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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.
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“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]
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“Synaptic loss correlates with cognitive decline and is more associated with the degree of dementia compared to plaques and tangles [5-8], especially within certain areas of the brain, such as the hippocampus [7,9].”
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“Synaptic loss in the hippocampus correlates well with memory deficits in AD patients [37,38], and APP transgenic mouse models also show synaptic deficits [39–42].”
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“In patients with Alzheimer’s disease, synaptophysin immunoreactivity is significantly reduced in the frontal cortex and hippocampus and is associated with impaired cognitive ability [20,41].”
BackgroundNeuropathologic Studies of the Baltimore Longitudinal Study of Aging (BLSA)
O'Brien, R. J., Resnick, S. M., Zonderman, A. B., Ferrucci, L., Crain, B. J., Pletnikova, O., Rudow, G., Iacono, D., Riudavets, M. A., Driscoll, I., et al. (2009) · Journal of Alzheimer's Disease · doi:10.3233/jad-2009-1179 · Cited by 137
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“In humans, a number of studies have shown reduced quantities of synapses and synaptic protein expression in several areas of AD brain, and have demonstrated the strong correlation between cognitive impairment and synapse loss [43,46,52,53].”
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Genome wide profiling of altered gene expression in the neocortex of Alzheimer's disease
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“, 2005; WyssCoray, 2006), synaptic failure (Sze et al., 1997; Selkoe, 2002), abnormal cholesterol metabolism (Shobab et al.”
BackgroundAssociations of cortical astrogliosis with cognitive performance and dementia status
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“…and NFT formation are not necessarily the result of enhanced expression of A β but such increases (e.g. in A β 1 − 42 ) can result in synapse loss [39] which invariably is associated with gliosis (e.g., see [32]), and synaptic loss itself may be the best correlate of cognitive decline in AD [4,55].”
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“Previous studies have further reinforced that loss of synaptic markers plays an important role in cognitive decline in AD, even being described as the best hallmarkmatching the state of behavioral deterioration (22).”
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Self-citationADDLs and the signaling web that leads to Alzheimer’s disease
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“…molecules in AD tissues, including presynaptic components syntaxin, GAP-43 and SNAP-25 (Davidsson and Blennow, 1998; Masliah et al., 2001; Sze et al., 1997, 2000), postsynaptic molecules drebrin and neurogranin (Chang et al., 1997; Davidsson and Blennow, 1998; Harigaya et al., 1996;…”
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“Spine loss is the best correlate of AD progression; however, acute disruption of synaptic plasticity is not accompanied by loss of spines (DeKosky and Scheff, 1990; Terry et al., 1991; Sze et al., 1997).”
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Neuronal Structure is Altered by Amyloid Plaques
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The Role of Astrocytic Aquaporin-4 in Synaptic Plasticity and Learning and Memory
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“These proteins are known to be altered in the hippocampus and cause memory deficits during the progression of AD (Sze et al., 1997; Xu et al., 2015).”
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“Synaptic alteration in the hippocampus and frontal cortex is proposed to be an early event in AD as indicated by a progressive loss of synaptophysin in subjects rated clinically and pathologically as mild, moderate and severe [26,44,66].”
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“Although total synaptophysin levels are reduced in AD [16, 19, 27, 29, 4, 50 ], increased synaptophysin expression is a typical feature in diffuse plaques, as detailed in previous studies [3, 5, 12, 26, 37].”
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“A prominent decrease in synaptic density is found in the hippocampus and association cortex in AD, and the severity of cognitive impairment in AD patients strongly correlates with synaptic loss and dysfunction (DeKosky and Scheff, 1990; Sze et al., 1997).”
