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1.
Amyloid-β oligomers are captured by the DNAJB6 chaperone: Direct detection of interactions that can prevent primary nucleation.
Österlund, N, Lundqvist, M, Ilag, LL, Gräslund, A, Emanuelsson, C
The Journal of biological chemistry. 2020;(24):8135-8144
Abstract
A human molecular chaperone protein, DnaJ heat shock protein family (Hsp40) member B6 (DNAJB6), efficiently inhibits amyloid aggregation. This inhibition depends on a unique motif with conserved serine and threonine (S/T) residues that have a high capacity for hydrogen bonding. Global analysis of kinetics data has previously shown that DNAJB6 especially inhibits the primary nucleation pathways. These observations indicated that DNAJB6 achieves this remarkably effective and sub-stoichiometric inhibition by interacting not with the monomeric unfolded conformations of the amyloid-β symbol (Aβ) peptide but with aggregated species. However, these pre-nucleation oligomeric aggregates are transient and difficult to study experimentally. Here, we employed a native MS-based approach to directly detect oligomeric forms of Aβ formed in solution. We found that WT DNAJB6 considerably reduces the signals from the various forms of Aβ (1-40) oligomers, whereas a mutational DNAJB6 variant in which the S/T residues have been substituted with alanines does not. We also detected signals that appeared to represent DNAJB6 dimers and trimers to which varying amounts of Aβ are bound. These data provide direct experimental evidence that it is the oligomeric forms of Aβ that are captured by DNAJB6 in a manner which depends on the S/T residues. We conclude that, in agreement with the previously observed decrease in primary nucleation rate, strong binding of Aβ oligomers to DNAJB6 inhibits the formation of amyloid nuclei.
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2.
Cerebrospinal fluid ceruloplasmin levels predict cognitive decline and brain atrophy in people with underlying β-amyloid pathology.
Diouf, I, Bush, AI, Ayton, S, ,
Neurobiology of disease. 2020;:104810
Abstract
OBJECTIVES The mechanisms leading to neurodegeneration in Alzheimer's disease (AD) may involve oxidative stress and neuroinflammation. Ceruloplasmin (Cp) is a circulating protein that intersects both these pathways, since its expression is increased during the acute phase response, and the protein acts to lower pro-oxidant iron in cells. Since the role of Cp in AD, and its potential for use as a biomarker is not established, we investigated CSF Cp and its association with longitudinal outcome measures related to AD. METHODS This was an observational study of 268 people from the Alzheimer's Disease Neuroimaging (ADNI) cohort. Subjects were classified clinically as having AD, mild cognitive impairment (MCI) or were cognitively normal (CN), and were also classified as being positive for β-amyloid using established thresholds in the CSF t-tau/Aβ42 ratio. Subjects underwent cognitive tests and MRI studies every 6 months for 2 years, then yearly thereafter for up to 6 years. RESULTS At baseline, CSF Cp was not associated with clinical or pathological diagnosis, but we found an unexpected association between CSF Cp and levels of CSF apolipoprotein E. In longitudinal analysis, high level of CSF Cp was associated with accelerated cognitive decline (as assessed by ADAS-Cog, CDR-SB, and MMSE) and ventricular volume enlargement in people classified as MCI and who had underlying β-amyloid pathology. CONCLUSION These results raise new questions into the role of Cp in neuroinflammation, oxidative stress, and APOE pathways involved in AD, and reveal the potential for this protein to be used as a biomarker in disease prognostication.
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3.
Inactivation of GAP-43 due to the depletion of cellular calcium by the Pb and amyloid peptide induced toxicity: An in vitro approach.
Ayyalasomayajula, N, Bandaru, M, Dixit, PK, Ajumeera, R, Chetty, CS, Challa, S
Chemico-biological interactions. 2020;:108927
Abstract
Environmental pollutant, Lead (Pb) is known to induce neurotoxicity in human. The central nervous system is the most vulnerable to the minute levels of Pb induced toxicity. Pb has been linked to Alzheimer's disease (AD) as a probable risk factor, as it shows epigenetic and developmental link associated with Alzheimer's disease-like pathology. Beta amyloid peptides were considered as the crucial factors in the beta amyloid plaque formation in Alzheimer's disease brain. In this context, we investigated the molecular mechanism involved in the development of Pb induced Alzheimer's disease in in vitro. Previous data from our studies have reported that Pb in the presence of beta Amyloid peptide (1-40) and (25-35) induces more apoptosis than individual exposures. Here, to further evaluate the molecular mechanism underlying Pb induced Alzheimer's disease; we focussed on the involvement of calcium signalling in inducing cell death. Our experimental observations suggesting that Pb in the presence of beta amyloid peptide alters intracellular calcium levels, which leads to the increased beta-secretase activity, which further promotes the generation of beta amyloid peptides. It also showed depression in the levels of GAP-43 expression, inhibition of PKC activity and altering synaptic activity further leads to cell death.
