited by 203 · see citing works
“In patients with Alzheimer’s disease, synaptophysin immunoreactivity is signi¢cantly reduced in frontal cortex and hippocampus, and is correlated with impaired cognitive abilities (Terry et al., 1991; Zhan et al., 1993; Liu et al., 1996; Sze et al., 1997).”
BackgroundSynapse pathology in Alzheimer’s disease
Griffiths, J., & Grant, S. G. N. (2022) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2022.05.028 · Cited by 203 · see citing works
BENNETT, J., McRae, P. A., Levy, L. J., & Frick, K. M. (2005) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2005.09.003 · Cited by 198 · see citing works
“Reductions in synaptophysin have been associated with age-related cognitive decline in normal and demented humans (Liu, Erikson, & Brun, 1996; Sze et al., 1997) and aged rodents (Smith, Adams, Gallagher, Morrison, & Rapp, 2000).”
Blass, J. P., Sheu, R. K.-F., & Gibson, G. E. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06370.x · Cited by 200 · see citing works
Ji, Y., Gong, Y., Gan, W., Beach, T., Holtzman, D. M., & Wisniewski, T. (2003) · Neuroscience · doi:10.1016/j.neuroscience.2003.08.007 · Cited by 189 · see citing works
“One major hallmark of AD is the massive loss of synapses that occurs at an early clinical stage of the disease, particularly in the molecular layer of the dentate gyrus (DG) of the hippocampal formation (Masliah et al., 1991, 1992; Sze et al., 1997) and, to a lesser degree, in other hippocampal and neocortical regions…”
BackgroundReed, T. T., Pierce, W. M., Markesbery, W. R., & Butterfield, D. A. (2009) · Brain Research · doi:10.1016/j.brainres.2009.04.009 · Cited by 190 · see citing works
“One synaptic protein in particular, synaptophysin, is greatly reduced in AD hippocampus (Sze et al., 1997).”
Neuronal Hypertrophy in Asymptomatic Alzheimer Disease
Iacono, D., O'Brien, R., Resnick, S. M., Zonderman, A. B., Pletnikova, O., Rudow, G., An, Y., West, M. J., Crain, B., & Troncoso, J. C. (2008) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e3181772794 · Cited by 188 · see citing works
Self-citationThrombospondins as key regulators of synaptogenesis in the central nervous system
Risher, W. C., & Eroğlu, Ç. (2012) · Matrix Biology · doi:10.1016/j.matbio.2012.01.004 · Cited by 184 · see citing works
“Alzheimer’s disease (AD) is a progressive neurodegenerative disorder in which massive synapse loss occurs in the early clinical stage (Masliah et al., 1991; Sze et al., 1997).”
BackgroundArendt, T. (2003) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2003.09.007 · Cited by 188 · see citing works
Kirvell, S. L., Esiri, M. M., & Francis, P. T. (2006) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2006.03935.x · Cited by 187 · see citing works
Buttini, M., Yu, G.-Q., Shockley, K., Huang, Y., Jones, B., Masliah, E., Mallory, M., Yeo, T., Longo, F. M., & Mucke, L. (2002) · The Journal of Neuroscience · doi:10.1523/jneurosci.22-24-10539.2002 · Cited by 183 · see citing works
“We focused our analysis on SYN-IR presynaptic terminals, choline acetyltransferase (ChAT) activity, and cholinergic fibers, because decreases in these parameters correlate well with cognitive decline in AD (Terry et al., 1991; Samuel et al., 1997; Sze et al., 1997; Brown et al., 1998).”
BackgroundFluid Biomarkers for Synaptic Dysfunction and Loss
Camporesi, E., Nilsson, J., Brinkmalm, A., Becker, B., Ashton, N. J., Blennow, K., & Zetterberg, H. (2020) · Biomarker Insights · doi:10.1177/1177271920950319 · Cited by 165 · see citing works
Huang, S.-M., Mouri, A., Kokubo, H., Nakajima, R., Suemoto, T., Higuchi, M., Staufenbiel, M., Noda, Y., Yamaguchi, H., Nabeshima, T., et al. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m601372200 · Cited by 179 · see citing works
DHA Improves Cognition and Prevents Dysfunction of Entorhinal Cortex Neurons in 3xTg-AD Mice
Arsenault, D., Julien, C., Tremblay, C., & Calon, F. (2011) · PLoS ONE · doi:10.1371/journal.pone.0017397 · Cited by 177 · see citing works
“gic synapses were found in AD patients and mouse models of AD [2,20,26,45,46].”
