Thiophene-Based Optical Ligands That Selectively Detect Aβ Pathology in Alzheimer's Disease.
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ABSTRACT:
SUBMITTER: Klingstedt T
PROVIDER: S-EPMC8409278 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The accumulation of protein aggregates is associated with many devastating neurodegenerative diseases and the development of molecular ligands able to detect these pathological hallmarks is essential. Here, the synthesis of thiophene based optical ligands, denoted bi-thiophene-vinyl-benzothiazoles (bTVBTs) that can be utilized for selective assignment of tau aggregates in brain tissue with Alzheimer's disease (AD) pathology is reported. The ability of the ligands to selectively distinguish tau deposits from the other AD associated pathological hallmark, senile plaques consisting of aggregated amyloid-? (A?) peptide, was reduced when the chemical composition of the ligands was altered, verifying that specific molecular interactions between the ligands and the aggregates are necessary for the selective detection of tau deposits. Our findings provide the structural and functional basis for the development of new fluorescent ligands that can distinguish between aggregated proteinaceous species consisting of different proteins. In addition, the bTVBT scaffold might be utilized to create powerful practical research tools for studying the underlying molecular events of tau aggregation and for creating novel agents for clinical imaging of tau pathology in AD.
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Project description:Aggregated species of amyloid-β (Aβ) are one of the pathological hallmarks in Alzheimer's disease (AD), and ligands that selectively target different Aβ deposits are of great interest. In this study, fluorescent thiophene-based ligands have been used to illustrate the features of different types of Aβ deposits found in AD brain tissue. A dual-staining protocol based on two ligands, HS-276 and LL-1, with different photophysical and binding properties, was developed and applied on brain tissue sections from patients affected by sporadic AD or familial AD associated with the PSEN1 A431E mutation. When binding to Aβ deposits, the ligands could easily be distinguished for their different fluorescence, and distinct staining patterns were revealed for these two types of AD. In sporadic AD, HS-276 consistently labeled all immunopositive Aβ plaques, whereas LL-1 mainly stained cored and neuritic Aβ deposits. In the PSEN1 A431E cases, each ligand was binding to specific types of Aβ plaques. The ligand-labeled Aβ deposits were localized in distinct cortical layers, and a laminar staining pattern could be seen. Biochemical characterization of the Aβ aggregates in the individual layers also showed that the variation of ligand binding properties was associated with certain Aβ peptide signatures. For the PSEN1 A431E cases, it was concluded that LL-1 was binding to cotton wool plaques, whereas HS-276 mainly stained diffuse Aβ deposits. Overall, our findings showed that a combination of ligands was essential to identify distinct aggregated Aβ species associated with different forms of AD.
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Project description:Protein deposits composed of specific proteins or peptides are associated with several neurodegenerative diseases and fluorescent ligands able to detect these pathological hallmarks are vital. Here, we report the synthesis of a class of thiophene-based ligands, denoted proteophenes, with different amino acid side-chain functionalities along the conjugated backbone, which display selectivity towards specific disease-associated protein aggregates in tissue sections with Alzheimer's disease (AD) pathology. The selectivity of the ligands towards AD associated pathological hallmarks, such as aggregates of the amyloid-β (Aβ) peptide or tau filamentous inclusions, was highly dependent on the chemical nature of the amino acid functionality, as well as on the location of the functionality along the pentameric thiophene backbone. Finally, the concept of synthesizing donor-acceptor-donor proteophenes with distinct photophysical properties was shown. Our findings provide the structural and functional basis for the development of new thiophene-based ligands that can be utilized for optical assignment of different aggregated proteinaceous species in tissue sections.
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Project description:Alzheimer's disease (AD) is characterised by amyloid-beta (Aβ) protein deposition in the brain. Posttranslational modifications in Aβ play an important role in Aβ deposition. Tissue transglutaminase (tTG) is an enzyme involved in posttranslational cross-linking of proteins. tTG levels and activity are increased in AD brains, and tTG is associated with Aβ deposits and lesion-associated astrocytes in AD cases. Furthermore, Aβ is a substrate of tTG-catalysed cross-linking. To study the role of tTG in Aβ pathology, we compared tTG distribution and activity in both the APPSWE/PS1ΔE9 and APP23 mice models with human AD. Using immunohistochemistry, we found association of both tTG and in situ active tTG with Aβ plaques and vascular Aβ, in early and late stages of Aβ deposition. In addition, tTG staining colocalised with Aβ-associated reactive astrocytes. Thus, alike human AD cases, tTG was associated with Aβ depositions in these AD models. Although, distribution pattern and spatial overlay of both tTG and its activity with Aβ pathology was substantially different from human AD cases, our findings provide evidence for an early role of tTG in Aβ pathology. Yet, species differences should be taken into account when using these models to study the role of tTG in Aβ pathology.
