Antiamyloidogenic and proamyloidogenic chaperone effects of C-reactive protein and serum amyloid P component

Ozawa, Daisaku; Nomura, Ryo; Mangione, Palma; Hara, Kazuhiro; Okoshi, Tadakazu; Porcari, Riccardo; Bellotti, Vittorio; Naiki, Hironobu

doi:10.1080/13506129.2017.1295943

Cited by 3 publications

(1 citation statement)

References 5 publications

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“…Although its role is controversial, i.e. both anti‐amyloidogenic and pro‐amyloidogenic effects have been described , its presence is usually attributed to its role in stabilizing the fibrils, thereby preventing proteolytic degradation . A recent study has suggested that in addition to the most common proteins, serum amyloid P component, Apo‐E, and Apo‐AIV, the amyloid proteomic signature should also include vitronectin and clusterin as co‐deposited proteins .…”

Section: Discussionmentioning

confidence: 99%

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Reglődi

Jungling

Longuespée

et al. 2018

The Journal of Pathology

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Dysregulation of neuropeptides may play an important role in aging‐induced impairments. Among them, pituitary adenylate cyclase‐activating polypeptide (PACAP) is a potent cytoprotective peptide that provides an endogenous control against a variety of tissue‐damaging stimuli. We hypothesized that the progressive decline of PACAP throughout life and the well‐known general cytoprotective effects of PACAP lead to age‐related pathophysiological changes in PACAP deficiency, supported by the increased vulnerability to various stressors of animals partially or totally lacking PACAP. Using young and aging CD1 PACAP knockout (KO) and wild type (WT) mice, we demonstrated pre‐senile amyloidosis in young PACAP KO animals and showed that senile amyloidosis appeared accelerated, more generalized, more severe, and affected more individuals. Histopathology showed age‐related systemic amyloidosis with mainly kidney, spleen, liver, skin, thyroid, intestinal, tracheal, and esophageal involvement. Mass spectrometry‐based proteomic analysis, reconfirmed with immunohistochemistry, revealed that apolipoprotein‐AIV was the main amyloid protein in the deposits together with several accompanying proteins. Although the local amyloidogenic protein expression was disturbed in KO animals, no difference was found in laboratory lipid parameters, suggesting a complex pathway leading to increased age‐related degeneration with amyloid deposits in the absence of PACAP. In spite of no marked inflammatory histological changes or blood test parameters, we detected a disturbed cytokine profile that possibly creates a pro‐inflammatory milieu favoring amyloid deposition. In summary, here we describe accelerated systemic senile amyloidosis in PACAP gene‐deficient mice, which might indicate an early aging phenomenon in this mouse strain. Thus, PACAP KO mice could serve as a model of accelerated aging with human relevance. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

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Section: Discussionmentioning

confidence: 99%

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Reglődi

Jungling

Longuespée

et al. 2018

The Journal of Pathology

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Pentraxins in invertebrates and vertebrates: From structure, function and evolution to clinical applications

Wang,

Chen,

Ding

et al. 2023

Developmental & Comparative Immunology

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Structurally Altered, Not Wild-Type, Pentameric C-Reactive Protein Inhibits Formation of Amyloid-β Fibrils

Ngwa

Agrawal

2022

The Journal of Immunology

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The structure of wild-type pentameric C-reactive protein (CRP) is stabilized by two calcium ions that are required for the binding of CRP to its ligand phosphocholine. CRP in its structurally altered pentameric conformations also binds to proteins that are denatured and aggregated by immobilization on microtiter plates; however, the identity of the ligand on immobilized proteins remains unknown. We tested the hypotheses that immobilization of proteins generated an amyloid-like structure and that amyloid-like structure was the ligand for structurally altered pentameric CRP. We found that the Abs to amyloid-β peptide 1–42 (Aβ) reacted with immobilized proteins, indicating that some immobilized proteins express an Aβ epitope. Accordingly, four different CRP mutants capable of binding to immobilized proteins were constructed, and their binding to fluid-phase Aβ was determined. All CRP mutants bound to fluid-phase Aβ, suggesting that Aβ is a ligand for structurally altered pentameric CRP. In addition, the interaction between CRP mutants and Aβ prevented the formation of Aβ fibrils. The growth of Aβ fibrils was also halted when CRP mutants were added to growing fibrils. Biochemical analyses of CRP mutants revealed altered topology of the Ca2+-binding site, suggesting a role of this region of CRP in binding to Aβ. Combined with previous reports that structurally altered pentameric CRP is generated in vivo, we conclude that CRP is a dual pattern recognition molecule and an antiamyloidogenic protein. These findings have implications for Alzheimer’s and other neurodegenerative diseases caused by amyloidosis and for the diseases caused by the deposition of otherwise fluid-phase proteins.

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Antiamyloidogenic and proamyloidogenic chaperone effects of C-reactive protein and serum amyloid P component

Cited by 3 publications

References 5 publications

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Accelerated pre‐senile systemic amyloidosis in PACAP knockout mice – a protective role of PACAP in age‐related degenerative processes

Pentraxins in invertebrates and vertebrates: From structure, function and evolution to clinical applications

Structurally Altered, Not Wild-Type, Pentameric C-Reactive Protein Inhibits Formation of Amyloid-β Fibrils

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