laura colombo
@marionegri.it
Department of Molecular Biochemistry and Pharmacology
Institute of Pharmacological Research "Mario Negri" IRCCS
Scopus Publications
Scopus Publications
Alice Passoni, Monica Favagrossa, Marta Valenza, Giulia Birolini, Alessia Lanno, Caterina Mariotti, Elena Cattaneo, Mario Salmona, Laura Colombo, and Renzo Bagnati
Elsevier BV
Barbara Sciandrone, Alessandro Palmioli, Carlotta Ciaramelli, Roberta Pensotti, Laura Colombo, Maria Elena Regonesi, and Cristina Airoldi
American Chemical Society (ACS)
Spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disorder characterized by ataxia and other neurological manifestations, with a poor prognosis and a lack of effective therapies. The amyloid aggregation of the ataxin-3 protein is a hallmark of SCA3 and one of the main biochemical events prompting its onset, making it a prominent target for the development of preventive and therapeutic interventions. Here, we tested the efficacy of an aqueous Lavado cocoa extract and its polyphenolic components against ataxin-3 aggregation and neurotoxicity. The combination of biochemical assays and atomic force microscopy morphological analysis provided clear evidence of cocoa flavanols' ability to hinder ATX3 amyloid aggregation through direct physical interaction, as assessed by NMR spectroscopy. The chemical identity of the flavanols was investigated by ultraperformance liquid chromatography-high-resolution mass spectrometry. The use of the preclinical model Caenorhabditis elegans allowed us to demonstrate cocoa flavanols' ability to ameliorate ataxic phenotypes in vivo. To the best of our knowledge, Lavado cocoa is the first natural source whose extract is able to directly interfere with ATX3 aggregation, leading to the formation of off-pathway species.
Laura Tapella, Giulia Dematteis, Pietro La Vitola, Susanna Leva, Elisa Tonelli, Marco Raddi, Marta Delconti, Letizia Dacomo, Alberto La Macchia, Elisa Murari,et al.
Wiley
AbstractAlzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell‐target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD‐related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN‐KO). In the former, we evaluated the ability of β‐amyloid oligomers (AβOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN‐KO mice. Next, we generated a tamoxifen‐inducible astrocyte‐specific CaNB1 knock‐out in 3xTg‐AD mice (indACNKO‐AD). CaNB1 was deleted, by tamoxifen injection, in 11.7‐month‐old 3xTg‐AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; β‐amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AβOs in 2‐month‐old wild type mice impaired recognition memory and fostered a pro‐inflammatory microglia phenotype, whereas in ACN‐KO mice, AβOs were inactive. In indACNKO‐AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte‐specific CaNB1 deletion is beneficial for both the abolishment of AβO‐mediated detrimental effects and treatment of ongoing AD‐related pathology, hence representing an intriguing target for AD therapy.
Giulia Birolini, Marta Valenza, Ilaria Ottonelli, Francesca Talpo, Lucia Minoli, Andrea Cappelleri, Mauro Bombaci, Claudio Caccia, Caterina Canevari, Arianna Trucco,et al.
Elsevier BV
Luisa Diomede, Elisa R. Zanier, Federico Moro, Gloria Vegliante, Laura Colombo, Luca Russo, Alfredo Cagnotto, Carmina Natale, Federica Marta Xodo, Ada De Luigi,et al.
