Brain Serum Amyloid P Levels are Reduced in Individuals that Lack Dementia While Having Alzheimer’s Disease Neuropathology

Crawford, Jeffrey R.; Bjorklund, Nicole L.; Taglialatela, Giulio; Gomer, Richard H.

doi:10.1007/s11064-011-0674-0

Cited by 25 publications

(19 citation statements)

References 37 publications

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“…However, inhibition of SAPC, cathepsin B, or both proteins from HIV-infected MCM before addition to neurons was neuroprotective. Previous reports indicated that SAPC possess neurotoxic properties [31], including the stabilization of amyloid fibrils, which is the hallmark of AD neurodegenerative process [30]. These results suggest that HIV-1 infection is promoting the association of SAPC with cathepsin B more than a change in SAPC expression and/or secretion to increase neurotoxicity.…”

Section: Discussionmentioning

confidence: 77%

“…SAPC is involved in acute phase response and is linked to amyloid plaque accumulation by stabilizing amyloid fibrils, thus preventing their degradation [28,29]. It is present in AD patients [30], and induced neuronal apoptosis when injected into rat hippocampus [31]. There is proof of efflux of SAPC at the blood brain barrier (BBB) [32], and accumulation of SAPC in the brain of rats with permeabilized BBB, demonstrating its role in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 99%

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Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

Cantres-Rosario

Hernández

Negron

et al. 2015

Aids

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Objective HIV-1 infection of macrophages increases cathepsin B secretion and induces neuronal apoptosis, but the molecular mechanism remains unclear. Design We identified macrophage secreted cathepsin B protein interactions extracellularly and their contribution to neuronal death in vitro. Methods Cathepsin B was immunoprecipitated from monocyte-derived macrophage supernatants after 12 days post-infection. The cathepsin B interactome was quantified by label-free tandem mass spectrometry and compared to uninfected supernatants. Proteins identified were validated by western blot. Neurons were exposed to macrophage-conditioned media in presence or absence of antibodies against cathepsin B and interacting proteins. Apoptosis was measured using TUNEL labeling. Immunohistochemistry of post-mortem brain tissue samples from healthy, HIV-infected, and Alzheimer’s disease patients was performed to observe the ex vivo expression of the proteins identified. Results Nine proteins co-immunoprecipitated differentially with cathepsin B between uninfected and HIV-infected macrophages. Serum amyloid p component (SAPC) -cathepsin B interaction increased in HIV-infected macrophage supernatants, while matrix metalloprotease 9 (MMP-9) -cathepsin B interaction decreased. Pre-treatment of HIV-infected macrophage-conditioned media with antibodies against cathepsin B and SAPC decreased neuronal apoptosis. The addition of MMP-9 antibodies was not protective. SAPC was over-expressed in post-mortem brain tissue from HIV-positive neurocognitive impaired patients compared to HIV positive with normal cognition and healthy controls, while MMP-9 expression was similar in all tissues. Conclusions Inhibiting SAPC-cathepsin B interaction protects against HIV–induced neuronal death and may help to find alternative treatments for HIV-associated neurocognitive disorders.

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Section: Discussionmentioning

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

Cantres-Rosario

Hernández

Negron

et al. 2015

Aids

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“…Proteomic analysis from a preliminary study shows strong upregulation of SAP in capillary cerebral amyloid angiopathy [48], and this fi nding is supported by immunochemistry indicating signifi cantly more SAP deposits in microvascular Aβ deposits [23,49]. Previous studies suggested that SAP content of the AD brain can be originated from local synthesis in CNS [24,32] or SAP synthesized by the liver can be transported through BBB by an unknown mechanism [21]. Our in vitro studies on the brain endothelial monolayers demonstrated that SAP can cross BBB in both directions.…”

