65 results found
Bigi A, Napolitano L, Vadukul DM, et al., 2024, A single-domain antibody detects and neutralises toxic Aβ42 oligomers in the Alzheimer's disease CSF, Alzheimer's Research and Therapy, Vol: 16, ISSN: 1758-9193
BACKGROUND: Amyloid-β42 (Aβ42) aggregation consists of a complex chain of nucleation events producing soluble oligomeric intermediates, which are considered the major neurotoxic agents in Alzheimer's disease (AD). Cerebral lesions in the brain of AD patients start to develop 20 years before symptom onset; however, no preventive strategies, effective treatments, or specific and sensitive diagnostic tests to identify people with early-stage AD are currently available. In addition, the isolation and characterisation of neurotoxic Aβ42 oligomers are particularly difficult because of their transient and heterogeneous nature. To overcome this challenge, a rationally designed method generated a single-domain antibody (sdAb), named DesAb-O, targeting Aβ42 oligomers. METHODS: We investigated the ability of DesAb-O to selectively detect preformed Aβ42 oligomers both in vitro and in cultured neuronal cells, by using dot-blot, ELISA immunoassay and super-resolution STED microscopy, and to counteract the toxicity induced by the oligomers, monitoring their interaction with neuronal membrane and the resulting mitochondrial impairment. We then applied this approach to CSF samples (CSFs) from AD patients as compared to age-matched control subjects. RESULTS: DesAb-O was found to selectively detect synthetic Aβ42 oligomers both in vitro and in cultured cells, and to neutralise their associated neuronal dysfunction. DesAb-O can also identify Aβ42 oligomers present in the CSFs of AD patients with respect to healthy individuals, and completely prevent cell dysfunction induced by the administration of CSFs to neuronal cells. CONCLUSIONS: Taken together, our data indicate a promising method for the improvement of an early diagnosis of AD and for the generation of novel therapeutic approaches based on sdAbs for the treatment of AD and other devastating neurodegenerative conditions.
Raguseo F, Wang Y, Li J, et al., 2023, The ALS/FTD-related C9orf72 hexanucleotide repeat expansion forms RNA condensates through multimolecular G-quadruplexes, Nature Communications, Vol: 14, ISSN: 2041-1723
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative diseases that exist on a clinico-pathogenetic spectrum, designated ALS/FTD. The most common genetic cause of ALS/FTD is expansion of the intronic hexanucleotide repeat (GGGGCC)n in C9orf72. Here, we investigate the formation of nucleic acid secondary structures in these expansion repeats, and their role in generating condensates characteristic of ALS/FTD. We observe significant aggregation of the hexanucleotide sequence (GGGGCC)n, which we associate to the formation of multimolecular G-quadruplexes (mG4s) by using a range of biophysical techniques. Exposing the condensates to G4-unfolding conditions leads to prompt disassembly, highlighting the key role of mG4-formation in the condensation process. We further validate the biological relevance of our findings by detecting an increased prevalence of G4-structures in C9orf72 mutant human motor neurons when compared to healthy motor neurons by staining with a G4-selective fluorescent probe, revealing signal in putative condensates. Our findings strongly suggest that RNA G-rich repetitive sequences can form protein-free condensates sustained by multimolecular G-quadruplexes, highlighting their potential relevance as therapeutic targets for C9orf72 mutation-related ALS/FTD.
Yue TTC, Ge Y, Aprile FA, et al., 2023, Site-Specific <SUP>68</SUP>Ga Radiolabeling of Trastuzumab Fab via Methionine for ImmunoPET Imaging, BIOCONJUGATE CHEMISTRY, ISSN: 1043-1802
Tortora P, Aprile FA, 2023, Natural Inhibitors of Amyloid Aggregation, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 24, ISSN: 1661-6596
Vadukul D, Papp M, Thrush R, et al., 2023, Α-synuclein aggregation is triggered by oligomeric amyloid-β 42 via heterogeneous primary nucleation, Journal of the American Chemical Society, Vol: 145, Pages: 18276-18285, ISSN: 0002-7863
An increasing number of cases where amyloids of different proteins are found in the same patient are beingreported. This observation complicates diagnosis and clinical intervention. Amyloids of the amyloid-β peptide or the proteinα-synuclein are traditionally considered hallmarks of Alzheimer’s and Parkinson’s diseases, respectively. However, the cooccurrence of amyloids of these proteins has also been reported in patients diagnosed with either disease. Here, we show thatsoluble species containing amyloid-β can induce the aggregation of α-synuclein. Fibrils formed under these conditions aresolely composed of α-synuclein to which amyloid-β can be found associated, but not as part of the core of the fibrils. Importantly, by global kinetic analysis, we found that the aggregation of α-synuclein under these conditions occurs via heterogeneous primary nucleation, triggered by soluble aggregates containing amyloid-β.
