Astroglial tracer BU99008 detects multiple binding sites in Alzheimer's disease brain.
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ABSTRACT:
SUBMITTER: Kumar A
PROVIDER: S-EPMC8758481 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Tauopathies are a subclass of neurodegenerative diseases characterized by an accumulation of microtubule binding tau fibrils in brain regions. Diseases such as Alzheimer's (AD), chronic traumatic encephalopathy (CTE), Pick's disease (PiD), and corticobasal degeneration (CBD) belong to this subclass. Development of tracers which can visualize and discriminate between different tauopathies is of clinical importance in the diagnosis of various tauopathies. Currently, several tau tracers are available for in vivo imaging using a positron emission tomography (PET) technique. Among these tracers, PBB3 is reported to bind to various types of tau fibrils with comparable binding affinities. In contrast, tau tracer AV-1451 is reported to bind to specific types of tau fibrils (in particular to AD-associated and CTE) with higher binding affinity and only show nonspecific or weaker binding toward tau fibrils dominant with 3R isoforms (associated with PiD). The tau fibrils associated with different tauopathies can adopt different microstructures with different binding site microenvironments. By using detailed studies of the binding profiles of tau tracers for different types of tau fibrils, it may be possible to design tracers with high selectivity toward a specific tauopathy. The microstructures for the tau fibrils from patients with AD, PiD, and CTE have recently been demonstrated by cryogenic electron microscopy (cryo-EM) measurements allowing structure-based in silico simulations. In the present study, we have performed a multiscale computational study involving molecular docking, molecular dynamics, free energy calculations, and QM fragmentation calculations to understand the binding profiles of tau tracer AV-1451 and its potential use for diagnosis of AD, CTE, and PiD tauopathies. Our computational study reveals that different affinity binding sites exist for AV-1451 in the tau fibrils associated with different tauopathies. The binding affinity of this tracer toward different tau fibrils goes in this order: PiD > AD > CTE. The interaction energies for different tau fibril-tracer complexes using the QM fragmentation scheme also showed the same trend. However, by carrying out molecular dynamics simulations for the AD-derived tau fibrils in organic solvents, we found additional high affinity binding sites for AV-1451. The AV-1451 binding profile in these cryptic sites correctly explains the preferential binding of this tracer toward the AD fibrils when compared with the PiD fibrils. This study clearly demonstrates having a cryo-EM structure is still not sufficient for the structure-based tracer discovery for certain targets, as they may have "potential but hidden" high affinity binding sites, and we need additional strategies to identify them.
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Project description:Alzheimer's disease (AD) is currently incurable, but there is general agreement that a minimally invasive blood biomarker for screening in preclinical stages would be crucial for future therapy. Diagnostic tools for detection of AD are either invasive like cerebrospinal fluid (CSF) biomarkers or expensive such as positron emission tomography (PET) scanning. Here, we determine the secondary structure change of amyloid-β (Aβ) in human blood. This change used as blood amyloid biomarker indicates prodromal AD and correlates with CSF AD biomarkers and amyloid PET imaging in the cross-sectional BioFINDER cohort. In a further population-based longitudinal cohort (ESTHER), the blood biomarker detected AD several years before clinical diagnosis in baseline samples with a positive likelihood ratio of 7.9; that is, those who were diagnosed with AD over the years were 7.9 times more likely to test positive. This assay may open avenues for blood screening of early AD stages as a funnel for further more invasive and expensive tests.
