Cited by 562Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroscience and Neuropharmacology Research

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Loss of the Presynaptic Vesicle Protein Synaptophysin in Hippocampus Correlates with Cognitive Decline in Alzheimer Disease

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SZE, CHUN-I, TRONCOSO, JUAN C., KAWAS, CLAUDIA, MOUTION, PETER, PRICE, DONALD L., MARTIN, LEE J.·1997·Journal of Neuropathology and Experimental Neurology

DOI 10.1097/00005072-199708000-00011

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Abstract

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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“…cor- related with neurodegenerative changes in APP/PSEN1/ Endo-B1 / mice, synaptic input to CA3 pyramidal neu- rons was assessed using immunoreactivity for synaptophy- sin, a presynaptic marker commonly lost in human Alzheimer’s disease and mouse models (Sze et al., 1997; Gimbel et al., 2010).”
Method
Methamphetamine augment HIV-1 Tat mediated memory deficits by altering the expression of synaptic proteins and neurotrophic factors
Nookala, A. R., Schwartz, D. C., Chaudhari, N. S., Glazyrin, A., Stephens, E. B., Berman, N. E. J., & Kumar, A. (2018) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2018.04.018 · Cited by 42
RETRACTED: 5-Lipoxygenase Activating Protein Reduction Ameliorates Cognitive Deficit, Synaptic Dysfunction, and Neuropathology in a Mouse Model of Alzheimer’s Disease
Giannopoulos, P. F., Chu, J., Joshi, Y. B., Sperow, M., Li, J.-G., Kirby, L. G., & Praticò, D. (2013) · Biological Psychiatry · doi:10.1016/j.biopsych.2013.04.009 · Cited by 41
“Data from transgenic mouse models of the disease as well as human AD samples have convincingly demonstrated that the biochemical substrate for cognitive impairments and memory deficits are changes in synaptic density as reflected by changes in presynaptic markers, such as synaptophysin, and postsynaptic markers (20-23…”
Background
Retracted
Regional and progressive changes in brain expression of complexin II in a mouse transgenic for the Huntington’s Disease mutation
Freeman, W., & Morton, A. J. (2004) · Brain Research Bulletin · doi:10.1016/j.brainresbull.2003.12.004 · Cited by 40
Synaptophysin protein and mRNA expression in the human hippocampal formation from birth to old age
Eastwood, S. L., Weickert, C. S., Webster, M. J., Herman, M. M., Kleinman, J. E., & Harrison, P. J. (2006) · Hippocampus · doi:10.1002/hipo.20194 · Cited by 41
“, 1994b), whereas subsequent reports have found, as here, that hippocampal synaptophysin mRNA and protein expression remains generally stable across adulthood (Sze et al., 1997; Young et al., 1998; Eastwood and Harrison, 1999; Vawter et al., 1999; Webster et al., 2001).”
Identification of Novel Small Molecule Inhibitors of Amyloid Precursor Protein Synthesis as a Route to Lower Alzheimer’s Disease Amyloid-β Peptide
Utsuki, T., Yu, Q.-S., Davidson, D., Chen, D., Holloway, H. W., Brossi, A. R., Sambamurti, K., Lahiri, D. K., Greig, N. H., & Giordano, T. (2006) · Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.106.103309 · Cited by 39
Probiotics (Bacillus clausii and Lactobacillus fermentum NMCC-14) Ameliorate Stress Behavior in Mice by Increasing Monoamine Levels and mRNA Expression of Dopamine Receptors (D1 and D2) and Synaptophysin
Rehman, M. U., Ghazanfar, S., Haq, R. U., Ullah, S., Khan, S., Wu, J., Ahmad, W., & Tipu, M. K. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.915595 · Cited by 42
Abnormal Expression of Synaptophysin, SNAP-25, and Synaptotagmin 1 in the Hippocampus of Kainic Acid-Exposed Rats with Behavioral Deficits