Shmool TA, Martin LK, Jirkas A, et al., 2023, Unveiling the Rational Development of Stimuli-Responsive Silk Fibroin-Based Ionogel Formulations, CHEMISTRY OF MATERIALS, Vol: 35, Pages: 5798-5808, ISSN: 0897-4756
Thrush R, Vadukul D, Allerton S, et al., 2023, Different regions of a-Synuclein N-terminus regulate the interaction with amyloid fibrils or biomolecular condensates., Publisher: SPRINGER, Pages: S109-S109, ISSN: 0175-7571
Ge Y, Yang J, Aprile F, 2023, Probing Post-translational Modifications of Amyloidogenic Proteins, Publisher: SPRINGER, Pages: S182-S182, ISSN: 0175-7571
Aprile FA, Ge Y, Vadukul DM, et al., 2023, Integrative Antibody Discovery to Target Challenging Protein Assemblies, Publisher: SPRINGER, Pages: S37-S37, ISSN: 0175-7571
García-Revilla J, Boza-Serrano A, Jin Y, et al., 2023, Galectin-3 shapes toxic alpha-synuclein strains in Parkinson's disease, Acta Neuropathologica, Vol: 146, Pages: 51-75, ISSN: 0001-6322
Parkinson's Disease (PD) is a neurodegenerative and progressive disorder characterised by intracytoplasmic inclusions called Lewy bodies (LB) and degeneration of dopaminergic neurons in the substantia nigra (SN). Aggregated α-synuclein (αSYN) is known to be the main component of the LB. It has also been reported to interact with several proteins and organelles. Galectin-3 (GAL3) is known to have a detrimental function in neurodegenerative diseases. It is a galactose-binding protein without known catalytic activity and is expressed mainly by activated microglial cells in the central nervous system (CNS). GAL3 has been previously found in the outer layer of the LB in post-mortem brains. However, the role of GAL3 in PD is yet to be elucidated. In post-mortem samples, we identified an association between GAL3 and LB in all the PD subjects studied. GAL3 was linked to less αSYN in the LB outer layer and other αSYN deposits, including pale bodies. GAL3 was also associated with disrupted lysosomes. In vitro studies demonstrate that exogenous recombinant Gal3 is internalised by neuronal cell lines and primary neurons where it interacts with endogenous αSyn fibrils. In addition, aggregation experiments show that Gal3 affects spatial propagation and the stability of pre-formed αSyn fibrils resulting in short, amorphous toxic strains. To further investigate these observations in vivo, we take advantage of WT and Gal3KO mice subjected to intranigral injection of adenovirus overexpressing human αSyn as a PD model. In line with our in vitro studies, under these conditions, genetic deletion of GAL3 leads to increased intracellular αSyn accumulation within dopaminergic neurons and remarkably preserved dopaminergic integrity and motor function. Overall, our data suggest a prominent role for GAL3 in the aggregation process of αSYN and LB formation, leading to the production of short species to the detriment of larger strains which
Kulenkampff K, Emin D, Staats R, et al., 2022, An antibody scanning method for the detection of α-synuclein oligomers in the serum of Parkinson's disease patients, Chemical Science, Vol: 13, Pages: 13815-13828, ISSN: 2041-6520
Misfolded α-synuclein oligomers are closely implicated in the pathology of Parkinson's disease and related synucleinopathies. The elusive nature of these aberrant assemblies makes it challenging to develop quantitative methods to detect them and modify their behavior. Existing detection methods use antibodies to bind α-synuclein aggregates in biofluids, although it remains challenging to raise antibodies against α-synuclein oligomers. To address this problem, we used an antibody scanning approach in which we designed a panel of 9 single-domain epitope-specific antibodies against α-synuclein. We screened these antibodies for their ability to inhibit the aggregation process of α-synuclein, finding that they affected the generation of α-synuclein oligomers to different extents. We then used these antibodies to investigate the size distribution and morphology of soluble α-synuclein aggregates in serum and cerebrospinal fluid samples from Parkinson's disease patients. Our results indicate that the approach that we present offers a promising route for the development of antibodies to characterize soluble α-synuclein aggregates in biofluids.