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Project description:Recent advances have highlighted the importance of several innate immune receptors expressed by microglia in Alzheimer's disease (AD). In particular, mounting evidence from AD patients and experimental models indicates pivotal roles for TREM2, CD33, and CD22 in neurodegenerative disease progression. While there is growing interest in targeting these microglial receptors to treat AD, we still lack knowledge of the downstream signaling molecules used by these receptors to orchestrate immune responses in AD. Notably, TREM2, CD33, and CD22 have been described to influence signaling associated with the intracellular adaptor molecule CARD9 to mount downstream immune responses outside of the brain. However, the role of CARD9 in AD remains poorly understood. Here, we show that genetic ablation of CARD9 in the 5xFAD mouse model of AD results in exacerbated amyloid beta (Aβ) deposition, increased neuronal loss, worsened cognitive deficits, and alterations in microglial responses. We further show that pharmacological activation of CARD9 promotes improved clearance of Aβ deposits from the brains of 5xFAD mice. These results help to establish CARD9 as a key intracellular innate immune signaling molecule that regulates Aβ-mediated disease and microglial responses. Moreover, these findings suggest that targeting CARD9 might offer a strategy to improve Aβ clearance in AD.
| S-EPMC10268238 | biostudies-literature
Project description:Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by the accumulation of amyloid-beta (Ab) plaques and neurofibrillary tangles, neuroinflammation, and glial activation. Asrij/OCIAD1 (Ovarian Carcinoma Immunoreactive Antigen Domain containing protein 1) is an AD-associated factor. Increased Asrij levels in the brains of AD patients and mouse models are linked to the severity of neurodegeneration. However, the contribution of Asrij to AD progression and whether reducing Asrij levels is sufficient to mitigate Ab pathology in vivo is unclear. To explore the impact of Asrij on AD pathology, we deleted asrij in the APP/PS1 mouse model of AD and analyzed the effects on AD hallmarks. We find that Asrij depletion ameliorates cognitive impairments, Ab deposition, neuronal and synaptic damage, and reactive astrogliosis in the AD mouse. Emerging evidence indicates a critical role of microglia in influencing AD pathology. Notably, Asrij-deficient microglia exhibit reduced plaque-associated proliferation and decreased phagocytic activity. Transcriptomic analyses of AD microglia reveal upregulation of energy metabolism pathways and downregulation of innate immunity and inflammatory pathways upon Asrij depletion. Mechanistically, loss of Asrij increases mitochondrial activity and Akt/mTOR signaling and impedes the pro-inflammatory Disease-Associated Microglia (DAM) state. Reduced levels of pro-inflammatory cytokines and decreased STAT3 and NF-kB activation indicate protective changes in AD microglia. Taken together, our results suggest that increased Asrij levels reported in AD, may suppress microglial metabolic activity and promote inflammatory microglial activation, thereby exacerbating AD pathology. Our study establishes a novel role for Asrij in regulating microglial responses to Ab pathology, and could be a potential target for therapeutic intervention.
2024-07-20 | GSE272625 | GEO
Project description:The greatest risk factor for Alzheimer's disease (AD) is age, and changes in the ageing nervous system are likely contributors to AD pathology. Amyloid beta (Aβ) accumulation, which occurs as a result of the amyloidogenic processing of amyloid precursor protein (APP), is thought to initiate the pathogenesis of AD, eventually leading to neuronal cell death. Previously, we developed an adult-onset Drosophila model of AD. Mutant Aβ42 accumulation led to increased mortality and neuronal dysfunction in the adult flies. Furthermore, we showed that lithium reduced Aβ42 protein, but not mRNA, and was able to rescue Aβ42-induced toxicity. In the current study, we investigated the mechanism/s by which lithium modulates Aβ42 protein levels and Aβ42 induced toxicity in the fly model. We found that lithium caused a reduction in protein synthesis in Drosophila and hence the level of Aβ42. At both the low and high doses tested, lithium rescued the locomotory defects induced by Aβ42, but it rescued lifespan only at lower doses, suggesting that long-term, high-dose lithium treatment may have induced toxicity. Lithium also down-regulated translation in the fission yeast Schizosaccharomyces pombe associated with increased chronological lifespan. Our data highlight a role for lithium and reduced protein synthesis as potential therapeutic targets for AD pathogenesis.
