C reactive protein, the first innate immunity receptor identified, and serum amyloid P component are classic short pentraxins produced in the liver. Long pentraxins, including the prototype PTX3, are expressed in a variety of tissues. Some long pentraxins are expressed in the brain and some are involved in neuronal plasticity and degeneration. PTX3 is produced by a variety of cells and tissues, most notably dendritic cells and macrophages, in response to Toll-like receptor (TLR) engagement and inflammatory cytokines. PTX3 acts as a functional ancestor of antibodies, recognizing microbes, activating complement, and facilitating pathogen recognition by phagocytes, hence playing a nonredundant role in resistance against selected pathogens. In addition, PTX3 is essential in female fertility because it acts as a nodal point for the assembly of the cumulus oophorus hyaluronan-rich extracellular matrix. Thus, the prototypic long pentraxin PTX3 is a multifunctional soluble pattern recognition receptor at the crossroads between innate immunity, inflammation, matrix deposition, and female fertility.

Inability to form new memories is an early clinical sign of Alzheimer's disease (AD). There is ample evidence that the amyloid-β (Aβ) peptide plays a key role in the pathogenesis of this disorder. Soluble, bio-derived oligomers of Aβ are proposed as the key mediators of synaptic and cognitive dysfunction, but more tractable models of Aβ−mediated cognitive impairment are needed. Here we report that, in mice, acute intracerebroventricular injections of synthetic Aβ 1-42 oligomers impaired consolidation of the long-term recognition memory, whereas mature Aβ 1-42 fibrils and freshly dissolved peptide did not. The deficit induced by oligomers was reversible and was prevented by an anti-Aβ antibody. It has been suggested that the cellular prion protein (PrP C ) mediates the impairment of synaptic plasticity induced by Aβ. We confirmed that Aβ 1-42 oligomers interact with PrP C , with nanomolar affinity. However, PrP-expressing and PrP knock-out mice were equally susceptible to this impairment. These data suggest that Aβ 1-42 oligomers are responsible for cognitive impairment in AD and that PrP C is not required.Alzheimer | neurotoxicity | object recognition test | surface plasmon resonance | protein aggregation

PTX3 is a prototypic long pentraxin that plays a non-redundant role in innate immunity against selected pathogens and in female fertility. Here, we report that the infertility of Ptx3–/– mice is associated with severe abnormalities of the cumulus oophorus and failure of in vivo, but not in vitro, oocyte fertilization. PTX3 is produced by mouse cumulus cells during cumulus expansion and localizes in the matrix. PTX3 is expressed in the human cumulus oophorus as well. Cumuli from Ptx3–/– mice synthesize normal amounts of hyaluronan (HA), but are unable to organize it in a stable matrix. Exogenous PTX3 restores a normal cumulus phenotype. Incorporation in the matrix of inter-α-trypsin inhibitor is normal in Ptx3–/– cumuli. PTX3 does not interact directly with HA, but it binds the cumulus matrix hyaladherin tumor necrosis factor α-induced protein 6 (TNFAIP6, also known as TSG6) and thereby may form multimolecular complexes that can cross-link HA chains. Thus, PTX3 is a structural constituent of the cumulus oophorus extracellular matrix essential for female fertility.

Abstractβ-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673→valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced β-amyloid (Aβ) production and formation of amyloid fibrils in vitro. Coincubation of mutated and wild-type peptides conferred instability on Aβ aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.Acentral pathological feature of Alzheimer's disease (AD) is the accumulation of β-Aβ in the form of oligomers and amyloid fibrils in the brain (1). Aβ is generated by sequential cleavage of the APP by β-and γ-secretases and exists as short and long isoforms, Aβ1-40 and Aβ1-42 (2). Aβ1-42 is especially prone to misfolding and builds up aggregates that are thought to be the primary neurotoxic species involved in AD pathogenesis (2,3). AD is usually sporadic, but *To whom correspondence should be addressed. E-mail: ftagliavini@istituto-besta.it. Publisher's Disclaimer: This manuscript has been accepted for publication in Science. This version has not undergone final editing. Please refer to the complete version of record at http://www.sciencemag.org/. The manuscript may not be reproduced or used in any manner that does not fall within the fair use provisions of the Copyright Act without the prior, written permission of AAAS. NIH Public Access Author ManuscriptScience. Author manuscript; available in PMC 2010 March 13. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript a small fraction of cases is familial (4). The familial forms show an autosomal dominant pattern of inheritance with virtually complete penetrance and are linked to mutations in the APP, presenilin 1, and presenilin 2 genes (5). The APP mutations close to the sites of β-or γ-secretase cleavage flanking the Aβ sequence overproduce total Aβ or only Aβ1-42, respectively, whereas those that alter amino acids within Aβ result in greater propensity to aggregation in vitro (6, 7).We have identified an APP mutation [Ala 673 →Val 673 (A673V)] that causes disease only in the homozygous state. The mutation consists of a C-to-T transition that results in an alanineto-valine substitution at position 673 (APP770 numbering) corresponding to position 2 of Aβ ( Fig. 1A and fig. S1) (8). The genetic defect was found in a patient with early-onset dementia and in his younger sister, who now shows multiple-domain mild cognitive impairment (MCI) In the patient, the disease presented with behavioral changes and cognitive deficits at the age of 36 years and evolved towar...