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4.
Associations of Green Tea Consumption and Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.
Ma, YH, Wu, JH, Xu, W, Shen, XN, Wang, HF, Hou, XH, Cao, XP, Bi, YL, Dong, Q, Feng, L, et al
Journal of Alzheimer's disease : JAD. 2020;(1):411-421
Abstract
BACKGROUND Green tea has been widely recognized in ameliorating cognitive impairment and Alzheimer's disease (AD), especially the progression of cognitive dysfunction. But the underlying mechanism is still unclear. OBJECTIVE This study was designed to determine the role of green tea consumption in the association with cerebrospinal fluid (CSF) biomarkers of AD pathology and to ascertain whether specific population backgrounds showed the differences toward these relationships. METHODS Multivariate linear models analyzed the available data on CSF biomarkers and frequency of green tea consumption of 722 cognitively intact participants from the Chinese Alzheimer's Biomarker and LifestylE (CABLE) database, and we additionally detected the interaction effects of tea consumption with APOEɛ4 status and gender using a two-way analysis of covariance. RESULTS Frequent green tea consumption was associated with a decreased level of CSF total-tau protein (t-tau) (p = 0.041) but not with the levels of CSF amyloid-β 42 (Aβ42) and CSF phosphorylated tau. The more pronounced associations of green tea consumption with CSF t-tau (p = 0.007) and CSF t-tau/Aβ42 (p = 0.039) were observed in individuals aged 65 years or younger. Additionally, males with frequent green tea consumption had a significantly low level of CSF t-tau/Aβ42 and a modest trend toward decreased CSF t-tau. There were no interaction effects of green tea consumption with APOEɛ4 and gender. CONCLUSION Collectively, our findings consolidated the favorable effects of green tea on the mitigation of AD risk. The constituents of green tea may improve abnormal tau metabolism and are promising targets in interventions and drug therapies.
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5.
Molecular Imaging of Fluorinated Probes for Tau Protein and Amyloid-β Detection.
Yeo, SK, Shepelytskyi, Y, Grynko, V, Albert, MS
Molecules (Basel, Switzerland). 2020;(15)
Abstract
Alzheimer's disease (AD) is the most common form of dementia and results in progressive neurodegeneration. The incidence rate of AD is increasing, creating a major public health issue. AD is characterized by neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau protein and senile plaques composed of amyloid-β (Aβ). Currently, a definitive diagnosis of AD is accomplished post-mortem. Thus, the use of molecular probes that are able to selectively bind to NFTs or Aβ can be valuable tools for the accurate and early diagnosis of AD. The aim of this review is to summarize and highlight fluorinated molecular probes that can be used for molecular imaging to detect either NFTs or Aβ. Specifically, fluorinated molecular probes used in conjunction with 19F MRI, PET, and fluorescence imaging will be explored.
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6.
Inflammation: A Major Target for Compounds to Control Alzheimer's Disease.
Maccioni, RB, Navarrete, LP, González, A, González-Canacer, A, Guzmán-Martínez, L, Cortés, N
Journal of Alzheimer's disease : JAD. 2020;(4):1199-1213
Abstract
Several hypotheses have been postulated to explain how Alzheimer's disease is triggered, but none of them provide a unified view of its pathogenesis. The dominant hypothesis based on build-ups of the amyloid-β peptide has been around for longer than three decades; however, up to today, numerous clinical trials based on the amyloid postulates have been attempted, but all of them have failed. Clearly, the revisited tau hypothesis provides a better explanation of the clinical observations of patients, but it needs to integrate the cumulative observations on the onset of this disease. In this context, the neuroimmuno modulation theory, based on the involvement of inflammatory events in the central nervous system, accounts for all these observations. In this review we intend to emphasize the idea that neuroinflammation is a main target for the search of new therapeutic strategies to control Alzheimer's disease. Beyond mono-targeting approaches using synthetic drugs that control only specific pathophysiological events, emerging therapeutics views based on multi targeting compounds appear to provide a new pathway for Alzheimer's disease treatment.