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“As reduced levels/ activation of the NMDAR pathway CaMK-II/CREB/ BDNF [42,68,69] are observed in AD patients and associated with impaired neuronal function in vitro and in vivo [70-73], these downstream signaling molecules, specifically the levels of BDNF (Figure 6D) and activated p-CaMK-II (Figure 6B) and pCREB (Figu…”
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ResultPathogenesis of Alzheimer's disease: Involvement of the choroid plexus
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“In AD patients, synaptophysin levels are reduced in the hippocampus and in the frontal cortex, when compared with controls, and hippocampal synaptophysin levels correlated with neuropsychological measurements, including Minimental State Examination scores [49, 50].”
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BackgroundThe morbid anatomy of dementia in Parkinson’s disease
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Aβ oligomers inhibit synapse remodelling necessary for memory consolidation
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Up‐regulation of the Kv3.4 potassium channel subunit in early stages of Alzheimer's disease
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“In AD, synaptic loss, as reflected by alterations in the expression levels of dendritic and synaptic markers, is known to correlate better with cognitive decline than either Aβ plaque load or neurofibrillary tangles (Sze et al., 1997; Terry et al., 1991).”
Ginsberg, S. D., Alldred, M. J., & Che, S. (2011) · Neurobiology of Disease · doi:10.1016/j.nbd.2011.07.013 · Cited by 88
Scheff, S. W., PRICE, D. A., & Sparks, D. L. (2001) · Neurobiology of Aging · doi:10.1016/s0197-4580(01)00222-6 · Cited by 82
Self-citationBerliocchi, L., Fava, E., Leist, M., Horvat, V., Dinsdale, D. D., Read, D., & Nicotera, P. (2005) · The Journal of Cell Biology · doi:10.1083/jcb.200406126 · Cited by 82
“Our results suggest that, in response to widespread synaptic damage, neurons first dismantle their connections and finally undergo apoptosis, when their spatial relationships are lost.”
ResultLaClair, K. D., Donde, A., Ling, J. P., Jeong, Y. H., Chhabra, R., Martin, L. J., & Wong, P. C. (2016) · Acta Neuropathologica · doi:10.1007/s00401-016-1637-y · Cited by 76
“These findings are consistent with observations that presynaptic terminals are initially affected in the cases of AD and that this loss correlates with cognitive decline [55, 61].”
Self-citationMerlo, S., Spampinato, S. F., & Sortino, M. A. (2018) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.13050 · Cited by 82
COL25A1 triggers and promotes Alzheimer’s disease-like pathology in vivo
Tong, Y., Xu, Y., Scearce-Levie, K. A., Ptáček, L. J., & Fu, Y. (2009) · Neurogenetics · doi:10.1007/s10048-009-0201-5 · Cited by 78
“Loss of synaptic proteins is more severe in AD patients and mouse models [20, 21].”
BackgroundThree-dimensional analysis of synapses in the transentorhinal cortex of Alzheimer’s disease patients
Domínguez-Álvaro, M., Montero-Crespo, M., Blazquez-Llorca, L., Insausti, R., DeFelipe, J., & Alonso-Nanclares, L. (2018) · Acta Neuropathologica Communications · doi:10.1186/s40478-018-0520-6 · Cited by 79
“Among them, synaptic loss seems to be the major structural correlate of cognitive decline observed in AD patients, and it is considered to be the earliest mechanism that precedes neuronal loss [5, 18, 23, 43, 70, 82].”
BackgroundSarnat, H. B., & Born, D. E. (1999) · Brain and Development · doi:10.1016/s0387-7604(98)00068-0 · Cited by 79
“Alzheimer’s disease [4,5], and to help define the architecture of particular regions of the adult brain, such as the cochlear nuclei [6], synaptophysin has rarely been applied to neuronal maturation in developing normal fetal brain or in cerebral dysgeneses.”
BackgroundBolognin, S., Blanchard, J., Wang, X., Basurto‐Islas, G., Tung, Y. C., Kohlbrenner, E., Grundke, I., & Iqbal, K. (2011) · Acta Neuropathologica · doi:10.1007/s00401-011-0908-x · Cited by 80
“In addition, early studies supported a link between the degree of cognitive decline in AD patients and changes in the levels of presynaptic markers [55].”