Ge Y, Masoura A, Yang J, et al., 2022, A chemical mutagenesis approach to insert post-translational modifications in aggregation-prone proteins, ACS Chemical Neuroscience, Vol: 13, Pages: 1714-1718, ISSN: 1948-7193
Neurodegenerative diseases are a class of disorders linked to the formation in the nervous system of fibrillar protein aggregates called amyloids. This aggregation process is affected by a variety of post-translational modifications, whose specific mechanisms are not fully understood yet. Emerging chemical mutagenesis technology is currently striving to address the challenge of introducing protein post-translational modifications, while maintaining the stability and solubility of the proteins during the modification reaction. Several amyloidogenic proteins are highly aggregation-prone, and current modification procedures can lead to unexpected precipitation of these proteins, affecting their yield and downstream characterization. Here, we present a method for maintaining amyloidogenic protein solubility during chemical mutagenesis. As proof-of-principle, we applied our method to mimic the phosphorylation of serine-26 and the acetylation of lysine-28 of the 40-residue long variant of amyloid-β peptide, whose aggregation is linked to Alzheimer’s disease.
Thrush RJ, Vadukul D, Aprile F, 2022, A facile method to produce N-terminally truncated α-synuclein, Frontiers in Neuroscience, Vol: 16, Pages: 1-9, ISSN: 1662-453X
α-Synuclein is a key protein of the nervous system, which regulates the release and recycling of neurotransmitters in the synapses. It is also involved in several neurodegenerative conditions, including Parkinson’s disease and Multiple System Atrophy, where it forms toxic aggregates. The N-terminus of α-synuclein is of particular interest as it has been linked to both the physiological and pathological functions of the protein and undergoes post-translational modification. One such modification, N-terminal truncation, affects the aggregation propensity of the protein in vitro and is also found in aggregates from patients’ brains. To date, our understanding of the role of this modification has been limited by the many challenges of introducing biologically relevant N-terminal truncations with no overhanging starting methionine. Here, we present a method to produce N-terminally truncated variants of α-synuclein that do not carry extra terminal residues. We show that our method can generate highly pure protein to facilitate the study of this modification and its role in physiology and disease. Thanks to this method, we have determined that the first six residues of α-synuclein play an important role in the formation of the amyloids.
Ge Y, Masoura A, Yang J, et al., 2022, A Chemical Mutagenesis Approach to Insert Post-Translational Modifications in Aggregation-Prone Proteins
<jats:title>ABSTRACT</jats:title><jats:p>Neurodegenerative diseases are a class of disorders linked to the formation in the nervous system of fibrillar protein aggregates called amyloids. This aggregation process is affected by a variety of post-translational modifications, whose specific mechanisms are not fully understood yet. Emerging chemical mutagenesis technology is currently striving to address the challenge of introducing protein post-translational modifications, while maintaining proteins stable and soluble during the modification reaction. Several amyloidogenic proteins are highly aggregation-prone, and current modification procedures lead to unexpected precipitation of these proteins, affecting their yield and downstream characterization. Here, we present a method for maintaining amyloidogenic proteins soluble during chemical mutagenesis. As proof-of-principle, we applied our method to mimic the phosphorylation of the serine 26 and the acetylation of the lysine 28 of the 40-residue long variant of amyloid-β peptide, whose aggregation is linked to Alzheimer’s disease.</jats:p>
Aprile FA, Temussi PA, Pastore A, 2021, Man does not live by intrinsically unstructured proteins alone: The role of structured regions in aggregation., BioEssays, Vol: 43, Pages: 1-9, ISSN: 0265-9247
Protein misfolding is a topic that is of primary interest both in biology and medicine because of its impact on fundamental processes and disease. In this review, we revisit the concept of protein misfolding and discuss how the field has evolved from the study of globular folded proteins to focusing mainly on intrinsically unstructured and often disordered regions. We argue that this shift of paradigm reflects the more recent realisation that misfolding may not only be an adverse event, as originally considered, but also may fulfil a basic biological need to compartmentalise the cell with transient reversible granules. We nevertheless provide examples in which structure is an important component of a much more complex aggregation behaviour that involves both structured and unstructured regions of a protein. We thus suggest that a more comprehensive evaluation of the mechanisms that lead to aggregation might be necessary.