Springer Science and Business Media LLC
AbstractAlzheimer’s disease (AD), the leading cause of dementia in older adults, is a double proteinopathy characterized by amyloid-β (Aβ) and tau pathology. Despite enormous efforts that have been spent in the last decades to find effective therapies, late pharmacological interventions along the course of the disease, inaccurate clinical methodologies in the enrollment of patients, and inadequate biomarkers for evaluating drug efficacy have not allowed the development of an effective therapeutic strategy. The approaches followed so far for developing drugs or antibodies focused solely on targeting Aβ or tau protein. This paper explores the potential therapeutic capacity of an all-D-isomer synthetic peptide limited to the first six amino acids of the N-terminal sequence of the A2V-mutated Aβ, Aβ1-6A2V(D), that was developed following the observation of a clinical case that provided the background for its development. We first performed an in-depth biochemical characterization documenting the capacity of Aβ1-6A2V(D) to interfere with the aggregation and stability of tau protein. To tackle Aβ1-6A2V(D) in vivo effects against a neurological decline in genetically predisposed or acquired high AD risk mice, we tested its effects in triple transgenic animals harboring human PS1(M146 V), APP(SW), and MAPT(P301L) transgenes and aged wild-type mice exposed to experimental traumatic brain injury (TBI), a recognized risk factor for AD. We found that Aβ1-6A2V(D) treatment in TBI mice improved neurological outcomes and reduced blood markers of axonal damage. Exploiting the C. elegans model as a biosensor of amyloidogenic proteins’ toxicity, we observed a rescue of locomotor defects in nematodes exposed to the brain homogenates from TBI mice treated with Aβ1-6A2V(D) compared to TBI controls. By this integrated approach, we demonstrate that Aβ1-6A2V(D) not only impedes tau aggregation but also favors its degradation by tissue proteases, confirming that this peptide interferes with both Aβ and tau aggregation propensity and proteotoxicity.
Margarita C. Dinamarca, Laura Colombo, Urszula Brykczynska, Amandine Grimm, Isabelle Fruh, Imtiaz Hossain, Daniela Gabriel, Anne Eckert, Matthias Müller, and Eline Pecho-Vrieseling
Frontiers Media SA
Neuron-to-neuron transmission of aggregation-prone, misfolded proteins may potentially explain the spatiotemporal accumulation of pathological lesions in the brains of patients with neurodegenerative protein-misfolding diseases (PMDs). However, little is known about protein transmission from the central nervous system to the periphery, or how this propagation contributes to PMD pathology. To deepen our understanding of these processes, we established two functional neuromuscular systems derived from human iPSCs. One was suitable for long-term high-throughput live-cell imaging and the other was adapted to a microfluidic system assuring that connectivity between motor neurons and muscle cells was restricted to the neuromuscular junction. We show that the Huntington's disease (HD)-associated mutant HTT exon 1 protein (mHTTEx1) is transmitted from neurons to muscle cells across the human neuromuscular junction. We found that transmission is an active and dynamic process that starts before aggregate formation and is regulated by synaptic activity. We further found that transmitted mHTTEx1 causes HD-relevant pathology at both molecular and functional levels in human muscle cells, even in the presence of the ubiquitous expression of mHTTEx1. In conclusion, we have uncovered a causal link between mHTTEx1 synaptic transmission and HD pathology, highlighting the therapeutic potential of blocking toxic protein transmission in PMDs.
Marcella Catania, Laura Colombo, Stefano Sorrentino, Alfredo Cagnotto, Jacopo Lucchetti, Maria Chiara Barbagallo, Ilaria Vannetiello, Elena Rita Vecchi, Monica Favagrossa, Massimo Costanza,et al.
Springer Science and Business Media LLC
AbstractAlzheimer’s disease (AD) is an irreversible neurodegenerative disorder that affects millions of people worldwide. AD pathogenesis is intricate. It primarily involves two main molecular players—amyloid-β (Aβ) and tau—which actually have an intrinsic trend to generate molecular assemblies that are toxic to neurons. Incomplete knowledge of the molecular mechanisms inducing the onset and sustaining the progression of the disease, as well as the lack of valid models to fully recapitulate the pathogenesis of human disease, have until now hampered the development of a successful therapy for AD. The overall experience with clinical trials with a number of potential drugs—including the recent outcomes of studies with monoclonal antibodies against Aβ—seems to indicate that Aβ-targeting is not effective if it is not accompanied by an efficient challenge of Aβ neurotoxic properties. We took advantage from the discovery of a naturally-occurring variant of Aβ (AβA2V) that has anti-amyloidogenic properties, and designed a novel bio-inspired strategy for AD based on the intranasal delivery of a six-mer peptide (Aβ1-6A2V) retaining the anti-amyloidogenic abilities of the full-length AβA2V variant. This approach turned out to be effective in preventing the aggregation of wild type Aβ and averting the synaptic damage associated with amyloidogenesis in a mouse model of AD. The results of our preclinical studies inspired by a protective model already existing in nature, that is the human heterozygous AβA2V carriers which seem to be protected from AD, open the way to an unprecedented and promising approach for the prevention of the disease in humans.