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7.
Cortical β-Amyloid in Older Adults Is Associated with Multidomain Interventions with and without Omega 3 Polyunsaturated Fatty Acid Supplementation.
Hooper, C, Coley, N, De Souto Barreto, P, Payoux, P, Salabert, AS, Andrieu, S, Weiner, M, Vellas, B
The journal of prevention of Alzheimer's disease. 2020;(2):128-134
Abstract
Multidomain lifestyle interventions (including combinations of physical exercise, cognitive training and nutritional guidance) are attracting increasing research attention for reducing the risk of Alzheimer's disease (AD). Here we examined for the first time the cross-sectional relationship between cortical β-amyloid (Aβ) and multidomain lifestyle interventions (nutritional and exercise counselling and cognitive training), omega 3 polyunsaturated fatty acid (n-3 PUFA) supplementation or their combination in 269 participants of the Multidomain Alzheimer Preventive Trial (MAPT). In adjusted multiple linear regression models, compared to the control group (receiving placebo alone), cortical Aβ, measured once during follow-up (mean 512.7 ± 249.6 days post-baseline), was significantly lower in the groups receiving multidomain lifestyle intervention + placebo (mean difference, -0.088, 95 % CI, -0.148,-0.029, p = 0.004) or multidomain lifestyle intervention + n-3 PUFA (-0.100, 95 % CI, -0.160,-0.041, p = 0.001), but there was no difference in the n-3 PUFA supplementation alone group (-0.011, 95 % CI, -0.072,0.051, p = 0.729). Secondary analysis provided mixed results. Our findings suggest that multidomain interventions both with and without n-3 PUFA supplementation might be associated with lower cerebral Aβ. Future trials should investigate if such multidomain lifestyle interventions are causally associated with a reduction or the prevention of the accumulation of cerebral Aβ.
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8.
Tryptophan metabolites modify brain Aβ peptide degradation: A role in Alzheimer's disease?
Maitre, M, Klein, C, Patte-Mensah, C, Mensah-Nyagan, AG
Progress in neurobiology. 2020;:101800
Abstract
Among several processes, a decrease in amyloid-beta (Aβ) peptide elimination is thought to be one of the major pathophysiological factors in Alzheimer's disease (AD). Neprilysin (NEP) is a key metalloproteinase controlling the degradation and clearance of Aβ peptides in the brain. NEP is induced by several pharmacological substances, amyloid deposits and somatostatin, but the physiological regulation of its expression remains unclear. This situation hampers the exploitation of NEP regulatory factors/mechanisms to develop effective strategies against Aβ peptide accumulation-induced brain toxicity. Based on recent data aimed at elucidating this major question, the present paper addresses and critically discusses the role of 5-hydroxyindole-acetic acid (5-HIAA) and kynurenic acid (KYNA) in the regulation of NEP activity/expression in the brain. Both 5-HIAA and KYNA are endogenous metabolites of tryptophan, an essential amino-acid obtained through diet and gut microbiome. By interacting with the aryl hydrocarbon receptor, various tryptophan metabolites modulate several metalloproteinases regulating brain Aβ peptide levels under normal and pathological conditions such as AD. In particular, interesting data reviewed here show that 5-HIAA and KYNA stimulate NEP activity/expression to prevent Aβ peptide-induced neurotoxicity. These data open promising perspectives for the development of tryptophan metabolite-based therapies against AD.
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9.
Association of Vascular Risk Factors With β-Amyloid Peptide and Tau Burdens in Cognitively Unimpaired Individuals and Its Interaction With Vascular Medication Use.