Backgroundβ-Amyloid Immunotherapy Prevents Synaptic Degeneration in a Mouse Model of Alzheimer's Disease
Buttini, M., Masliah, E., Barbour, R., Grajeda, H., Motter, R., Johnson-Wood, K., Khan, K., Seubert, P., Freedman, S., Schenk, D., et al. (2005) · The Journal of Neuroscience · doi:10.1523/jneurosci.1697-05.2005 · Cited by 176 · see citing works
“…strongly correlates with cognitive decline (DeKosky and Scheff, 1990; Masliah et al., 1991; Terry et al., 1991; Dickson et al., 1995; Terry, 1996; Sze et al., 1997; Scheff and Price, 2003) In contrast, the relationship between amyloid plaques and cognitive decline remains controversial (Terry,…”
BackgroundPerez-Cruz, C., Nolte, M. W., van Gaalen, M. M., Rustay, N. R., Termont, A., Tanghe, A., Kirchhoff, F., & Ebert, U. (2011) · The Journal of Neuroscience · doi:10.1523/jneurosci.6142-10.2011 · Cited by 172 · see citing works
“One major hallmark of AD is the massive loss of synapses that occurs at an early clinical stage of the disease (Masliah et al., 1991; Sze et al., 1997).”
BackgroundCa 2+ signals and death programmes in neurons
Berliocchi, L., Bano, D., & Nicotera, P. (2005) · Philosophical Transactions of the Royal Society B Biological Sciences · doi:10.1098/rstb.2005.1765 · Cited by 174 · see citing works
“B (2005) and a good correlation has been reported between cognitive decline and loss of pre-synaptic terminals (Sze et al. 1997; Hatanpaa et al. 1999).”
Alzheimer's disease as a disorder of mechanisms underlying structural brain self-organization
Arendt, T. (2001) · Neuroscience · doi:10.1016/s0306-4522(00)00516-9 · Cited by 168 · see citing works
Hippocampal plasticity during the progression of Alzheimer’s disease
Mufson, E. J., Mahady, L. J., Waters, D., Counts, S., Perez, S. E., DeKosky, S. T., Ginsberg, S. D., Ikonomović, M. D., Scheff, S. W., & Binder, L. I. (2015) · Neuroscience · doi:10.1016/j.neuroscience.2015.03.006 · Cited by 172 · see citing works
“…correlated with the degree of cognitive impairment than classic pathological changes related to AD (DeKosky and Scheff, 1990; Terry et al., 1991; Sze et al., 1997; Scheff and Price, 2003; Scheff et al., 2006), very few studies have investigated synaptic contact integrity or evidence for a…”
BackgroundNeuroplasticity in Alzheimer's disease
Teter, B., & Ashford, J. W. (2002) · Journal of Neuroscience Research · doi:10.1002/jnr.10441 · Cited by 170 · see citing works
“…Terry et al., 1991; Honer et al., 1992; Lassmann et al., 1992, 1993; Zhan et al., 1993; Martin et al., 1994; Masliah et al., 1994, 1995a; Dickson et al., 1995; Heinonen et al., 1995; DeKosky et al., 1996; Sze et al., 1997; Cotman and Anderson, 2000; Mattson et al., 2001; reviewed in Arendt, 2001a).”
BackgroundPortelius, E., Olsson, B., Höglund, K., Cullen, N. C., Kvartsberg, H., Andréasson, U., Zetterberg, H., Sandelius, Å., Shaw, L. M. J., Lee, V. M. ‐., et al. (2018) · Acta Neuropathologica · doi:10.1007/s00401-018-1851-x · Cited by 167 · see citing works
“In addition, neuropathological studies have shown that this synaptic dysfunction is more linked to memory dysfunction than plaque and tangle pathologies, which are the two major pathological hallmarks of ADD [3, 9, 29, 48].”
