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  1. Article: Evidence for a protective effect of the loss of α4-containing nicotinic acetylcholine receptors on Aβ-related neuropathology in Tg2576 mice.

    Vilella, Antonietta / Romoli, Benedetto / Bodria, Martina / Pons, Stéphanie / Maskos, Uwe / Zoli, Michele

    Frontiers in neuroscience

    2023  Volume 17, Page(s) 1097857

    Abstract: Introduction: Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer's disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high ... ...

    Abstract Introduction: Loss of cholinergic neurons as well as α4β2* (* = containing) nicotinic acetylcholine receptors (nAChRs) is a prominent feature of Alzheimer's disease (AD). Specifically, amyloid β (Aβ), the principal pathogenic factor of AD, is a high affinity ligand for nAChRs. Yet, the pathophysiological role of nAChRs in AD is not well established.
    Methods: In the present study, we have investigated the effects of the loss of α4* nAChRs on the histological alterations of the Tg2576 mouse model of AD (APPswe) crossing hemizygous APPswe mice with mice carrying the genetic inactivation of α4 nAChR subunit (α4KO).
    Results: A global decrease in Aβ plaque load was observed in the forebrain of APPswe/α4KO mice in comparison with APPswe mice, that was particularly marked in neocortex of 15 month-old mice. At the same age, several alterations in synaptophysin immunoreactivity were observed in cortico-hippocampal regions of APPswe mice that were partially counteracted by α4KO. The analysis of the immunoreactivity of specific astroglia (glial fibrillary acidic protein, GFAP) and microglia (ionized calcium-binding adapter molecule, Iba1) markers showed an increase in the number as well as in the area occupied by these cells in APPswe mice that were partially counteracted by α4KO.
    Conclusion: Overall, the present histological study points to a detrimental role of α4* nAChRs that may be specific for Aβ-related neuropathology.
    Language English
    Publishing date 2023-04-11
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2411902-7
    ISSN 1662-453X ; 1662-4548
    ISSN (online) 1662-453X
    ISSN 1662-4548
    DOI 10.3389/fnins.2023.1097857
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Melanocortin receptor agonist NDP-α-MSH improves cognitive deficits and microgliosis but not amyloidosis in advanced stages of AD progression in 5XFAD and 3xTg mice.

    Daini, Eleonora / Vandini, Eleonora / Bodria, Martina / Liao, Wenjie / Baraldi, Carlo / Secco, Valentina / Ottani, Alessandra / Zoli, Michele / Giuliani, Daniela / Vilella, Antonietta

    Frontiers in immunology

    2023  Volume 13, Page(s) 1082036

    Abstract: Introduction: Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs ... ...

    Abstract Introduction: Alzheimer's disease (AD) is the most frequent cause of dementia and still lacks effective therapy. Clinical signs of AD include low levels of endogenous melanocortins (MCs) and previous studies have shown that treatment with MC analogs induces neuroprotection in the early stages of AD.
    Methods: We investigated the neuroprotective role of MCs in two transgenic mouse models of severe AD using 5 and 7 month-old (mo) 5XFAD mice and 9 and 12 mo 3xTg mice. These mice were subjected to a chronic stimulation of MC receptors (MCRs) with MC analogue Nle4-D-Phe7-α-melanocyte stimulating hormone (NDP-α-MSH, 340 μg/kg, i.p.). Mouse behavior and ex-vivo histological and biochemical analyses were performed after 50 days of treatment.
    Results: Our analysis demonstrated an improvement in cognitive abilities of AD mice at late stage of AD progression. We also showed that these protective effects are associated with decreased levels of hyperphosphorylated Tau but not with Aβ burden, that was unaffected in the hippocampus and in the cortex of AD mice. In addition, an age-dependent NDP effect on glial reactivity was observed only in 3xTg mice whereas a global downregulation of p38 mitogen-activated protein kinase was selectively observed in 7 mo 5XFAD and 14 mo 3xTg mice.
    Conclusion: Our results suggest that MCR stimulation by NDP-α-MSH could represent a promising therapeutic strategy in managing cognitive decline also at late stage of AD, whereas the effects on neuroinflammation may be restricted to specific stages of AD progression.
    MeSH term(s) Animals ; Mice ; Alzheimer Disease/drug therapy ; Alzheimer Disease/metabolism ; Cognition ; Cognitive Dysfunction/drug therapy ; Cognitive Dysfunction/etiology ; Mice, Transgenic ; Receptor, Melanocortin, Type 4/agonists
    Chemical Substances MSH, 4-Nle-7-Phe-alpha- (75921-69-6) ; Receptor, Melanocortin, Type 4
    Language English
    Publishing date 2023-01-10
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2022.1082036
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Identification of 4-amino-2-Pyridones as new potent PCSK9 inhibitors: From phenotypic hit discovery to in vivo tolerability.

