Differential synaptic loss in the cortex in Alzheimerʼs disease: a study using archival material

Clinton, J.; Blackman, Sidney; Royston, M.C.; Roberts, G. W.

doi:10.1097/00001756-199401120-00032

Cited by 37 publications

(18 citation statements)

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“…Clinton et al [40] reported that SNAP-25 and the relatively synaptic index in cortical areas is decreased in brains of patients with AD, a finding confirmed by Shimohama et al [41], which is in agreement with our data of ß-SNAP, i.e. significantly decreased ß-SNAP in temporal cortex.…”

Section: Discussionsupporting

confidence: 93%

Synaptosomal Proteins, Beta-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein (Beta-SNAP), Gamma-SNAP and Synaptotagmin I in Brain of Patients with Down Syndrome and Alzheimer’s Disease

Yoo

Cairns

Fountoulakis

et al. 2001

Dement Geriatr Cogn Disord

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Although it is well-known that synaptosomal proteins are deranged in neurodegenerative disorders, no information is available at the protein-chemical level as mainly immunochemical or immunohistochemical data were reported previously. We therefore investigated synaptosomal proteins in brain specimens from patients with Down syndrome (DS) and Alzheimer’s disease (AD) to challenge the DS synaptic pathology as well as the relevance of DS to AD in synaptic pathology. For the aim of this study, we employed two-dimensional electrophoresis and matrix-associated laser desorption ionization mass spectroscopy and determined β-soluble N-ethylmaleimide-sensitive factor attachment protein (β-SNAP), γ-SNAP and synaptotagmin I (SYT I) in 7 individual brain regions of controls and patients with DS and AD. In DS brain, β-SNAP was significantly reduced in temporal cortex (p < 0.01). SYT I (p65) and SYT I (pI 7.0) were significantly reduced in thalamus (p < 0.01 and p < 0.05, respectively). In AD brain, β-SNAP was significantly decreased in temporal cortex (p < 0.05). SYT I (p65) was significantly reduced in cerebellum (p < 0.05), and temporal (p < 0.001) and parietal cortex (p < 0.01). SYT I (pI 7.0) was significantly reduced in temporal (p < 0.001) and parietal cortex (p < 0.01) and thalamus (p < 0.01). γ-SNAP did not show any change in both DS and AD. The findings may explain impaired synaptogenesis in DS and AD brain, which is well documented in DS brain already early in life, and/or synaptosomal loss secondary to neuronal loss observed in both neurodegenerative disorders. It may also represent, reflect or account for the impaired neuronal transmission in DS and AD, caused by deterioration of the exocytic machinery. Here, we provide evidence for several deranged synaptosomal proteins in several brain regions at the protein level indicating deficient synaptosomal wiring of the brain in DS and AD.

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Section: Discussionsupporting

confidence: 93%

Synaptosomal Proteins, Beta-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein (Beta-SNAP), Gamma-SNAP and Synaptotagmin I in Brain of Patients with Down Syndrome and Alzheimer’s Disease

Yoo

Cairns

Fountoulakis

et al. 2001

Dement Geriatr Cogn Disord

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“…The down-regulation in sensitive regions of genes related to synaptic vesicle docking and recycling at the synapse, such as dynamin I, is also likely to be linked to the decline in cognitive function in AD, because of the ensuing decreases in neurotransmitter release at synapses. This observation suggests a selective weakening or loss of neuronal connections in AD-affected brain regions, and may help explain the decreases in synaptic density observed by quantitative morphometric analyses performed on brain regions vulnerable to AD-induced damage [114-116]. Biochemical analyses of these protein products are in agreement with the transcriptional profile described above [117-119].…”

Section: Selective Neuronal Vulnerability In Alzheimer’s Diseasesupporting

confidence: 67%

Functional Genomics of Brain Aging and Alzheimers Disease: Focus on Selective Neuronal Vulnerability