BackgroundZheng, A., Li, H., Cao, K. J., Xu, J., Zou, X., Li, Y., Chen, C., Liu, J., & Feng, Z. (2014) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2014.10.006 · Cited by 80
“SYP is also required for neurotransmitter release, and loss of SYP in the hippocampus is correlated with the cognitive dysfunction seen in Alzheimer's disease [34].”
BackgroundSynaptic Pathology in Prefrontal Cortex is Present Only with Severe Dementia in Alzheimer Disease
Minger, S. L., Honer, W. G., Esiri, M. M., McDonald, B., Keene, J., Nicoll, J. A. R., Carter, J., Hope, T., & Francis, P. T. (2001) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/60.10.929 · Cited by 75
TGF-β Signaling: A Therapeutic Target to Reinstate Regenerative Plasticity in Vascular Dementia?
Kandasamy, M., Anusuyadevi, M., Aigner, K. M., Unger, M. S., Kniewallner, K. M., Sousa, D. M. B. D., Altendorfer, B., Mrowetz, H., Bogdahn, U., & Aigner, L. (2020) · Aging and disease · doi:10.14336/ad.2020.0222 · Cited by 77
“preparations from various brain regions of subjects with AD and VaD revealed a reduction of synaptophysin levels in the hippocampus [200].”
BackgroundLennox, R., Porter, D. W., Flatt, P. R., Hölscher, C., Irwin, N., & Gault, V. A. (2014) · Neuropharmacology · doi:10.1016/j.neuropharm.2014.06.026 · Cited by 79
“Moreover, synaptophysin protein levels are significantly reduced in the hippocampal region in the brains of Alzheimer's patients (Sze et al., 1997; Heffernan et al., 1998).”
BackgroundAccumulation of Insoluble α-Synuclein in Dementia with Lewy Bodies
Campbell, B. C. V., Li, Q., Culvenor, J. G., Jäkälä, P., Cappai, R., Beyreuther, K. T., Masters, C. L., & McLean, C. (2000) · Neurobiology of Disease · doi:10.1006/nbdi.2000.0286 · Cited by 77
Blennow, K., & Zetterberg, H. (2015) · Frontiers in Neuroscience · doi:10.3389/fnins.2015.00345 · Cited by 79
“In 2011, similar, but not identical, criteria for MCI due to AD (Albert et al., 2011) and dementia due to AD (McKhann et al., 2011) were published by the National Institute on Aging— Alzheimer’s Association (NIA-AA) workgroups on diagnostic guidelines for AD.”
Jiang, Y., Liu, Y., Zhu, C., Ma, X., Ma, L., Zhou, L., Huang, Q., Lei, C., Pi, R., & Chen, X. (2015) · Neurobiology of Learning and Memory · doi:10.1016/j.nlm.2015.03.003 · Cited by 75
Synaptic Vesicle-Recycling Machinery Components as Potential Therapeutic Targets
Li, Y. C., & Kavalali, E. T. (2017) · Pharmacological Reviews · doi:10.1124/pr.116.013342 · Cited by 74
“These changes in synaptophysin in neurons of the hippocampus and association cortices correlate with changes in the cognitive decline in AD patients (Terry et al., 1991; Sze et al., 1997).”
Grabrucker, A. M., Schmeißer, M. J., Udvardi, P. T., Arons, M. H., Schoen, M., Woodling, N. S., Andreasson, K. I., Hof, P. R., Buxbaum, J. D., Garner, C. C., et al. (2011) · Molecular Neurodegeneration · doi:10.1186/1750-1326-6-65 · Cited by 77
“Moreover, introduction of Ab oligomers leads to a significant reduction (about 25%) in synapse density in hippocampal cultures, which is in agreement with previous studies reporting 11 to 77% declines in synaptophysin immunostaining in brain sections [46,47].”