BackgroundSynaptic Change in the Posterior Cingulate Gyrus in the Progression of Alzheimer's Disease
Scheff, S. W., PRICE, D. A., Ansari, M. A., Roberts, K. N., Schmitt, F. A., Ikonomović, M. D., & Mufson, E. J. (2014) · Journal of Alzheimer s Disease · doi:10.3233/jad-141518 · Cited by 163 · see citing works
Self-citationIvins, K. J., Bui, E. T. N., & Cotman, C. W. (1998) · Neurobiology of Disease · doi:10.1006/nbdi.1998.0228 · Cited by 164 · see citing works
Biology of Mitochondria in Neurodegenerative Diseases
Martin, L. J. (2012) · Progress in molecular biology and translational science · doi:10.1016/b978-0-12-385883-2.00005-9 · Cited by 162 · see citing works
Self-citationSelective regional loss of exocytotic presynaptic vesicle proteins in Alzheimer’s disease brains
Sze, C., Bi, H., Kleinschmidt-DeMasters, B. K., Filley, C. M., & Martin, L. J. (2000) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(00)00285-9 · Cited by 161 · see citing works
Self-citationProstaglandin signaling suppresses beneficial microglial function in Alzheimer’s disease models
Johansson, J. U., Woodling, N. S., Wang, Q., Panchal, M., Liang, X., Trueba-Saiz, A., Brown, H. D., Mhatre, S. D., Loui, T., & Andreasson, K. I. (2015) · Journal of Clinical Investigation · doi:10.1172/jci77487 · Cited by 161 · see citing works
“The loss of synaptophysin correlates with progression of cognitive decline in AD development (46); moreover, studies in transgenic mouse AD models have demonstrated that presynaptic proteins are disrupted early during amyloid accumulation (21, 47), with loss of postsynaptic markers occurring at…”
Curcuminoids enhance memory in an amyloid-infused rat model of Alzheimer’s disease
Ahmed, T., Enam, S. A., & Gilani, A. H. (2010) · Neuroscience · doi:10.1016/j.neuroscience.2010.05.078 · Cited by 156 · see citing works
Cosín‐Tomás, M., Antonell, A., Lladó, A., Alcolea, D. A., Fortea, J., Ezquerra, M., Lleó, A., Martı́, M. J., Pallàs, M., Sánchez‐Valle, R., et al. (2016) · Molecular Neurobiology · doi:10.1007/s12035-016-0088-8 · Cited by 157 · see citing works
“AD patients show reduced levels of synaptophysin in the hippocampus, and this correlates with their cognitive decline [84, 85].”
BackgroundHarris, J. A., Devidze, N., Halabisky, B., Lo, I., Thwin, M. T., Yu, G.-Q., Bredesen, D. E., Masliah, E., & Mucke, L. (2010) · The Journal of Neuroscience · doi:10.1523/jneurosci.5341-09.2010 · Cited by 146 · see citing works
“The D664A mutation does not prevent presynaptic and dendritic loss in the frontal cortex and dentate gyrus Loss of synaptic terminals is a characteristic feature of AD pathology and strongly correlates with the degree of cognitive decline in humans (Terry et al., 1991; Sze et al., 1997).”
BackgroundBendiske, J., & Bahr, B. A. (2003) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/62.5.451 · Cited by 153 · see citing works
“The presynaptic marker synaptophysin also declines in the model, and its loss in hippocampus and other regions correlates with the degree of cognitive decline in AD (29, 41, 42) and occurs early in some transgenic models of the disease (43, 44).”
Protein quality control in Alzheimer's disease by the ubiquitin proteasome system
de Vrij, F. M. S., Fischer, D. F., VANLEEUWEN, F., & Hol, E. M. (2004) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2004.10.001 · Cited by 152 · see citing works
Multiple events lead to dendritic spine loss in triple transgenic Alzheimer’s disease mice
Bittner, T., Fuhrmann, M., Burgold, S., Ochs, S. M., Hoffmann, N., Mitteregger, G., Kretzschmar, H., LaFerla, F. M., & Herms, J. (2010) · PLoS ONE · doi:10.1371/journal.pone.0015477 · Cited by 149 · see citing works
“Synaptic loss as one of the hallmarks of AD is the best correlate of cognitive decline and has previously been detected in the human cortex and hippocampus [1,3–9].”
Zumkehr, J., Rodríguez‐Ortiz, C. J., Cheng, D., Kieu, Z., Wai, T., Hawkins, C., Kilian, J., Lim, S., Medeiros, R., & Kitazawa, M. (2015) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2015.04.005 · Cited by 152 · see citing works
“Each shape represents 1 mouse 1, ceftriaxone-treated 3xTg-AD mice compared with the vehicle-treated 3xTg-AD mice tein 95 kDa; sec, seconds; SYP, synaptophysin; Veh, vehicle. pathology and cognitive decline in 3xTg-AD mice, we pharmacologically overexpressed GLT-1 and examined its pathological and behavioral consequenc…”
InfluentialAbnormalities of SNARE Mechanism Proteins in Anterior Frontal Cortex in Severe Mental Illness
Honer, W. G. (2002) · Cerebral Cortex · doi:10.1093/cercor/12.4.349 · Cited by 149 · see citing works
Mucke, L., Yu, G.-Q., McConlogue, L., Rockenstein, E. M., Abraham, C. R., & Masliah, E. (2000) · The American Journal of Pathology · doi:10.1016/s0002-9440(10)64839-0 · Cited by 145 · see citing works
The Past and the Future of Alzheimer’s Disease Fluid Biomarkers
Blennow, K., & Zetterberg, H. (2018) · Journal of Alzheimer s Disease · doi:10.3233/jad-170773 · Cited by 148 · see citing works
“Importantly, severity of synaptic loss is more tightly correlated with degree of cognitive impairment than either plaque or tangle counts [69–71], and synaptic degeneration has been suggested as the best anatomical correlate of cognitive deficits in AD [69, 72].”