Valeria Rondelli, Alexandros Koutsioubas, Emanuela Di Cola, Giovanna Fragneto, I. Grillo, Elena Del Favero, Laura Colombo, Laura Cantù, Paola Brocca, and Mario Salmona
Elsevier BV
Alessandro Palmioli, Valeria Mazzoni, Ada De Luigi, Chiara Bruzzone, Gessica Sala, Laura Colombo, Chiara Bazzini, Chiara Paola Zoia, Mariagiovanna Inserra, Mario Salmona,et al.
American Chemical Society (ACS)
The relevant social and economic costs associated with aging and neurodegenerative diseases, particularly Alzheimer's disease (AD), entail considerable efforts to develop effective preventive and therapeutic strategies. The search for natural compounds, whose intake through diet can help prevent the main biochemical mechanisms responsible for AD onset, led us to screen hops, one of the main ingredients of beer. To explore the chemical variability of hops, we characterized four hop varieties, i.e., Cascade, Saaz, Tettnang, and Summit. We investigated the potential multitarget hop activity, in particular its ability to hinder Aβ1-42 peptide aggregation and cytotoxicity, its antioxidant properties, and its ability to enhance autophagy, promoting the clearance of misfolded and aggregated proteins in a human neuroblastoma SH-SY5Y cell line. Moreover, we provided evidence of in vivo hop efficacy using the transgenic CL2006Caenorhabditis elegans strain expressing the Aβ3-42 peptide. By combining cell-free and in vitro assays with nuclear magnetic resonance (NMR) and MS-based metabolomics, NMR molecular recognition studies, and atomic force microscopy, we identified feruloyl and p-coumaroylquinic acids flavan-3-ol glycosides and procyanidins as the main anti-Aβ components of hop.
Joseph Windheim, Laura Colombo, Nora C. Battajni, Luca Russo, Alfredo Cagnotto, Luisa Diomede, Paolo Bigini, Elena Vismara, Ferdinando Fiumara, Silvia Gabbrielli,et al.
MDPI AG
A significant portion of the world’s plastic is not properly disposed of and, through various processes, is degraded into microscopic particles termed micro- and nanoplastics. Marine and terrestrial faunae, including humans, inevitably get in contact and may inhale and ingest these microscopic plastics which can deposit throughout the body, potentially altering cellular and molecular functions in the nervous and other systems. For instance, at the cellular level, studies in animal models have shown that plastic particles can cross the blood–brain barrier and interact with neurons, and thus affect cognition. At the molecular level, plastics may specifically influence the folding of proteins, induce the formation of aberrant amyloid proteins, and therefore potentially trigger the development of systemic and local amyloidosis. In this review, we discuss the general issue of plastic micro- and nanoparticle generation, with a focus on their effects on protein folding, misfolding, and their possible clinical implications.
Margarita C. Dinamarca, Laura Colombo, Natalia E. Tousiaki, Matthias Müller, and Eline Pecho-Vrieseling
Frontiers Media SA
Huntington’s disease (HD) is a monogenic disease that results in a combination of motor, psychiatric, and cognitive symptoms. It is caused by a CAG trinucleotide repeat expansion in the exon 1 of the huntingtin (HTT) gene, which results in the production of a mutant HTT protein (mHTT) with an extended polyglutamine tract (PolyQ). Severe motor symptoms are a hallmark of HD and typically appear during middle age; however, mild cognitive and personality changes often occur already during early adolescence. Wild-type HTT is a regulator of synaptic functions and plays a role in axon guidance, neurotransmitter release, and synaptic vesicle trafficking. These functions are important for proper synapse assembly during neuronal network formation. In the present study, we assessed the effect of mHTT exon1 isoform on the synaptic and functional maturation of human induced pluripotent stem cell (hiPSC)-derived neurons. We used a relatively fast-maturing hiPSC line carrying a doxycycline-inducible pro-neuronal transcription factor, (iNGN2), and generated a double transgenic line by introducing only the exon 1 of HTT, which carries the mutant CAG (mHTTEx1). The characterization of our cell lines revealed that the presence of mHTTEx1 in hiPSC-derived neurons alters the synaptic protein appearance, decreases synaptic contacts, and causes a delay in the development of a mature neuronal activity pattern, recapitulating some of the developmental alterations observed in HD models, nonetheless in a shorted time window. Our data support the notion that HD has a neurodevelopmental component and is not solely a degenerative disease.