Pras A, Houben B, Aprile FA, et al., 2021, The cellular modifier MOAG-4/SERF drives amyloid formation through charge complementation, The EMBO Journal, Vol: 40, ISSN: 0261-4189
While aggregation-prone proteins are known to accelerate aging and cause age-related diseases, the cellular mechanisms that drive their cytotoxicity remain unresolved. The orthologous proteins MOAG-4, SERF1A, and SERF2 have recently been identified as cellular modifiers of such proteotoxicity. Using a peptide array screening approach on human amyloidogenic proteins, we found that SERF2 interacted with protein segments enriched in negatively charged and hydrophobic, aromatic amino acids. The absence of such segments, or the neutralization of the positive charge in SERF2, prevented these interactions and abolished the amyloid-promoting activity of SERF2. In protein aggregation models in the nematode worm Caenorhabditis elegans, protein aggregation and toxicity were suppressed by mutating the endogenous locus of MOAG-4 to neutralize charge. Our data indicate that MOAG-4 and SERF2 drive protein aggregation and toxicity by interactions with negatively charged segments in aggregation-prone proteins. Such charge interactions might accelerate primary nucleation of amyloid by initiating structural changes and by decreasing colloidal stability. Our study points at charge interactions between cellular modifiers and amyloidogenic proteins as potential targets for interventions to reduce age-related protein toxicity.
Scheidt T, Carozza JA, Kolbe CC, et al., 2021, The binding of the small heat-shock protein alpha B-crystallin to fibrils of alpha-synuclein is driven by entropic forces, Proceedings of the National Academy of Sciences of the United States of America, Vol: 118, Pages: 1-8, ISSN: 0027-8424
Molecular chaperones are key components of the cellular proteostasis network whose role includes the suppression of the formation and proliferation of pathogenic aggregates associated with neurodegenerative diseases. The molecular principles that allow chaperones to recognize misfolded and aggregated proteins remain, however, incompletely understood. To address this challenge, here we probe the thermodynamics and kinetics of the interactions between chaperones and protein aggregates under native solution conditions using a microfluidic platform. We focus on the binding between amyloid fibrils of α-synuclein, associated with Parkinson’s disease, to the small heat-shock protein αB-crystallin, a chaperone widely involved in the cellular stress response. We find that αB-crystallin binds to α-synuclein fibrils with high nanomolar affinity and that the binding is driven by entropy rather than enthalpy. Measurements of the change in heat capacity indicate significant entropic gain originates from the disassembly of the oligomeric chaperones that function as an entropic buffer system. These results shed light on the functional roles of chaperone oligomerization and show that chaperones are stored as inactive complexes which are capable of releasing active subunits to target aberrant misfolded species.
Chan TG, Ruehl CL, Morse SV, et al., 2021, Modulation of amyloid-beta aggregation by metal complexes with a dual binding mode and their delivery across the blood-brain barrier using focused ultrasound, Chemical Science, Vol: 12, Pages: 9485-9493, ISSN: 2041-6520
One of the key hallmarks of Alzheimer's disease is the aggregation of the amyloid-β peptide to form fibrils. Consequently, there has been great interest in studying molecules that can disrupt amyloid-β aggregation. While a handful of molecules have been shown to inhibit amyloid-β aggregation in vitro, there remains a lack of in vivo data reported due to their inability to cross the blood–brain barrier. Here, we investigate a series of new metal complexes for their ability to inhibit amyloid-β aggregation in vitro. We demonstrate that octahedral cobalt complexes with polyaromatic ligands have high inhibitory activity thanks to their dual binding mode involving π–π stacking and metal coordination to amyloid-β (confirmed via a range of spectroscopic and biophysical techniques). In addition to their high activity, these complexes are not cytotoxic to human neuroblastoma cells. Finally, we report for the first time that these metal complexes can be safely delivered across the blood–brain barrier to specific locations in the brains of mice using focused ultrasound.