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Project description:PurposeMK6240 is a second-generation tau PET tracer designed to detect the neurofibrillary tangles in the brains of patients with Alzheimer's disease (AD). The aim of the study was to characterize 3H-MK6240 in AD and control brain tissue and to compare its binding properties with those of first-generation tau PET tracers.MethodsSaturation binding assays with 3H-MK6240 were carried out in the temporal and parietal cortices of AD brains to determine the maximum number of binding sites (Bmax) and the dissociation constants (Kd) at these sites. Competitive binding assays were carried out between 3H-MK6240 and unlabelled MK6240, AV-1451 (aka T807, flortaucipir) and THK5117, and between 3H-THK5351 and unlabelled MK6240. Regional binding studies with 3H-MK6240 were carried out in homogenates from six AD and seven control brains and, using autoradiography, on large frozen sections from two AD brains and one control brain.ResultsThe saturation binding assays gave Bmax and Kd values of 59.2 fmol/mg and 0.32 nM in the temporal cortex and 154.7 fmol/mg and 0.15 nM in the parietal cortex. The competitive binding assays revealed two binding sites with affinities in the picomolar and nanomolar range shared by 3H-MK6240 and all the tested unlabelled compounds. There were no binding sites in common between 3H-THK5351 and unlabelled MK6240. Regional binding of 3H-MK6240 was significantly higher in AD brain tissue than in controls. Binding in brain tissue from AD patients with early-onset AD was significantly higher than in brain tissue from patients with late-onset AD. Binding of 3H-MK6240 was not observed in off-target regions. Autoradiography showed high regional cortical binding in the two AD brains and very low binding in the control brain.Conclusions3H-MK6240 has a high binding affinity for tau deposits in AD brain tissue but also has different binding characteristics from those of the first-generation tau tracers. This confirms the complexity of tau tracer binding on tau deposits with different binding affinities for different binding sites.
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Project description:Alzheimer's disease (AD) is the most common neurodegenerative disease associated with progressive loss of cognitive function, personality, and behavior. The present study evaluates neuronal and astroglial metabolic activity, and neurotransmitter cycle fluxes in AβPP-PS1 mouse model of AD by using 1H-[13C]-nuclear magnetic resonance (NMR) spectroscopy together with an infusion of either [1,6-13C2]glucose or [2-13C]acetate. The levels of N-acetyl-aspartate (NAA) and glutamate were found to be decreased in the cerebral cortex and hippocampus in AβPP-PS1 mice, when compared with wild type controls. The cerebral metabolic rate of acetate oxidation was increased in the hippocampus and cerebral cortex of AβPP-PS1 mice suggesting enhanced astroglial activity in AD. AβPP-PS1 mice exhibit severe reduction in glutamatergic and gamma-amino butyric acid (GABA)ergic neuronal metabolic activity and neurotransmitter cycling fluxes in the hippocampus, cerebral cortex, and striatum as compared with controls. These data suggest that metabolic activity of excitatory and inhibitory neurons is compromised across brain in AβPP-PS1 mouse model of AD.
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Project description:Alzheimer's disease (AD) is the most prevalent neurodegenerative disease in the elderly. Progressive accumulation of insoluble isoforms of amyloid-β peptide (Aβ) and tau protein are the major neuropathologic hallmarks, and the loss of cholinergic pathways underlies cognitive deficits in patients. Recently, glial involvement has gained interest regarding its effect on preservation and impairment of brain integrity. The limbic system, including temporal lobe regions and the olfactory bulb, is particularly affected in the early stages. In the early 1980s, the reduced expression of the somatostatin neuropeptide was described in AD. However, over the last three decades, research on somatostatin in Alzheimer's disease has been scarce in humans. Therefore, the aim of this study was to stereologically quantify the expression of somatostatin in the human hippocampus and olfactory bulb and analyze its spatial distribution with respect to that of Aβ and au neuropathologic proteins and astroglia. The results indicate that somatostatin-expressing cells are reduced by 50% in the hippocampus but are preserved in the olfactory bulb. Interestingly, the coexpression of somatostatin with the Aβ peptide is very common but not with the tau protein. Finally, the coexpression of somatostatin with astrocytes is rare, although their spatial distribution is very similar. Altogether, we can conclude that somatostatin expression is highly reduced in the human hippocampus, but not the olfactory bulb, and may play a role in Alzheimer's disease pathogenesis.