Zhang, F., Sun, Q., Zheng, X., Lin, Y.-T., Shang, W., Wang, A.-H., Duan, R., & Chi, Z.-F. (2014) · Cellular and Molecular Neurobiology · doi:10.1007/s10571-014-0068-3 · Cited by 39
Age-related increase in amyloid plaque burden is associated with impairment in conditioned fear memory in CRND8 mouse model of amyloidosis
Hanna, A., Iremonger, K., Das, P., Dickson, D., Golde, T., & Janus, C. (2012) · Alzheimer's Research & Therapy · doi:10.1186/alzrt124 · Cited by 38
“Senile amyloid plaques are found in large numbers in the limbic system, including amygdala (AD is often referred to as ‘limbic dementia’ [9]), hippocampus, and associative cortices which are affected first during the disease progression [10-18].”
Background
N-Acetyl-Cysteine: Modulating the Cysteine Redox Proteome in Neurodegenerative Diseases
Martínez, M. (2022) · Antioxidants · doi:10.3390/antiox11020416 · Cited by 46
“Synaptophysin plays a central role in the synaptic alterations found in AD, and its loss in the hippocampus correlates with cognitive decline in AD patients [105].”
Background
Cellular Cofactors for Amyloid β-Peptide-Induced Cell Stress
Yan, S. D., Roher, A. E., Schmidt, A. M., & Stern, D. M. (1999) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)65452-1 · Cited by 40
Relationship between cerebrospinal fluid biomarkers of Alzheimer's disease and cognition in cognitively normal older adults
Pettigrew, C., Soldan, A., Moghekar, A., Wang, M.-C., Gross, A. L., O’Brien, R., & Albert, M. (2015) · Neuropsychologia · doi:10.1016/j.neuropsychologia.2015.09.024 · Cited by 38
The impacts of diabetes in pregnancy on hippocampal synaptogenesis in rat neonates
Vafaei‐Nezhad, S., Hami, J., Sadeghi, A., Ghaemi, K., Hosseini, M., Abedini, M. R., & Haghir, H. (2016) · Neuroscience · doi:10.1016/j.neuroscience.2016.01.025 · Cited by 38
“Conversely, aberrant SYP expression has been associated with several neurodegenerative diseases and psychiatric disorders, such as schizophrenia and Alzheimer’s disease (Chambers et al. 2005; Sze et al. 1997; Eastwood et al. 1995; Heinonen et al. 1995).”
Influential
Advances on the Understanding of the Origins of Synaptic Pathology in AD
Lacor, P. N. (2007) · Current Genomics · doi:10.2174/138920207783769530 · Cited by 40
Synaptophysin immunogold labelling of synapses decreases in dentate gyrus of the hippocampus of aged rats
Davies, H. A., Kelly, A. M., Dhanrajan, T. M., Lynch, M. A., guez, J. J. R. X., & Stewart, M. G. (2003) · Brain Research · doi:10.1016/s0006-8993(03)03251-7 · Cited by 37
Mesenchymal Stem Cells Therapy Improved the Streptozotocin-Induced Behavioral and Hippocampal Impairment in Rats
Villar, M. F. Z., Hanotte, J. L., Pardo, J., Morel, G. R., Mazzolini, G. D., García, M. G., & Reggiani, P. C. (2019) · Molecular Neurobiology · doi:10.1007/s12035-019-01729-z · Cited by 37
Synapses, Microglia, and Lipids in Alzheimer’s Disease
Paasila, P. J., Aramideh, J. A., Sutherland, G. T., & Graeber, M. B. (2022) · Frontiers in Neuroscience · doi:10.3389/fnins.2021.778822 · Cited by 40
“…include subpial bands (Thal et al., 2000), cotton-wool plaques which feature prominently in PSEN1 (also PS1; encoding presenilin 1) familial AD (Tabira et al., 2002), lake-like patches in the presubiculum (Wisniewski et al., 1998), and the recently described coarse-grained plaques in early…”
Background
Structure, function, and pathology of Neurexin-3
Zhang, R., Jiang, H., Liu, Y., & He, G. (2022) · Genes & Diseases · doi:10.1016/j.gendis.2022.04.008 · Cited by 44
Absence of synaptophysin near cortical neurons containing oligomer Aβ in Alzheimer's disease brain