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Project description:Familial Alzheimer's disease (FAD) is caused by autosomal dominant mutations in the PSEN1, PSEN2 or APP genes, giving rise to considerable clinical and pathological heterogeneity in FAD. Here we investigate variability in clinical data and the type and distribution of Aβ pathologies throughout the cortical layers of different FAD mutation cases. Brain tissue from 20 FAD cases [PSEN1 pre-codon 200 (n = 10), PSEN1 post-codon 200 (n = 6), APP (n = 4)] were investigated. Frontal cortex sections were stained immunohistochemically for Aβ, and Nissl to define the cortical layers. The frequency of different amyloid-beta plaque types was graded for each cortical layer and the severity of cerebral amyloid angiopathy (CAA) was determined in cortical and leptomeningeal blood vessels. Comparisons were made between FAD mutations and APOE4 status, with associations between pathology, clinical and genetic data investigated. In this cohort, possession of an APOE4 allele was associated with increased disease duration but not with age at onset, after adjusting for mutation sub-group and sex. We found Aβ pathology to be heterogeneous between cases although Aβ load was highest in cortical layer 3 for all mutation groups and a higher Aβ load was associated with APOE4. The PSEN1 post-codon 200 group had a higher Aβ load in lower cortical layers, with a small number of this group having increased cotton wool plaque pathology in lower layers. Cotton wool plaque frequency was positively associated with the severity of CAA in the whole cohort and in the PSEN1 post-codon 200 group. Carriers of the same PSEN1 mutation can have differing patterns of Aβ deposition, potentially because of differences in risk factors. Our results highlight possible influences of APOE4 genotype, and PSEN1 mutation type on Aβ deposition, which may have effects on the clinical heterogeneity of FAD.
| S-EPMC9048809 | biostudies-literature
Project description:BackgroundAmyloid β (Aβ)-directed immunotherapy has shown promising results in preclinical and early clinical Alzheimer's disease (AD) trials, but successful translation to late clinics has failed so far. Compelling evidence suggests that post-translationally modified Aβ peptides might play a decisive role in onset and progression of AD and first clinical trials targeting such Aβ variants have been initiated. Modified Aβ represents a small fraction of deposited material in plaques compared to pan-Aβ epitopes, opening up pathways for tailored approaches of immunotherapy. Here, we generated the first monoclonal antibodies that recognize L-isoaspartate-modified Aβ (isoD7-Aβ) and tested a lead antibody molecule in 5xFAD mice.MethodsThis work comprises a combination of chemical and biochemical techniques as well as behavioral analyses. Aβ peptides, containing L-isoaspartate at position 7, were chemically synthesized and used for immunization of mice and antibody screening methods. Biochemical methods included anti-isoD7-Aβ monoclonal antibody characterization by surface plasmon resonance, immunohistochemical staining of human and transgenic mouse brain, and the development and application of isoD7-Aβ ELISA as well as different non-modified Aβ ELISA. For antibody treatment studies, 12 mg/kg anti-isoD7-Aβ antibody K11_IgG2a was applied intraperitoneally to 5xFAD mice for 38 weeks. Treatment controls implemented were IgG2a isotype as negative and 3D6_IgG2a, the parent molecule of bapineuzumab, as positive control antibodies. Behavioral studies included elevated plus maze, pole test, and Morris water maze.ResultsOur advanced antibody K11 showed a KD in the low nM range and > 400fold selectivity for isoD7-Aβ compared to other Aβ variants. By using this antibody, we demonstrated that formation of isoD7-Aβ may occur after formation of aggregates; hence, the presence of the isoD7-modification differentiates aged Aβ from newly formed peptides. Importantly, we also show that the Tottori mutation responsible for early-onset AD in a Japanese pedigree is characterized by massively accelerated formation of isoD7-Aβ in cell culture. The presence of isoD7-Aβ was verified by K11 in post mortem human cortex and 5xFAD mouse brain tissue. Passive immunization of 5xFAD mice resulted in a significant reduction of isoD7-Aβ and total Aβ in brain. Amelioration of cognitive impairment was demonstrated by Morris water maze, elevated plus maze, pole, and contextual fear conditioning tests. Interestingly, despite the lower abundance of the isoD7-Aβ epitope, the application of anti-isoD7-Aβ antibodies showed comparable treatment efficacy in terms of reduction of brain amyloid and spatial learning but did not result in an increase of plasma Aβ concentration as observed with 3D6 treatment.ConclusionsThe present study demonstrates, for the first time, that the antibody-mediated targeting of isoD7-modified Aβ peptides leads to attenuation of AD-like amyloid pathology. In conjunction with previously published data on antibodies directed against pGlu-modified Aβ, the results highlight the crucial role of modified Aβ peptides in AD pathophysiology. Hence, the results also underscore the therapeutic potential of targeting modified amyloid species for defining tailored approaches in AD therapy.
| S-EPMC7666770 | biostudies-literature