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Project description:Alzheimer's disease (AD) is a neurodegenerative disorder with clinical manifestations of progressive memory decline and loss of executive function and language. AD affects an estimated 5.3 million Americans alone and is the most common form of age-related dementia with a rapidly growing prevalence among the aging population-those 65?years of age or older. AD is characterized by accumulation of aggregated amyloid-beta (A?) in the brain, which leads to one of the pathological hallmarks of AD-A? plaques. As a result, A? plaques have been extensively studied after being first described over a century ago. Advances in brain imaging and quantitative measures of A? in biological fluids have yielded insight into the time course of plaque development decades before and after AD symptom onset. However, despite the fundamental role of A? plaques in AD, in vivo measures of individual plaque growth, growth distribution, and dynamics are still lacking. To address this question, we combined stable isotope labeling kinetics (SILK) and nanoscale secondary ion mass spectrometry (NanoSIMS) imaging in an approach termed SILK-SIMS to resolve plaque dynamics in three human AD brains. In human AD brain, plaques exhibit incorporation of a stable isotope tracer. Tracer enrichment was highly variable between plaques and the spatial distribution asymmetric with both quiescent and active nanometer sub-regions of tracer incorporation. These data reveal that A? plaques are dynamic structures with deposition rates over days indicating a highly active process. Here, we report the first, direct quantitative measures of in vivo deposition into plaques in human AD brain. Our SILK-SIMS studies will provide invaluable information on plaque dynamics in the normal and diseased brain and offer many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development.
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Project description:Alzheimer’s Disease (AD) is characterized by the deposition of protein aggregates such as neurofibrillary tangles (NFTs) and amyloid (Aβ) plaques in the brain. Post-translational modification through ubiquitylationplays critical roles in clearing misfolded protein aggregates. Investigating global ubiquitylation changes inAD brain may provide insights regarding the underlying mechanisms of proteostasis and disease pathogenesis.Here, we utilizedan immunoaffinity approach to specifically enrichubiquitinated(di-glycine) peptides frompostmortemhuman control and AD braintissues.Mass spectrometry(MS)based proteomicanalysis identified global ubiquitylation changes associated with ADand hierarchical clustering of the human brain ubiquitylome clearly classified AD cases from healthy controls based on ubiquitylation patterns. Polyubiquitin linkage analysis identified increased levels of all seven polyubiquitin linkage typesas well as total ubiquitin in the AD brain tissues.We also report novel ubiquitylation sites in the microtubulebinding repeatof Tauwith potential implicationsfor Tauaggregation. Dually modified peptides with both phosphorylation and ubiquitylationsites, many of which originated from Tauprotein are also differentially enriched in AD.Furthermore, all the KXGS motifswithin themicrotubule binding region (MTBR)of Tauprotein,which represents the core ofNFTs,are enriched among dually modified peptides. Collectively, these studieshighlight the utility of an immunoaffinity enrichment approach coupled with MSanalysis for mapping AD associated global ubiquitylome changesas well as to gain insights intounderlying proteostasis pathwaysaltered in AD brain.
2019-06-25 | PXD009199 | Pride
Project description:Harmine, a ?-carboline alkaloid, is a high affinity inhibitor of the dual specificity tyrosine phosphorylation regulated kinase 1A (DYRK1A) protein. The DYRK1A gene is located within the Down Syndrome Critical Region (DSCR) on chromosome 21. We and others have implicated DYRK1A in the phosphorylation of tau protein on multiple sites associated with tau pathology in Down Syndrome and in Alzheimer's disease (AD). Pharmacological inhibition of this kinase may provide an opportunity to intervene therapeutically to alter the onset or progression of tau pathology in AD. Here we test the ability of harmine, and numerous additional ?-carboline compounds, to inhibit the DYRK1A dependent phosphorylation of tau protein on serine 396, serine 262/serine 356 (12E8 epitope), and threonine 231 in cell culture assays and in vitro phosphorylation assays. Results demonstrate that the ?-carboline compounds (1) potently reduce the expression of all three phosphorylated forms of tau protein, and (2) inhibit the DYRK1A catalyzed direct phosphorylation of tau protein on serine 396. By assaying several ?-carboline compounds, we define certain chemical groups that modulate the affinity of this class of compounds for inhibition of tau phosphorylation.
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