    Giannessi, Lisa / Lupo, Maria Giovanna / Rossi, Ilaria / Martina, Maria Grazia / Vilella, Antonietta / Bodria, Martina / Giuliani, Daniela / Zimetti, Francesca / Zanotti, Ilaria / Potì, Francesco / Bernini, Franco / Ferri, Nicola / Radi, Marco

    European journal of medicinal chemistry

    2023  Volume 265, Page(s) 116063

    Abstract: Among the strategies to overcome the underperformance of statins in cardiovascular diseases (CVDs), the development of drugs targeting the Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is considered one of the most promising. However, only ... ...

    Abstract Among the strategies to overcome the underperformance of statins in cardiovascular diseases (CVDs), the development of drugs targeting the Proprotein Convertase Subtilisin-like Kexin type 9 (PCSK9) is considered one of the most promising. However, only anti-PCSK9 biological drugs have been approved to date, and orally available small-molecules for the treatment of hypercholesterolemic conditions are still missing on the market. In the present work, we describe the application of a phenotypic approach to the identification and optimization of 4-amino-2-pyridone derivatives as a new chemotype with anti-PCSK9 activity. Starting from an in-house collection of compounds, functional assays on HepG2 cells followed by a chemistry-driven hit optimization campaign, led to the potent anti-PCSK9 candidate 5c. This compound, at 5 μM, totally blocked PCSK9 secretion from HepG2 cells, significantly increased LDL receptor (LDLR) expression, and acted cooperatively with simvastatin by reducing its induction of PCSK9 expression. Finally, compound 5c also proved to be well tolerated in C57BL/6J mice at the tested concentration (40 mg/kg) with no sign of toxicity or behavior modifications.
    MeSH term(s) Animals ; Humans ; Mice ; Hep G2 Cells ; Mice, Inbred C57BL ; PCSK9 Inhibitors ; Proprotein Convertase 9/metabolism ; Receptors, LDL/metabolism ; Pyridones/chemistry ; Pyridones/metabolism
    Chemical Substances PCSK9 Inhibitors ; PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Receptors, LDL ; Pyridones
    Language English
    Publishing date 2023-12-20
    Publishing country France
    Document type Journal Article
    ZDB-ID 188597-2
    ISSN 1768-3254 ; 0009-4374 ; 0223-5234
    ISSN (online) 1768-3254
    ISSN 0009-4374 ; 0223-5234
    DOI 10.1016/j.ejmech.2023.116063
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.B 784: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 2021: Bestellungen von Artikeln über das Online-Bestellformular
    ab Jg. 2022: Lesesaal (EG)

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  4. Article ; Online: PCSK9 ablation attenuates Aβ pathology, neuroinflammation and cognitive dysfunctions in 5XFAD mice.

    Vilella, Antonietta / Bodria, Martina / Papotti, Bianca / Zanotti, Ilaria / Zimetti, Francesca / Remaggi, Giulia / Elviri, Lisa / Potì, Francesco / Ferri, Nicola / Lupo, Maria Giovanna / Panighel, Giovanni / Daini, Eleonora / Vandini, Eleonora / Zoli, Michele / Giuliani, Daniela / Bernini, Franco

    Brain, behavior, and immunity

    2023  Volume 115, Page(s) 517–534

    Abstract: Background: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/ ... ...