Carlotta Ciaramelli, Alessandro Palmioli, Irene Angotti, Laura Colombo, Ada De Luigi, Gessica Sala, Mario Salmona, and Cristina Airoldi
Frontiers Media SA
The anti-Alzheimer disease (AD) activity reported for an aqueous cinnamon bark extract prompted us to investigate and compare the anti-amyloidogenic properties of cinnamon extracts obtained from both bark and bud, the latter being a very little explored matrix. We prepared the extracts with different procedures (alcoholic, hydroalcoholic, or aqueous extractions). An efficient protocol for the rapid analysis of NMR spectra of cinnamon bud and bark extracts was set up, enabling the automatic identification and quantification of metabolites. Moreover, we exploited preparative reverse-phase (RP) chromatography to prepare fractions enriched in polyphenols, further characterized by UPLC-HR-MS. Then, we combined NMR-based molecular recognition studies, atomic force microscopy, and in vitro biochemical and cellular assays to investigate the anti-amyloidogenic activity of our extracts. Both bud and bark extracts showed a potent anti-amyloidogenic activity. Flavanols, particularly procyanidins, and cinnamaldehydes, are the chemical components of cinnamon hindering Aβ peptide on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line. Together with the previously reported ability to hinder tau aggregation and filament formation, these data indicate cinnamon polyphenols as natural products possessing multitarget anti-AD activity. Since cinnamon is a spice increasingly present in the human diet, our results support its use to prepare nutraceuticals useful in preventing AD through an active contrast to the biochemical processes that underlie the onset of this disease. Moreover, the structures of cinnamon components responsible for cinnamon anti-AD activities represent molecular templates for designing and synthesizing new anti-amyloidogenic drugs.
Ada De Luigi, Laura Colombo, Luca Russo, Caterina Ricci, Antonio Bastone, Sara Cimini, Fabrizio Tagliavini, Giacomina Rossi, Laura Cantù, Elena Del Favero,et al.
Elsevier BV
Emiliano Bedini, Alfonso Iadonisi, Chiara Schiraldi, Laura Colombo, Diego Albani, Paola Petrini, Carmen Giordano, and Marta Tunesi
MDPI AG
Chondroitin sulfates (CS) are a class of sulfated glycosaminoglycans involved in many biological processes. Several studies reported their protective effect against neurodegenerative conditions like Alzheimer’s disease. CS are commonly derived from animal sources, but ethical concerns, the risk of contamination with animal proteins, and the difficulty in controlling the sulfation pattern have prompted research towards non-animal sources. Here we exploited two microbiological-chemical sourced CS (i.e., CS-A,C and CS-A,C,K,L) and Carbopol 974P NF/agarose semi-interpenetrating polymer networks (i.e., P.NaOH.0 and P.Ethanol.0) to set up a release system, and tested the neuroprotective role of released CS against H2O2-induced oxidative stress. After assessing that our CS (1–100 µM) require a 3 h pre-treatment for neuroprotection with SH-SY5Y cells, we evaluated whether the autoclave type (i.e., N- or B-type) affects hydrogel viscoelastic properties. We selected B-type autoclaves and repeated the study after loading CS (1 or 0.1 mg CS/0.5 mL gel). After loading 1 mg CS/0.5 mL gel, we evaluated CS release up to 7 days by 1,9-dimethylmethylene blue (DMMB) assay and verified the neuroprotective role of CS-A,C (1 µM) in the supernatants. We observed that CS-A,C exhibits a broader neuroprotective effect than CS-A,C,K,L. Moreover, sulfation pattern affects not only neuroprotection, but also drug release.