Ishibashi, K., Tomiyama, T., Nishitsuji, K., Hara, M., & Mori, H. (2006) · Journal of Neuroscience Research · doi:10.1002/jnr.20952 · Cited by 37
“It is likely that the two molecules were not colocalized, because the synapses were affected by oligomer Ab (Sze et al., 1997; Walsh et al., 2002).”
Background
Ethanol protects cultured neurons against amyloid-β and α-synuclein-induced synapse damage
Bate, C., & Williams, A. (2011) · Neuropharmacology · doi:10.1016/j.neuropharm.2011.08.030 · Cited by 38
“neurotransmission, are features of AD that strongly correlate with cognitive decline (Counts et al., 2006; Sze et al., 1997).”
α‐tocopherol affects neuronal plasticity in adult rat dentate gyrus: The possible role of PKCδ
Ferri, P., Cecchini, T., Ambrogini, P., Betti, M., Cuppini, R., Grande, P. D., & Ciaroni, S. (2006) · Journal of Neurobiology · doi:10.1002/neu.20255 · Cited by 36
Cortical Neuropathology in Aging and Dementing Disorders
Hof, P. R., Bouras, C., & Morrison, J. H. (1999) · Cerebral cortex · doi:10.1007/978-1-4615-4885-0_8 · Cited by 35
Neuronal degeneration, synaptic defects, and behavioral abnormalities in tau45-230 transgenic mice
Lang, A. E., Riherd Methner, D. N., & Ferreira, A. (2014) · Neuroscience · doi:10.1016/j.neuroscience.2014.06.017 · Cited by 35
“In addition, studies have shown that the hippocampal content of synaptophysin significantly decreases during the progression of AD in moderate to severe cases of dementia (Mukaetova-Ladinska et al., 2000; Sze et al., 1997).”
Background
Neuroprotective Effects of Protocatechuic Aldehyde against Neurotoxin-Induced Cellular and Animal Models of Parkinson’s Disease
Zhao, X. S., Zhai, S., An, M.-S., Wang, Y., Yang, Y.-F., Ge, H.-Q., Liu, J., & Pu, X. (2013) · PLoS ONE · doi:10.1371/journal.pone.0078220 · Cited by 35
“Loss of dendritic spines and synaptic connections is strongly correlated with functional deficits in neurodegenerative diseases such as PD [42-44].”
Background
Neuropathological quantification of dtg APP/PS1: neuroimaging, stereology, and biochemistry
Manaye, K. F., Wang, P. C., O’Neil, J. N., Huang, S., Xu, T., Lei, D.-L., Tizabi, Y., Ottinger, M. A., Ingram, D. K., & Mouton, P. R. (2007) · AGE · doi:10.1007/s11357-007-9035-y · Cited by 35
Effect of Selective Cholinergic Denervation on the Serotonergic System: Implications for Learning and Memory
Garcı́a-Alloza, M., Zaldua, N., Diez-Ariza, M., Marcos, B., Lasheras, B., Gil-Bea, F. J., & Ramírez, M. J. (2006) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/01.jnen.0000240469.20167.89 · Cited by 36
“Senile plaques, neurofibrillary tangles, and cholinergic dysfunction are major hallmarks of the disease, and although the number of tangles correlates better than the number of amyloid plaques with the severity of dementia, the best statistical correlations occur between synaptic density and degree of dementia (1).”
Background
Neuroprotective effect and mechanism of daucosterol palmitate in ameliorating learning and memory impairment in a rat model of Alzheimer’s disease
Ji, Z.-H., Zhongqi, X., Hong, Z., & Yu, X. (2017) · Steroids · doi:10.1016/j.steroids.2017.01.003 · Cited by 35
“Furthermore, loss of synaptophysin in the hippocampus of AD patients correlated with the severity of cognitive impairment [29].”
Background
3D Analysis of the Synaptic Organization in the Entorhinal Cortex in Alzheimer’s Disease
Domínguez-Álvaro, M., Montero‐Crespo, M., Blázquez‐Llorca, L., Plaza‐Alonso, S., Cano‐Astorga, N., DeFelipe, J., & Alonso‐Nanclares, L. (2021) · eNeuro · doi:10.1523/eneuro.0504-20.2021 · Cited by 35
“The loss and dysfunction of synapses have been proposed as the major structural correlates of the cognitive decline associated with AD (Coleman et al., 2004; Dickson et al., 1995; Selkoe, 2002; Sze et al., 1997).”