    Abstract Background: Increasing evidence highlights the importance of novel players in Alzheimer's disease (AD) pathophysiology, including alterations of lipid metabolism and neuroinflammation. Indeed, a potential involvement of Proprotein convertase subtilisin/kexin type 9 (PCSK9) in AD has been recently postulated. Here, we first investigated the effects of PCSK9 on neuroinflammation in vitro. Then, we examined the impact of a genetic ablation of PCSK9 on cognitive performance in a severe mouse model of AD. Finally, in the same animals we evaluated the effect of PCSK9 loss on Aβ pathology, neuroinflammation, and brain lipids.
    Methods: For in vitro studies, U373 human astrocytoma cells were treated with Aβ fibrils and human recombinant PCSK9. mRNA expression of the proinflammatory cytokines and inflammasome-related genes were evaluated by q-PCR, while MCP-1 secretion was measured by ELISA. For in vivo studies, the cognitive performance of a newly generated mouse line - obtained by crossing 5XFAD
    Results: In vitro, PCSK9 significantly increased IL6, IL1B and TNFΑ mRNA levels in Aβ fibrils-treated U373 cells, without influencing inflammasome gene expression, except for an increase in NLRC4 mRNA levels. In vivo, PCSK9 ablation in 5XFAD mice significantly improved the performance at the Morris water maze test; these changes were accompanied by a reduced corticohippocampal Aβ burden without affecting plaque spatial/regional distribution and composition or global BACE1 expression. Furthermore, PCSK9 loss in 5XFAD mice induced decreased microgliosis and astrocyte reactivity in several brain regions. Conversely, knocking out PCSK9 had minimal impact on brain cholesterol and hydroxysterol levels.
    Conclusions: In vitro studies showed a pro-inflammatory effect of PCSK9. Consistently, in vivo data indicated a protective role of PCSK9 ablation against cognitive impairments, associated with improved Aβ pathology and attenuated neuroinflammation in a severe mouse model of AD. PCSK9 may thus be considered a novel pharmacological target for the treatment of AD.
    MeSH term(s) Mice ; Humans ; Animals ; Mice, Transgenic ; Proprotein Convertase 9/therapeutic use ; Amyloid Precursor Protein Secretases/metabolism ; Amyloid Precursor Protein Secretases/therapeutic use ; Neuroinflammatory Diseases ; Chromatography, Liquid ; Inflammasomes ; Aspartic Acid Endopeptidases/genetics ; Aspartic Acid Endopeptidases/metabolism ; Aspartic Acid Endopeptidases/therapeutic use ; Tandem Mass Spectrometry ; Alzheimer Disease/metabolism ; Cognitive Dysfunction ; RNA, Messenger ; Cholesterol ; Amyloid beta-Peptides/metabolism ; Disease Models, Animal
    Chemical Substances PCSK9 protein, human (EC 3.4.21.-) ; Proprotein Convertase 9 (EC 3.4.21.-) ; Amyloid Precursor Protein Secretases (EC 3.4.-) ; Inflammasomes ; Aspartic Acid Endopeptidases (EC 3.4.23.-) ; RNA, Messenger ; Cholesterol (97C5T2UQ7J) ; Amyloid beta-Peptides
    Language English
    Publishing date 2023-11-13
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 639219-2
    ISSN 1090-2139 ; 0889-1591
    ISSN (online) 1090-2139
    ISSN 0889-1591
    DOI 10.1016/j.bbi.2023.11.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

    Zs.A 2276: Show issues Location:
    Je nach Verfügbarkeit (siehe Angabe bei Bestand)
    bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular
    Jg. 1995 - 2021: Lesesall (2.OG)
    ab Jg. 2022: Lesesaal (EG)
    Zs.MO 327: Show issues

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  5. Article ; Online: S100B dysregulation during brain development affects synaptic SHANK protein networks via alteration of zinc homeostasis.