Synaptic proteins, neuropathology and cognitive status in the oldest-old
Head, E., Corrada, M. M., Kahle-Wrobleski, K., Kim, R. C., Sarsoza, F., Goodus, M., & Kawas, C. H. (2009) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.10.001 · Cited by 145 · see citing works
“…a reduction in proteins associated with ynapses using multiple methodologies (Alford et al., 1994; ickson et al., 1995; Heinonen et al., 1995; Honer et al., 992; Ingelsson et al., 2004; Lassmann et al., 1992; Lue et l., 1999; Masliah et al., 1989, 1991b, 2001; Reddy et al., 005; Sze et al., 1997).”
MethodResultSelf-citationSze, C., Bi, H., Kleinschmidt-DeMasters, B. K., Filley, C. M., & Martin, L. J. (2001) · Journal of the Neurological Sciences · doi:10.1016/s0022-510x(00)00467-6 · Cited by 146 · see citing works
Self-citationTarget Identification for CNS Diseases by Transcriptional Profiling
Altar, C. A., Vawter, M. P., & Ginsberg, S. D. (2008) · Neuropsychopharmacology · doi:10.1038/npp.2008.172 · Cited by 139 · see citing works
“Indeed, the losses of synapses and the nerve terminal-specific protein, synaptophysin (SYP), correlate better with cognitive decline than do increases in amyloid load or t pathology (Heffernan et al, 1998; Shimohama et al, 1997; Sze et al, 1997, 2000).”
Mitophagy in neurological disorders
Zhang, L., Dai, L., & Li, D. (2021) · Journal of Neuroinflammation · doi:10.1186/s12974-021-02334-5 · Cited by 141 · see citing works
“The main pathological basis of memory loss is energy deficiency and synaptic inhibition [73, 74].”
BackgroundHuman apoE4-targeted replacement mice display synaptic deficits in the absence of neuropathology.
Wang, C., Wilson, W. A., Moore, S. D., Mace, B. E., Maeda, N., Schmechel, D. E., & Sullivan, P. M. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.10.013 · Cited by 138 · see citing works
“In the early stages of AD, considerable loss of synapses occurs in the hippocampus followed by losses in the neocortex (Masliah et al., 1994; Sze et al., 1997).”
Background
- Authors
- SZE, C.-I., TRONCOSO, J. C., KAWAS, C., MOUTION, P., PRICE, D. L., & MARTIN, L. J.
- Affiliations
- University of Colorado Health (US)
- Johns Hopkins University (US)
- Corresponding author
- MARTIN, LEE J.
- Venue
- Journal of Neuropathology and Experimental Neurology
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-08
- Volume
- 56
- Issue
- 8
- Pages
- 933-944
- ISSN
- 0022-3069 (ISSN-L)
- OpenAlex
- W2055361873
- Cited by
- 562
- References
- 0
- Citations by year
- 2026: 15 · 2025: 16 · 2024: 16 · 2023: 26 · 2022: 21 · 2021: 21 · 2020: 31 · 2019: 20 · 2018: 28 · 2017: 21 · 2016: 27 · 2015: 28 · 2014: 20 · 2013: 29 · 2012: 18
- FWCI
- 7.34
- Type
- journal article
- Language
- en
- Open access
- green
- escholarship.org
- Licence
- cc-by
- Locations
- Journal of Neuropathology & Experimental Neurology (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by)
- Funders
- National Institutes of Health (5r35ag007914-03)
- National Institute on Aging (AG07914)
- National Institute of Neurological Disorders and Stroke (NS34 100, R01NS034100)
- 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 › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Alzheimer's disease, synaptophysin, presynaptic vesicles, hippocampus, synaptic dysfunction, cognitive decline, amyloid plaques, neurofibrillary tangles, Braak staging, entorhinal cortex, memory impairment, synaptic membrane proteins
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cognition, Cognition Disorders, Female, Hippocampus, Humans, Male, Immunoblotting, Synaptophysin
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.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