Wang¹,

Michaelis²,

Michaelis³

2010

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Pivotal brain functions, such as neurotransmission, cognition, and memory, decline with advancing age and, especially, in neurodegenerative conditions associated with aging, such as Alzheimer’s disease (AD). Yet, deterioration in structure and function of the nervous system during aging or in AD is not uniform throughout the brain. Selective neuronal vulnerability (SNV) is a general but sometimes overlooked characteristic of brain aging and AD. There is little known at the molecular level to account for the phenomenon of SNV. Functional genomic analyses, through unbiased whole genome expression studies, could lead to new insights into a complex process such as SNV. Genomic data generated using both human brain tissue and brains from animal models of aging and AD were analyzed in this review. Convergent trends that have emerged from these data sets were considered in identifying possible molecular and cellular pathways involved in SNV. It appears that during normal brain aging and in AD, neurons vulnerable to injury or cell death are characterized by significant decreases in the expression of genes related to mitochondrial metabolism and energy production. In AD, vulnerable neurons also exhibit down-regulation of genes related to synaptic neurotransmission and vesicular transport, cytoskeletal structure and function, and neurotrophic factor activity. A prominent category of genes that are up-regulated in AD are those related to inflammatory response and some components of calcium signaling. These genomic differences between sensitive and resistant neurons can now be used to explore the molecular underpinnings of previously suggested mechanisms of cell injury in aging and AD.

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“…The most widely-analyzed synaptic marker in the brains of AD patients is the synaptic vesicle protein synaptophysin [1, 12]; however, several other synaptic proteins have been shown to be altered in the brains of patients with AD including: synaptobrevin [19, 72, 77], SNAP 25 [19, 21, 77, 108], synaptotagmin [20, 55, 63, 72, 77, 98], syntaxin [19, 21, 67, 77], Rab3a [55, 72, 77, 104], synapsin I [19, 77, 109-112], and postsynaptic proteins PSD-95 [19, 64, 65, 67], Homer and IRSp53 [89]. The 83 publications reported at least one synaptic marker level and combined provided information on 67 different markers (Table 1).…”

Section: 0 Resultsmentioning

confidence: 99%

Meta‐analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

Wilde

Overk

Sijben

et al. 2016

Alzheimer's & Dementia

203

177

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Introduction Loss of synapses best correlates to cognitive deficits in Alzheimer's disease (AD) in which oligomeric neurotoxic species of amyloid β appears to contribute synaptic pathology. While a number of clinical pathological studies have been performed with limited sample size, there are no systematic studies encompassing large samples. Therefore, we performed a meta-analysis study. Methods We identified 417 publications reporting post-mortem synapse and synaptic marker loss from AD patients. Two meta-analyses were performed using a single database of sub-selected publications and calculating the standard mean differences. Results Meta-analysis confirmed synaptic loss in selected brain regions is an early event in AD pathogenesis. The second meta-analysis of 57 synaptic markers revealed that pre-synaptic makers were affected more than postsynaptic markers. Discussion The present meta-analysis study showed a consistent synaptic loss across brain regions and that molecular machinery including endosomal pathways, vesicular assembly mechanisms, glutamate receptors and axonal transport are often affected.

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Differential synaptic loss in the cortex in Alzheimerʼs disease: a study using archival material

Cited by 37 publications

References 0 publications

Synaptosomal Proteins, Beta-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein (Beta-SNAP), Gamma-SNAP and Synaptotagmin I in Brain of Patients with Down Syndrome and Alzheimer’s Disease

Synaptosomal Proteins, Beta-Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein (Beta-SNAP), Gamma-SNAP and Synaptotagmin I in Brain of Patients with Down Syndrome and Alzheimer’s Disease

Functional Genomics of Brain Aging and Alzheimers Disease: Focus on Selective Neuronal Vulnerability

Meta‐analysis of synaptic pathology in Alzheimer's disease reveals selective molecular vesicular machinery vulnerability

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