Background
Liver X Receptor Agonist Modifies the DNA Methylation Profile of Synapse and Neurogenesis-Related Genes in the Triple Transgenic Mouse Model of Alzheimer’s Disease
Sandoval-Hernández, A. G., Hernández, H. G., Restrepo, A., Muñoz‐Manco, J. I., Bayón, G. F., Fernández, A. F., Fraga, M. F., Cardona‐Gómez, G. P., Arboleda, H., & Arboleda, G. (2015) · Journal of Molecular Neuroscience · doi:10.1007/s12031-015-0665-8 · Cited by 35
“These genes are reduced in the postmortem brain from AD patients (Proctor et al. 2010; Qin et al. 2004; Sze et al. 1997) and show decreased methylation following GW3965 treatment in the present analysis.”
BackgroundInfluential
Identification of Age-Dependent Changes in Expression of Senescence-Accelerated Mouse (SAMP8) Hippocampal Proteins by Expression Array Analysis
Kumar, V. B., Franko, M. W., Farr, S. A., et al. (2000) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.2000.2719 · Cited by 34
Contactin-2, a synaptic and axonal protein, is reduced in cerebrospinal fluid and brain tissue in Alzheimer’s disease
Chatterjee, M., del Campo, M., Morrema, T. H. J., de Waal, M. W. J., van der Flier, W. M., Hoozemans, J. J. M., & Teunissen, C. E. (2018) · Alzheimer s Research & Therapy · doi:10.1186/s13195-018-0383-x · Cited by 33
Psychedelics as Novel Therapeutics in Alzheimer’s Disease: Rationale and Potential Mechanisms
Garcia‐Romeu, A., Darcy, S., Jackson, H., White, T., & Rosenberg, P. B. (2021) · Current topics in behavioral neurosciences · doi:10.1007/7854_2021_267 · Cited by 33
“For example, synaptophysin (a characteristic marker of synaptic integrity) is decreased in prodromal AD (Masliah et al. 2001; Sze et al. 1997; Yuki et al. 2014).”
Background
SO2 inhalation causes synaptic injury in rat hippocampus via its derivatives in vivo
Yun, Y., Yao, G., Yue, H., Guo, L., Qin, G., Li, G., & Sang, N. (2013) · Chemosphere · doi:10.1016/j.chemosphere.2013.08.063 · Cited by 32
“This suggests that the loss of SYP after SO2 derivatives exposure might lead to synaptic depression during sustained activity and thereby contribute to cognitive impairment early in AD (Sze et al., 1997).”
Background
Effect of Gender on Mitochondrial Toxicity of Alzheimer's A β Peptide
Viña, J., Lloret, A., Vallés, S. L., Borrás, C., Badía, M.-C., Pallardó, F. V., Sastre, J., & Alonso, M.-D. (2007) · Antioxidants and Redox Signaling · doi:10.1089/ars.2007.1773 · Cited by 33
“Synapse loss is an early phenotypic sign in the pathology of AD (60, 100, 103).”
An acute functional screen identifies an effective antibody targeting amyloid-β oligomers based on calcium imaging
Wang, X., Kastanenka, K. V., Arbel‐Ornath, M., Commins, C., Kuzuya, A., Lariviere, A., Krafft, G. A., Hefti, F. F., Jerecìć, J., & Bacskai, B. J. (2018) · Scientific Reports · doi:10.1038/s41598-018-22979-2 · Cited by 32
Oxytocin inhibits methamphetamine‐associated learning and memory alterations by regulating DNA methylation at the Synaptophysin promoter
Fan, X., Yang, J., Dong, Y., Hou, Y., Liu, S., & Wu, C. (2018) · Addiction Biology · doi:10.1111/adb.12697 · Cited by 33

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.
ORCID: SZE, CHUN-I
TRONCOSO, JUAN C.
KAWAS, CLAUDIA
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)
DOI: 10.1097/00005072-199708000-00011
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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Loss of the Presynaptic Vesicle Protein Synaptophysin in Hippocampus Correlates with Cognitive Decline in Alzheimer Disease

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