Elisa R. Zanier, Maria Monica Barzago, Gloria Vegliante, Margherita Romeo, Elena Restelli, Ilaria Bertani, Carmina Natale, Luca Colnaghi, Laura Colombo, Luca Russo,et al.
Elsevier BV
F. Del Gallo, S. Bianchi, I. Bertani, Massimo Messa, L. Colombo, C. Balducci, M. Salmona, L. Imeri and R. Chiesa
Sleep is severely impaired in patients with Alzheimer's disease. Amyloid-β deposition in the brain of Alzheimer's disease patients is a key event in its pathogenesis and is associated with disrupted sleep, even before the appearance of cognitive decline. Because soluble amyloid-β oligomers are the key mediators of synaptic and cognitive dysfunction in Alzheimer's disease and impair long-term memory in rodents, the first aim of this study was to test the hypothesis that amyloid-β oligomers would directly impair sleep in mice. The cellular prion protein is a cell surface glycoprotein of uncertain function. Because cellular prion protein binds oligomeric amyloid-β with high affinity and mediates some of its neurotoxic effects, the second aim of the study was to test whether amyloid-β oligomer-induced sleep alterations were mediated by cellular prion protein. To address these aims, wild-type and cellular prion protein-deficient mice were given acute intracerebroventricular injections (on different days, at lights on) of vehicle and synthetic amyloid-β oligomers. Compared to vehicle, amyloid-β oligomers significantly reduced the amount of time spent in non-rapid eye movement sleep by wild-type mice during both the light and dark phases of the light-dark cycle. The amount of time spent in rapid eye movement sleep was reduced during the dark phase. Sleep was also fragmented by amyloid-β oligomers, as the number of transitions between states increased in post-injection hours 9-24. No such effects were observed in cellular prion protein-deficient mice. These results show that amyloid-β oligomers do inhibit and fragment sleep, and that these effects are mediated by cellular prion protein.
Carlotta Ciaramelli, Alessandro Palmioli, Ada De Luigi, Laura Colombo, Gessica Sala, Mario Salmona, and Cristina Airoldi
Elsevier BV
The metabolic profile of Lavado cocoa was characterized for the first time by NMR spectroscopy, then compared with the profiles of fermented and processed varieties, Natural and commercial cocoa. The significant difference in the contents of theobromine and flavanols prompted us to examine the cocoa varieties to seek correlations between these metabolite concentrations and the anti-amyloidogenic activity reported for cocoa in the literature. We combined NMR spectroscopy, preparative reversed-phase (RP) chromatography, atomic force microscopy, in vitro biochemical and cell assays, to investigate and compare the anti-amyloidogenic properties of extracts and fractions enriched in different metabolite classes. Lavado variety was the most active and the catechins and theobromine were the chemical components of cocoa hindering Aβ peptide on-pathway aggregation and toxicity in a human neuroblastoma SH-SY5Y cell line.
Giulia Birolini, Marta Valenza, Ilaria Ottonelli, Alice Passoni, Monica Favagrossa, Jason T. Duskey, Mauro Bombaci, Maria Angela Vandelli, Laura Colombo, Renzo Bagnati,et al.
Elsevier BV
P. La Vitola, C. Balducci, M. Baroni, L. Artioli, G. Santamaria, M. Castiglioni, M. Cerovic, L. Colombo, L. Caldinelli, L. Pollegioni,et al.
Wiley
AIMS
Parkinson's disease and related disorders are devastating neurodegenerative pathologies. Since α-synuclein was identified as a main component of Lewy bodies and neurites, efforts have been made to clarify the pathogenic mechanisms of α-synuclein's detrimental effects. α-synuclein oligomers are the most harmful species and may recruit and activate glial cells. Inflammation is emerging as a bridge between genetic susceptibility and environmental factors co-fostering Parkinson's disease. However, direct evidence linking inflammation to the harmful activities of α-synuclein oligomers or to the Parkinson's disease behavioural phenotype is lacking.
