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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Expressions of visual pigments and synaptic proteins in neonatal chick retina exposed to light of variable photoperiods
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“There are few reports on changes in synaptophysin expression in disorders like diabetes retinopathy, increased intraocular pressure, retinal degeneration and Alzheimer’s disease (Sze et al. 1997; Kihara et al. 2008; Linberg et al. 2002; Sasaki et al. 2010).”
Background
Neural Regeneration as a Disease-Modifying Therapeutic Strategy for Alzheimer’s Disease
Kazim, S. F., & Iqbal, K. (2017) · Elsevier eBooks · doi:10.1016/b978-0-12-803690-7.00002-8 · Cited by 2
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“loss of synapses and synapse-associated proteins [110–124] and BDNF is observed in brain regions required for intact memory function [125–127], behavioral enrichment may help to improve or maintain cognitive function.”
Background
Quantitative Evaluation of Synaptophysin‐Like Immunoreactive Nerve Terminals or Varicosities in Anterior Pituitary of Normal and Adrenalectomized Rats
Liu, Y. ‐., & Ju, G. (2001) · Journal of Neuroendocrinology · doi:10.1111/j.1365-2826.2001.00720.x · Cited by 2
Aging-Dependent Loss of Connectivity in Alzheimer’s Model Mice with Rescue by mGluR5 ModulatorPreprint
Mandino, F., Shen, X., Desrosiers-Grégoire, G., O’Connor, D. A., Mukherjee, B., Owens, A., Qu, A., Onofrey, J. A., Papademetris, X., Chakravarty, M. M., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.15.571715 · Cited by 2
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Self-citation
Prevention of Stress-Induced Cognitive Impairment: Today and Tomorrow
Trofimiuk, E., & Braszko, J. J. (2015) · Springer eBooks · doi:10.1007/978-3-319-17103-6_10 · Cited by 2
Sex-Dependent Changes in the Gene Expression of UPR-Associated Calcium-Binding Proteins in the STZ–Induced Model of Alzheimer’s Disease
Schultz, B., Bobermin, L. D., Menezes, L., Gayger-Dias, V., Silva, V.-F. D., Taday, J., Alves, J., Tramontina, F. F., Zanotto, C., Dalmaz, C., et al. (2025) · Molecular Neurobiology · doi:10.1007/s12035-025-05046-6 · Cited by 1
“Hippocampal synaptophysin appears to be an early marker of cognitive impairment in AD [29] and sex-dependent changes have been observed in older individuals with Down syndrome [30].”
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Kara, B., Beck, J. S., Fu, Z., Hickey, S. L., Kanaan, N. M., Mufson, E. J., Ginsberg, S. D., & Counts, S. (2025) · Acta Neuropathologica Communications · doi:10.1186/s40478-025-02080-2 · Cited by 1
Brain, CSF, and Blood Metabolomics Signature in the TgF344-AD Rat Model of Alzheimer’s Disease
Samey, R. A., Mavel, S., Ceyzériat, K., Chalon, S., Nadal‐Desbarats, L., Bodard, S., Lefèvre, A., Busson, J., Chicheri, G., Antier, D., et al. (2025) · Journal of Proteome Research · doi:10.1021/acs.jproteome.5c00047 · Cited by 1
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Ercoli, S., Casares-Crespo, L., Juárez‐Escoto, E., & Mira, H. (2026) · Aging Cell · doi:10.1111/acel.70382 · Cited by 1
“On the other hand, SAMP8 Diff-Astrocyte cultures also show decreased TSP-1 protein levels, as quantified by immunofluorescence ( p < 0.05; Figure 4C,E) and Western blot (Figure S3), and reduced Thbs1 gene expression compared to SAMR1 Diff-Astrocytes ( p < 0.01; Figure 4F).”
Influential
Synaptic alterations are preceding the axonal loss in optic atrophy of Wolfram syndrome mouse model
Gurram, V., An, W., Bimal, S., & Urano, F. (2026) · Frontiers in Neuroscience · doi:10.3389/fnins.2026.1838257 · Cited by 1
Large amyloid plaques associate with early behavioral alterations in 6-month-old APPswe/PS1dE9 mice
Sitdikova, K., Tsoy, A., Chaprov, K., de Munter, J., Svirin, E. P., Torosyan, H., Yenkoyan, K. B., Askarova, S., Steinbusch, H. W. M., Anthony, D. C., et al. (2026) · Journal of Neuropathology & Experimental Neurology · doi:10.1093/jnen/nlag078 · Cited by 1
Chronic Smoking Impairs Glymphatic Transport and Cognitive Function in Adolescent Mice Through Cardiac, Vascular, and Perivascular Aquaporin‐4 Mechanisms
Lv, C., Xia, C., Li, Z., Liu, T., Sha, Z., Dong, S., Qian, Y., Liu, M., Zhang, K., Zhang, X., et al. (2026) · CNS Neuroscience & Therapeutics · doi:10.1002/cns.71040 · Cited by 1
Place cell physiology in a transgenic mouse model of Alzheimer's disease
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“The progressive dementia associated with AD is closely correlated with the loss of synapses, as measured by the loss of synaptic proteins including synaptophysin, synapsin-1 and synaptobre-vin (DeKosky and Scheff, 1990; Terry et al., 1991; Heinonen et al., 1995; Sze et al., 1997).”
The Use of Viral Vectors to Enhance Cognition
Ikezu, T. (2015) · Elsevier eBooks · doi:10.1016/b978-0-12-417042-1.00006-1 · Cited by 1
Molecular Mechanisms of Synaptic Plasticity and Memory and Their Dysfunction in Alzheimer's Disease ☆
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Can we switch production of toxic Aβ oligomers to neuroprotective Aβ monomers to allow synapse regeneration?
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“The pathogenesis of AD is intimately linked with the loss of synapses and many studies have demonstrated close correlations between the loss of synaptic proteins such as synaptophysin and the degree of dementia in AD (Sze et al., 1997).”
Background
Habituation of Somatosensory Evoked Potentials in Patients with Alzheimer’s Disease and Those with Vascular Dementia
Currà, A., Marinelli, L., Cotellessa, F., et al. (2021) · Medicina · doi:10.3390/medicina57121364 · Cited by 1
The Value of Transgenic Models for the Study of Neurodegenerative Diseases
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Self-citation
Environmental Enrichment and Aerobic Exercise Enhances Spatial Memory and Synaptophysin Expression in Rats
Dita, D. A. A., Paramita, N., Kodariah, R., & Kartinah, N. T. (2020) · The Indonesian Biomedical Journal · doi:10.18585/inabj.v12i1.945 · Cited by 1
Alzheimer’s Disease: Neural Stem Cell Therapy Using 3x-Tg Mice
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Cîrneci, D., & Silaghi-Dumitrescu, R. L. (2013) · PubMed · doi:10.3969/j.issn.1673-5374.2013.32.010 · Cited by 2
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Background
Alzheimer Disease: Protein Misfolding, Model Systems, and Experimental Therapeutics
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The aging synapse: Synaptic proteome changes in mouse models of aging
Végh, M. J. (2012) · Digital Academic REpository of VU University Amsterdam (Vrije Universiteit Amsterdam) · Cited by 1
Amyloid-b1-42 treatment does not have a specific effect on cholinergic neurons in in vitro basal forebrain neuronal cultures of rat
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Background
Elucidating the Cognitive Deficits following Doxorubicin treatment
Alhowail, A. H. (2014) · Cited by 1
Detection and Analysis of Synaptosis
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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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