Jin Y, Vadukul D, Gialama D, et al., 2021, The diagnostic potential of amyloidogenic proteins, International Journal of Molecular Sciences, Vol: 22, ISSN: 1422-0067
Neurodegenerative disorders are a highly prevalent class of diseases, whose pathological mechanisms start before the appearance of any clear symptoms. This fact has prompted scientists to search for biomarkers that could aid early treatment. These currently incurable pathologies share the presence of aberrant aggregates called amyloids in the nervous system, which are composed of specific proteins. In this review, we discuss how these proteins, their conformations and modifications could be exploited as biomarkers for diagnostic purposes. We focus on proteins that are associated with the most prevalent neurodegenerative disorders, including Alzheimer’s and Parkinson’s diseases, amyotrophic lateral sclerosis, and frontotemporal dementia. We also describe current challenges in detection, the most recent techniques with diagnostic potentials and possible future developments in diagnosis.
Perni M, van der Goot A, Limbocker R, et al., 2021, Comparative studies in the A30P and A53T alpha-Synuclein C. elegans strains to investigate the molecular origins of Parkinson's Disease, Frontiers in Cell and Developmental Biology, Vol: 9, Pages: 1-10, ISSN: 2296-634X
The aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a variety of related neurological disorders. A number of mutations in this protein, including A30P and A53T, are associated with familial forms of the disease. Patients carrying the A30P mutation typically exhibit a similar age of onset and symptoms as sporadic PD, while those carrying the A53T mutation generally have an earlier age of onset and an accelerated progression. We report two C. elegans models of PD (PDA30P and PDA53T), which express these mutational variants in the muscle cells, and probed their behavior relative to animals expressing the wild-type protein (PDWT). PDA30P worms showed a reduced speed of movement and an increased paralysis rate, control worms, but no change in the frequency of body bends. By contrast, in PDA53T worms both speed and frequency of body bends were significantly decreased, and paralysis rate was increased. α-Synuclein was also observed to be less well localized into aggregates in PDA30P worms compared to PDA53T and PDWT worms, and amyloid-like features were evident later in the life of the animals, despite comparable levels of expression of α-synuclein. Furthermore, squalamine, a natural product currently in clinical trials for treating symptomatic aspects of PD, was found to reduce significantly the aggregation of α-synuclein and its associated toxicity in PDA53T and PDWT worms, but had less marked effects in PDA30P. In addition, using an antibody that targets the N-terminal region of α-synuclein, we observed a suppression of toxicity in PDA30P, PDA53T and PDWT worms. These results illustrate the use of these two C. elegans models in fundamental and applied PD research.
Ikenoue T, Aprile FA, Sormanni P, et al., 2021, Rationally designed bicyclic peptides prevent the conversion of A beta 42 assemblies into fibrillar structures, Frontiers in Neuroscience, Vol: 15, Pages: 1-9, ISSN: 1662-453X
There is great interest in drug discovery programs targeted at the aggregation of the 42-residue form of the amyloid β peptide (Aβ42), since this molecular process is closely associated with Alzheimer’s disease. The use of bicyclic peptides may offer novel opportunities for the effective modification of Aβ42 aggregation and the inhibition of its cytotoxicity, as these compounds combine the molecular recognition ability of antibodies with a relatively small size of about 2 kD. Here, to pursue this approach, we rationally designed a panel of six bicyclic peptides targeting various epitopes along the sequence of Aβ42 to scan its most amyloidogenic region (residues 13–42). Our kinetic analysis and structural studies revealed that at sub-stoichiometric concentrations the designed bicyclic peptides induce a delay in the condensation of Aβ42 and the subsequent transition to a fibrillar state, while at higher concentrations they inhibit such transition. We thus suggest that designed bicyclic peptides can be employed to inhibit amyloid formation by redirecting the aggregation process toward amorphous assemblies.