METHODS
To clarify whether neuroinflammation influences Parkinson's disease pathogenesis, we developed: (i) a "double-hit" approach in C57BL/6 naïve mice where peripherally administered lipopolysaccharides were followed by intracerebroventricular injection of an inactive oligomer dose; (ii) a transgenic "double-hit" model where lipopolysaccharides were given to A53T α-synuclein transgenic Parkinson's disease mice.
RESULTS
Lipopolysaccharides induced a long-lasting neuroinflammatory response which facilitated the detrimental cognitive activities of oligomers. LPS-activated microglia and astrocytes responded differently to the oligomers. with microglia activating further and acquiring a proinflammatory M1 phenotype, while astrocytes atrophied. In the transgenic "double-hit" A53T mouse model, lipopolysaccharides aggravated cognitive deficits and increased microgliosis. Again, astrocytes responded differently to the double challenge. These findings indicate that peripherally-induced neuroinflammation potentiates the α-synuclein oligomer's actions and aggravates cognitive deficits in A53T mice.
CONCLUSIONS
The fine management of both peripheral and central inflammation may offer a promising therapeutic approach to prevent or slow down some behavioural aspects in α-synucleinopathies.
Marten Beeg, Elisabetta Battocchio, Ada De Luigi, Laura Colombo, Carmina Natale, Alfredo Cagnotto, Alessandro Corbelli, Fabio Fiordaliso, Luisa Diomede, Mario Salmona,et al.
Elsevier BV
Valeria Rondelli, Mario Salmona, Laura Colombo, Giovanna Fragneto, Giulia C. Fadda, Laura Cantu’, and Elena Del Favero
MDPI AG
The physiological and pathological roles of nascent amyloid beta (Aβ) monomers are still debated in the literature. Their involvement in the pathological route of Alzheimer’s Disease (AD) is currently considered to be the most relevant, triggered by their aggregation into structured oligomers, a toxic species. Recently, it has been suggested that nascent Aβ, out of the amyloidogenic pathway, plays a physiological and protective role, especially in the brain. In this emerging perspective, the study presented in this paper investigated whether the organization of model membranes is affected by contact with Aβ in the nascent state, as monomers. The outcome is that, notably, the rules of engagement and the resulting structural outcome are dictated by the composition and properties of the membrane, rather than by the Aβ variant. Interestingly, Aβ monomers are observed to favor the tightening of adjacent complex membranes, thereby affecting a basic structural event for cell-cell adhesion and cell motility.
Luca Zoia, Annalisa Morelli, Laura Talamini, Martina B Violatto, Arianna B Lovati, Silvia Lopa, Camilla Recordati, Chiara Toffanin, Anika Salanti, Luca Russo,et al.
Future Medicine Ltd
Aim: We investigated the use of cellulose nanocrystals (CNCs) as drug nanocarriers combining an anti-osteoporotic agent, alendronate (ALN), and an anti-cancer drug, doxorubicin (DOX). Materials & methods: CNC physicochemical characterization, in vivo imaging coupled with histology and in vitro uptake and toxicity assays were carried out. Results: In vivo CNC-ALN did not modify bone tropism and lung penetration, whereas its liver and kidney accumulation was slightly higher compared with CNCs alone. In vitro studies showed that CNC-ALN did not impair ALN's effect on osteoclasts, whereas CNC-DOX confirmed the therapeutic potential against bone metastatic cancer cells. Conclusions: This study provides robust proof of the potential of CNCs as easy, flexible and specific carriers to deliver compounds to the bone.
Debasmita Tripathy, Alice Migazzi, Federica Costa, Alessandro Roncador, Pamela Gatto, Federica Fusco, Lucia Boeri, Diego Albani, J. Leon Juárez-Hernández, Carlo Musio,et al.