Pentraxins are a superfamily of conserved proteins involved in the acute-phase response and innate immunity. Pentraxin 3 (PTX3), a prototypical member of the long pentraxin subfamily, is a key component of the humoral arm of innate immunity that is essential for resistance to certain pathogens. A regulatory role for pentraxins in inflammation has long been recognized, but the underlying mechanisms remain unclear. Here we report that PTX3 bound P-selectin and attenuated neutrophil recruitment at sites of inflammation. PTX3 released from activated leukocytes functioned locally to dampen neutrophil recruitment and regulate inflammation. Antibodies have glycosylation-dependent regulatory effect on inflammation. Therefore, PTX3, which is an essential component of humoral innate immunity, and immunoglobulins share functional outputs, including complement activation, opsonization and, as shown here, glycosylation-dependent regulation of inflammation.

The long pentraxin PTX3 is a multifunctional soluble molecule involved in inflammation and innate immunity. As an acute phase protein, PTX3 binds to the classical pathway complement protein C1q, limits tissue damage in inflammatory conditions by regulating apoptotic cell clearance, and plays a role in the phagocytosis of selected pathogens. This study was designed to investigate the interaction of PTX3 with factor H (FH), the main soluble alternative pathway regulatory protein. We report that PTX3 binds FH with an apparent Kd of 1.1 × 10−7 M, and define two binding sites for PTX3 on FH. The primary binding site is located on FH domains 19–20, which interact with the N-terminal domain of PTX3, while a secondary binding site on domain 7 binds the glycosylated PTX3 pentraxin domain. The FH Y402H polymorphism, which affects binding to the short pentraxin CRP, did not affect binding to PTX3. Surface-bound PTX3 enhances FH recruitment and iC3b deposition and PTX3-bound FH retains its activity as a cofactor for factor I-mediated C3b cleavage. Thus, our findings identify PTX3 as a unique FH ligand in that it can bind both of the two hot-spots of FH, namely SCR7 and SCR19–20 and indicate that PTX3 participates in the localization of functionally active FH.

Doni et al. use four tissue damage models in mice and find that the fluid phase pattern recognition molecule pentraxin 3 (PTX3) plays a role in tissue remodeling and repair. PTX3 binds fibrinogen/fibrin and plasminogen at an acidic pH within tissues. Mice deficient in PTX3 present defects in fibrin deposition, clot formation, collagen deposition, and macrophage-mediated fibrinolysis.

The long pentraxin 3 (PTX3) is a multifunctional soluble pattern recognition molecule that is crucial in innate immune protection against opportunistic fungal pathogens such as Aspergillus fumigatus. The mechanisms that mediate downstream effects of PTX3 are largely unknown. However, PTX3 interacts with C1q from the classical pathway of the complement. The ficolins are recognition molecules of the lectin complement pathway sharing structural and functional characteristics with C1q. Thus, we investigated whether the ficolins (Ficolin-1, -2, and -3) interact with PTX3 and whether the complexes are able to modulate complement activation on A. fumigatus. Ficolin-2 could be affinity-isolated from human plasma on immobilized PTX3. In binding studies, Ficolin-1 and particularly Ficolin-2 interacted with PTX3 in a calcium-independent manner. Ficolin-2, but not Ficolin-1 and Ficolin-3, bound A. fumigatus directly, but this binding was enhanced by PTX3 and vice versa. Ficolin-2-dependent complement deposition on the surface of A. fumigatus was enhanced by PTX3. A polymorphism in the FCN2 gene causing a T236M amino acid change in the fibrinogen-like binding domain of Ficolin-2, which affects the binding to GlcNAc, reduced Ficolin-2 binding to PTX3 and A. fumigatus significantly. These results demonstrate that PTX3 and Ficolin-2 may recruit each other on pathogens. The effect was alleviated by a common amino acid change in the fibrinogen-like domain of Ficolin-2. Thus, components of the humoral innate immune system, which activate different complement pathways, cooperate and amplify microbial recognition and effector functions.