Lindstedt PR, Aprile FA, Sormanni P, et al., 2021, Systematic Activity Maturation of a Single-Domain Antibody with Non-canonical Amino Acids through Chemical Mutagenesis, CELL CHEMICAL BIOLOGY, Vol: 28, Pages: 70-+, ISSN: 2451-9448
Heller GT, Aprile FA, Michaels TCT, et al., 2020, Small-molecule sequestration of amyloid-β as a drug discovery strategy for Alzheimer's disease, SCIENCE ADVANCES, Vol: 6, ISSN: 2375-2548
Ikenoue T, Aprile FA, Sormanni P, et al., 2020, A rationally designed bicyclic peptide remodels Aβ42 aggregation in vitro and reduces its toxicity in a worm model of Alzheimer's disease, SCIENTIFIC REPORTS, Vol: 10, ISSN: 2045-2322
Aprile FA, Sormanni P, Podpolny M, et al., 2020, Rational design of a conformation-specific antibody for the quantification of A beta oligomers, Proceedings of the National Academy of Sciences of the United States of America, Vol: 117, Pages: 13509-13518, ISSN: 0027-8424
Protein misfolding and aggregation is the hallmark of numerous human disorders, including Alzheimer’s disease. This process involves the formation of transient and heterogeneous soluble oligomers, some of which are highly cytotoxic. A major challenge for the development of effective diagnostic and therapeutic tools is thus the detection and quantification of these elusive oligomers. Here, to address this problem, we develop a two-step rational design method for the discovery of oligomer-specific antibodies. The first step consists of an “antigen scanning” phase in which an initial panel of antibodies is designed to bind different epitopes covering the entire sequence of a target protein. This procedure enables the determination through in vitro assays of the regions exposed in the oligomers but not in the fibrillar deposits. The second step involves an “epitope mining” phase, in which a second panel of antibodies is designed to specifically target the regions identified during the scanning step. We illustrate this method in the case of the amyloid β (Aβ) peptide, whose oligomers are associated with Alzheimer’s disease. Our results show that this approach enables the accurate detection and quantification of Aβ oligomers in vitro, and in Caenorhabditis elegans and mouse hippocampal tissues.
Limbocker R, Mannini B, Cataldi R, et al., 2020, Rationally Designed Antibodies as Research Tools to Study the Structure-Toxicity Relationship of Amyloid-β Oligomers, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 21
Faravelli G, Raimondi S, Marchese L, et al., 2019, C. elegans expressing D76N β2-microglobulin: a model for in vivo screening of drug candidates targeting amyloidosis., Sci Rep, Vol: 9
The availability of a genetic model organism with which to study key molecular events underlying amyloidogenesis is crucial for elucidating the mechanism of the disease and the exploration of new therapeutic avenues. The natural human variant of β2-microglobulin (D76N β2-m) is associated with a fatal familial form of systemic amyloidosis. Hitherto, no animal model has been available for studying in vivo the pathogenicity of this protein. We have established a transgenic C. elegans line, expressing the human D76N β2-m variant. Using the INVertebrate Automated Phenotyping Platform (INVAPP) and the algorithm Paragon, we were able to detect growth and motility impairment in D76N β2-m expressing worms. We also demonstrated the specificity of the β2-m variant in determining the pathological phenotype by rescuing the wild type phenotype when β2-m expression was inhibited by RNA interference (RNAi). Using this model, we have confirmed the efficacy of doxycycline, an inhibitor of the aggregation of amyloidogenic proteins, in rescuing the phenotype. In future, this C. elegans model, in conjunction with the INVAPP/Paragon system, offers the prospect of high-throughput chemical screening in the search for new drug candidates.
Lindstedt PR, Aprile FA, Matos MJ, et al., 2019, Enhancement of the Anti-Aggregation Activity of a Molecular Chaperone Using a Rationally Designed Post-Translational Modification, ACS CENTRAL SCIENCE, Vol: 5, Pages: 1417-1424, ISSN: 2374-7943
De S, Whiten DR, Ruggeri FS, et al., 2019, Soluble aggregates present in cerebrospinal fluid change in size and mechanism of toxicity during Alzheimer's disease progression, ACTA NEUROPATHOLOGICA COMMUNICATIONS, Vol: 7, ISSN: 2051-5960
De S, Wirthensohn DC, Flagmeier P, et al., 2019, Different soluble aggregates of Aβ42 can give rise to cellular toxicity through different mechanisms, Nature Communications, Vol: 10, Pages: 1541-1541, ISSN: 2041-1723
Protein aggregation is a complex process resulting in the formation of heterogeneous mixtures of aggregate populations that are closely linked to neurodegenerative conditions, such as Alzheimer's disease. Here, we find that soluble aggregates formed at different stages of the aggregation process of amyloid beta (Aβ42) induce the disruption of lipid bilayers and an inflammatory response to different extents. Further, by using gradient ultracentrifugation assay, we show that the smaller aggregates are those most potent at inducing membrane permeability and most effectively inhibited by antibodies binding to the C-terminal region of Aβ42. By contrast, we find that the larger soluble aggregates are those most effective at causing an inflammatory response in microglia cells and more effectively inhibited by antibodies targeting the N-terminal region of Aβ42. These findings suggest that different toxic mechanisms driven by different soluble aggregated species of Aβ42 may contribute to the onset and progression of Alzheimer's disease.
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