Section: Discussionmentioning

confidence: 91%

“…The excess of secreted SAP is precipitated in amyloid deposits resulted by different chronic infl ammatory processes [31]. SAP is also synthesized in brain, and increased mRNA and protein levels were detected in brain of AD patients compared to controls [17,24,32]. However, no signifi cant increase in SAP production could be detected in postmortem samples from hippocampus and frontal cortex of nondemented subjects with AD neuropathology [32].…”

Section: Introductionmentioning

confidence: 99%

“…SAP is also synthesized in brain, and increased mRNA and protein levels were detected in brain of AD patients compared to controls [17,24,32]. However, no signifi cant increase in SAP production could be detected in postmortem samples from hippocampus and frontal cortex of nondemented subjects with AD neuropathology [32]. Available data about SAP levels in cerebrospinal fl uid (CSF) of AD patients are controversial: a study showed elevated SAP concentration [33], whereas the others [34][35][36][37] did not detect signifi cant differences between AD and age-matched control patients.…”

Section: Introductionmentioning

confidence: 99%

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Efflux transport of serum amyloid P component at the blood-brain barrier

Veszelka¹,

Laszy²,

Pazmany³

et al. 2013

European Journal of Microbiology and Immunology

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Serum amyloid P component (SAP), a member of the innate immune system, does not penetrate the brain in physiological conditions; however, SAP is a stabilizing component of the amyloid plaques in neurodegenerative diseases. We investigated the cerebrovascular transport of human SAP in animal experiments and in culture blood-brain barrier (BBB) models. After intravenous injection, no SAP could be detected by immunohistochemistry or ELISA in healthy rat brains. Salmonella typhimurium lipopolysaccharide injection increased BBB permeability for SAP and the number of cerebral vessels labeled with fluorescein isothiocyanate (FITC)-SAP in mice. Furthermore, when SAP was injected to the rat hippocampus, a time-dependent decrease in brain concentration was seen demonstrating a rapid SAP efflux transport in vivo. A temperature-dependent bidirectional transport of FITC-SAP was observed in rat brain endothelial monolayers. The permeability coefficient for FITC-SAP was significantly higher in abluminal to luminal (brain to blood) than in the opposite direction. The luminal release of FITC-SAP from loaded endothelial cells was also significantly higher than the abluminal one. Our data indicate the presence of BBB efflux transport mechanisms protecting the brain from SAP penetration. Damaged BBB integrity due to pathological insults may increase brain SAP concentration contributing to development of neurodegenerative diseases.

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Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease

et al. 2023

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Aging is the main risk factor for the appearance of age-related neurodegenerative diseases, including Alzheimer's disease (AD). AD is the most common form of dementia, characterized by the presence of senile plaques (SPs) and neurofibrillary tangles (NFTs), the main histopathological hallmarks in AD brains. The core of these deposits are predominantly amyloid fibrils in SPs and hyperphosphorylated Tau protein in NFTs, but other molecular components can be found associated with these pathological lesions. Herein, an extensive literature review was carried out to obtain the SPs and NFTs proteomes, followed by a bioinformatic analysis and further putative biomarker validation. For SPs, 857 proteins were recovered, and, for NFTs, 627 proteins of which 375 occur in both groups and represent the common proteome. Gene Ontology (GO) enrichment analysis permitted the identification of biological processes and the molecular functions most associated with these lesions. Analysis of the SPs and NFTs common proteins unraveled pathways and molecular targets linking both histopathological events. Further, validation of a putative phosphotarget arising from the in silico analysis was performed in serum-derived extracellular vesicles from AD patients. This bioinformatic approach contributed to the identification of putative molecular targets, valuable for AD diagnostic or therapeutic intervention.

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Brain Serum Amyloid P Levels are Reduced in Individuals that Lack Dementia While Having Alzheimer’s Disease Neuropathology

Cited by 25 publications

References 37 publications

Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

Interacting partners of macrophage-secreted cathepsin B contribute to HIV-induced neuronal apoptosis

Efflux transport of serum amyloid P component at the blood-brain barrier

Bioinformatic analysis of the SPs and NFTs proteomes unravel putative biomarker candidates for Alzheimer's disease

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