    Daini, Eleonora / Hagmeyer, Simone / De Benedictis, Chiara A / Cristóvão, Joana S / Bodria, Martina / Ross, Aisling M / Raab, Andrea / Boeckers, Tobias M / Feldmann, Joerg / Gomes, Cláudio M / Zoli, Michele / Vilella, Antonietta / Grabrucker, Andreas M

    Translational psychiatry

    2021  Volume 11, Issue 1, Page(s) 562

    Abstract: Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy- ... ...

    Abstract Autism Spectrum Disorders (ASD) are caused by a combination of genetic predisposition and nongenetic factors. Among the nongenetic factors, maternal immune system activation and zinc deficiency have been proposed. Intriguingly, as a genetic factor, copy-number variations in S100B, a pro-inflammatory damage-associated molecular pattern (DAMP), have been associated with ASD, and increased serum S100B has been found in ASD. Interestingly, it has been shown that increased S100B levels affect zinc homeostasis in vitro. Thus, here, we investigated the influence of increased S100B levels in vitro and in vivo during pregnancy in mice regarding zinc availability, the zinc-sensitive SHANK protein networks associated with ASD, and behavioral outcomes. We observed that S100B affects the synaptic SHANK2 and SHANK3 levels in a zinc-dependent manner, especially early in neuronal development. Animals exposed to high S100B levels in utero similarly show reduced levels of free zinc and SHANK2 in the brain. On the behavioral level, these mice display hyperactivity, increased stereotypic and abnormal social behaviors, and cognitive impairment. Pro-inflammatory factors and zinc-signaling alterations converge on the synaptic level revealing a common pathomechanism that may mechanistically explain a large share of ASD cases.
    MeSH term(s) Animals ; Autism Spectrum Disorder/genetics ; Brain/metabolism ; Female ; Genetic Predisposition to Disease ; Homeostasis ; Mice ; Microfilament Proteins ; Nerve Tissue Proteins/genetics ; Pregnancy ; S100 Calcium Binding Protein beta Subunit ; Zinc/metabolism
    Chemical Substances Microfilament Proteins ; Nerve Tissue Proteins ; S100 Calcium Binding Protein beta Subunit ; S100b protein, mouse ; Shank2 protein, mouse ; Shank3 protein, mouse ; Zinc (J41CSQ7QDS)
    Language English
    Publishing date 2021-11-05
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2609311-X
    ISSN 2158-3188 ; 2158-3188
    ISSN (online) 2158-3188
    ISSN 2158-3188
    DOI 10.1038/s41398-021-01694-z
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article: Identification of a Thyroid Hormone Derivative as a Pleiotropic Agent for the Treatment of Alzheimer's Disease.

    Runfola, Massimiliano / Perni, Michele / Yang, Xiaoting / Marchese, Maria / Bacci, Andrea / Mero, Serena / Santorelli, Filippo M / Polini, Beatrice / Chiellini, Grazia / Giuliani, Daniela / Vilella, Antonietta / Bodria, Martina / Daini, Eleonora / Vandini, Eleonora / Rudge, Simon / Gul, Sheraz / Wakelam, Michale O J / Vendruscolo, Michele / Rapposelli, Simona

    Pharmaceuticals (Basel, Switzerland)

    2021  Volume 14, Issue 12

    Abstract: The identification of effective pharmacological tools for Alzheimer's disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological ... ...

    Abstract The identification of effective pharmacological tools for Alzheimer's disease (AD) represents one of the main challenges for therapeutic discovery. Due to the variety of pathological processes associated with AD, a promising route for pharmacological intervention involves the development of new chemical entities that can restore cellular homeostasis. To investigate this strategy, we designed and synthetized SG2, a compound related to the thyroid hormone thyroxine, that shares a pleiotropic activity with its endogenous parent compound, including autophagic flux promotion, neuroprotection, and metabolic reprogramming. We demonstrate herein that SG2 acts in a pleiotropic manner to induce recovery in a
    Language English
    Publishing date 2021-12-19
    Publishing country Switzerland
    Document type Journal Article
    ZDB-ID 2193542-7
    ISSN 1424-8247
    ISSN 1424-8247
    DOI 10.3390/ph14121330
    Database MEDical Literature Analysis and Retrieval System OnLINE

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