Elsevier BV
Alzheimer's disease (AD) is the most common cause of dementia. At the pre-symptomatic phase of the disease, the processing of the amyloid precursor protein (APP) produces toxic peptides, called amyloid-β 1-42 (Aβ 1-42). The downstream effects of Aβ 1-42 production are not completely uncovered. Here, we report the involvement of transglutaminase 1 (TG1) in in vitro AD models of neuronal toxicity. TG1 was increased at late stages of the disease in the hippocampus of a mouse model of AD and in primary cortical neurons undergoing stress. Silencing of TGM1 gene was sufficient to prevent Aβ-mediated neuronal death. Conversely, its overexpression enhanced cell death. TGM1 upregulation was mediated at the transcriptional level by an activator protein 1 (AP1) binding site that when mutated halted TGM1 promoter activation. These results indicate that TG1 acts downstream of Aβ-toxicity, and that its stress-dependent increase makes it suitable for pharmacological intervention.
Roberta Ruotolo, Ilaria Minato, Pietro La Vitola, Luisa Artioli, Claudio Curti, Valentina Franceschi, Nicoletta Brindani, Davide Amidani, Laura Colombo, Mario Salmona,et al.
Wiley
SCOPE
Amyloid-β oligomers (AβO) are causally related to Alzheimer's disease (AD). Dietary natural compounds, especially flavonoids and flavan-3-ols, hold great promise as potential AD-preventive agents but their host and gut microbiota metabolism complicates identification of the most relevant bioactive species. This study aims to investigate the ability of a comprehensive set of phenyl-γ-valerolactones (PVL), the main circulating metabolites of flavan-3-ols and related dietary compounds in humans, to prevent AβO-mediated toxicity.
METHODS AND RESULTS
The anti-AβO activity of PVLs was examined in different cell model systems using a highly toxic β-oligomer-forming polypeptide (β23) as target toxicant. Multiple PVLs, and particularly the monohydroxylated 5-(4'-hydroxyphenyl)-γ-valerolactone metabolite [(4'-OH)-PVL], relieved β-oligomer-induced cytotoxicity in yeast and mammalian cells. As revealed by atomic force microscopy (AFM) and other in vitro assays, (4'-OH)-PVL interferes with AβO (but not fibril) assembly and actively remodels preformed AβOs into non-toxic amorphous aggregates. In keeping with the latter mode of action, treatment of AβOs with (4'-OH)-PVL prior to brain injection strongly reduced memory deterioration as well as neuroinflammation in a mouse model of AβO-induced memory impairment.
CONCLUSION
PVLs, which have been validated as biomarkers of the dietary intake of flavan-3-ols, lend themselves as novel AβO-selective, candidate AD-preventing compounds. This article is protected by copyright. All rights reserved.
Alice Passoni, Monica Favagrossa, Laura Colombo, Renzo Bagnati, Marco Gobbi, Luisa Diomede, Giulia Birolini, Eleonora Di Paolo, Marta Valenza, Elena Cattaneo,et al.
American Chemical Society (ACS)
The current pharmacological treatment of Huntington's disease (HD) is palliative, and therapies to restore functions in patients are needed. One of the pathways affected in HD involves brain cholesterol (Chol) synthesis, which is essential for optimal synaptic transmission. Recently it was reported that in a HD mouse model, the delivery of exogenous Chol to the brain with brain-permeable nanoparticles protected animals from cognitive decline and rescued synaptic communication, indicating Chol as a therapeutic candidate. We examined whether nose-to-brain delivery, already used in human therapy, could be an alternative, non-invasive strategy to deliver Chol to the adult brain and, in the future, replenish Chol in the HD brain. We gave wild-type (WT) mice a single intranasal (IN) dose of liposomes loaded with deuterium-labeled cholesterol (Chol-D6, to distinguish and quantify the exogenous cholesterol from the native one) (200 µg Chol-D6/dose). After different intervals, Chol-D6 levels, determined by LC-MS in plasma, striatum, cortex and cerebellum, reached a steady-state concentrations of 0.400 ng/mg between 24 and 72 hours. A subsequent acute study confirmed the kinetic profiles of Chol-D6 in all tissues, indicating correspondence between the dose (two doses of 200 µg Chol-D6/dose) and the calculated brain area concentrations (0.660 ng/mg). Finally, in WT mice given repeated IN doses, the average Chol-D6 level after 24 hours was about 1.5 ng/mg in all brain areas. Our data indicate the effectiveness of IN Chol-loaded liposomes to deliver Chol in different brain regions, opening the way to future investigations in HD mice.