ResultSingle cell gene expression profiling in Alzheimer’s disease
Ginsberg, S. D., Che, S., Counts, S., & Mufson, E. J. (2006) · NeuroRx · doi:10.1016/j.nurx.2006.05.007 · Cited by 76
Kim, D. H., Lim, H., Lee, D., Choi, S. J., Oh, W., Yang, Y. S., Oh, J. S., Hwang, H. H., & Jeon, H. B. (2018) · Scientific Reports · doi:10.1038/s41598-017-18542-0 · Cited by 76
Pan, M., Li, Z., Yeung, V., & Xu, R.-J. (2010) · Nutrition & Metabolism · doi:10.1186/1743-7075-7-75 · Cited by 74
“Loss of the synaptophysin in hippocampus correlates with cognitive decline in Alzheimer’s disease [33].”
BackgroundProtofibrils of amyloid β-protein inhibit specific K+ currents in neocortical cultures
Ye, C. P., Selkoe, D. J., & Hartley, D. M. (2003) · Neurobiology of Disease · doi:10.1016/s0969-9961(03)00068-8 · Cited by 74
Intracellular A-Beta Amyloid, A Sign for Worse Things to Come?
Echeverría, V., & Cuello, A. C. (2002) · Molecular Neurobiology · doi:10.1385/mn:26:2-3:299 · Cited by 81
“Thus, the loss of synaptophysin-immunoreactive (SYN-IR) presynaptic terminals in the frontal cortex has been shown to correlate with cognitive decline in AD (146,147).”
BackgroundWang, K., Song, F., Xu, K., Liu, Z., Han, S., Li, F., & Sun, Y. S. (2019) · Mediators of Inflammation · doi:10.1155/2019/1567179 · Cited by 75
In cerebrospinal fluid ER chaperones ERp57 and calreticulin bind β-amyloid
Erickson, R. R., Dunning, L. M., Olson, D. A., Cohen, S. J., Davis, A. T., Wood, W. G., Kratzke, R. A., & Holtzman, J. L. (2005) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2005.04.090 · Cited by 73
A role for the neurexin–neuroligin complex in Alzheimer's disease
Sindi, I. A., Tannenberg, R. K., & Dodd, P. R. (2013) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2013.09.032 · Cited by 65
The cytoskeleton in Alzheimer disease
Terry, R. (1998) · Journal of neural transmission. Supplementum · doi:10.1007/978-3-7091-6467-9_12 · Cited by 70
Boncristiano, S., Calhoun, M. E., Howard, V., Bondolfi, L., Kaeser, S. A., Wiederhold, K.-H., Staufenbiel, M., & Jucker, M. (2005) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2004.06.010 · Cited by 68
Bailey, J. A., Ray, B., Greig, N. H., & Lahiri, D. K. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021954 · Cited by 70
“Reductions in both pre- and post-synaptic proteins have been observed in AD and these losses correlate strongly with cognitive decline [57,58].”
BackgroundWang, S., Yu, L., Yang, H., Li, C., Hui, Z., Xu, Y., & Zhu, X. (2016) · PLoS ONE · doi:10.1371/journal.pone.0151397 · Cited by 72
Rodríguez‐Ortiz, C. J., Prieto, G. A., Martini, A. C., Forner, S., Trujillo‐Estrada, L., LaFerla, F. M., Baglietto‐Vargas, D., Cotman, C. W., & Kitazawa, M. (2020) · Aging Cell · doi:10.1111/acel.13118 · Cited by 69
“…underlying mechanisms by which neuropathological hallmarks, such as amyloid-beta (Aβ) plaques, neurofibrillary tangles, and neuroinflammation, mediate synapse loss (Dickson et al., 1995; Sze et al., 1997; Terry et al., 1991; Walsh & Selkoe, 2004) and dysfunction (Prieto et al., 2017; Selkoe, 2002).”
Background
Metadata
- 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
- 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 › 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
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