Köbe, T, Gonneaud, J, Pichet Binette, A, Meyer, PF, McSweeney, M, Rosa-Neto, P, Breitner, JCS, Poirier, J, Villeneuve, S, ,
JAMA network open. 2020;(2):e1920780
Abstract
IMPORTANCE Vascular risk factors are associated with increased risk of Alzheimer disease (AD), but it is unclear whether there is a direct association of these risk factors with AD pathogenesis. OBJECTIVES To assess the associations of vascular risk factors with AD pathogenesis in asymptomatic individuals, and to test whether this association is moderated among individuals who use vascular medications. DESIGN, SETTING, AND PARTICIPANTS This cross-sectional study used data from the Presymptomatic Evaluation of Experimental or Novel Treatments for Alzheimer Disease (PREVENT-AD) cohort of cognitively unimpaired individuals aged 55 to 82 years with a parental or multiple-sibling history of sporadic AD, who were recruited via advertisement from the greater Montreal, Quebec, Canada, metropolitan area. Participants were enrolled between September 9, 2011, to May, 3, 2017, and stratified by use vs no use of vascular medications. Data were analyzed July 1, 2018, to April 5, 2019. MAIN OUTCOMES AND MEASURES Principal analyses investigated associations of total, high-density lipoprotein, and low-density lipoprotein cholesterol levels, systolic and diastolic blood pressure, pulse pressure, and a combined vascular risk score (measured using the Framingham Coronary Risk Profile) with global β-amyloid peptide (Aβ) and entorhinal tau burden as measured by positron emission tomography (PET). Potential moderating associations of use of vascular medications with these associations were examined. Secondary similar analyses considered cerebrospinal fluid (CSF) Aβ1-42 and phosphorylated tau levels. RESULTS Among 215 participants (mean [SD] age, 62.3 [5.0] years; 161 [74.8%] women), 120 participants underwent PET, including 75 participants (62.5%) who were not using vascular medications, and 162 participants underwent CSF assessment, including 113 participants (69.8%) who were not using vascular medications. There was an overlap of 67 participants who underwent PET and CSF assessment. Interaction analyses showed that among participants not using vascular medications, higher Aβ deposition as measured by PET was associated with higher total cholesterol level (β = -0.002 [SE, 0.001]; P = .02), low-density lipoprotein cholesterol level (β = -0.002 [SE, 0.001]; P = .006), systolic blood pressure (β = -0.006 [SE, 0.002]; P = .02), pulse pressure (β = -0.007 [SE, 0.002]; P = .004), and Framingham Coronary Risk Profile score (β = -0.038 [SE, 0.011]; P = .001), but such associations were absent in participants who used vascular medications. Interactions were also found between vascular medication use and high-density lipoprotein cholesterol (β = -3.302 [SE, 1.540]; P = .03), low-density lipoprotein cholesterol (β = 1.546 [SE, 0.754]; P = .04), and Framingham Coronary Risk Profile score (β = 23.102 [SE, 10.993]; P = .04) on Aβ1-42 burden as measured in CSF. Higher Framingham Coronary Risk Profile scores were associated with reduced tau burden among participants using vascular medications but not among participants not using vascular medications (interaction, β = -0.010 [SE, 0.005]; P = .046). CONCLUSIONS AND RELEVANCE These findings corroborate previously reported associations of vascular risk factors with Aβ burden but not tau burden. However, these associations were found only among individuals who were not using vascular medications. These results suggest that medication use or other control of vascular risk factors should be considered in Alzheimer disease prevention trials.
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10.
Biased allosteric modulation of formyl peptide receptor 2 leads to distinct receptor conformational states for pro- and anti-inflammatory signaling.
Zhang, S, Gong, H, Ge, Y, Ye, RD
Pharmacological research. 2020;:105117
Abstract
BACKGROUND AND PURPOSE Formyl peptide receptor 2 (FPR2) is a Class A G protein-coupled receptor (GPCR) that interacts with multiple ligands and transduces both proinflammatory and anti-inflammatory signals. These ligands include weak agonists and modulators that are produced during inflammation. The present study investigates how prolonged exposure to FPR2 modulators influence receptor signaling. EXPERIMENTAL APPROACH Fluorescent biosensors of FPR2 were constructed based on single-molecule fluorescent resonance energy transfer (FRET) and used for measurement of ligand-induced receptor conformational changes. These changes were combined with FPR2-mediated signaling events and used as parameters for the conformational states of FPR2. Ternary complex models were developed to interpret ligand concentration-dependent changes in FPR2 conformational states. KEY RESULTS Incubation with Ac2-26, an anti-inflammatory ligand of FPR2, decreased FRET intensity at picomolar concentrations. In comparison, WKYMVm (W-pep) and Aβ42, both proinflammatory agonists of FPR2, increased FRET intensity. Preincubation with Ac2-26 at 10 pM diminished W-pep-induced Ca2+ flux but potentiated W-pep-stimulated β-arrestin2 membrane translocation and p38 MAPK phosphorylation. The opposite effects were observed with 10 pM of Aβ42. Neither Ac2-26 nor Aβ42 competed for W-pep binding at the picomolar concentrations. CONCLUSIONS AND IMPLICATIONS The results support the presence of two allosteric binding sites on FPR2, each for Ac2-26 and Aβ42, with high and low affinities. Sequential binding of the two allosteric ligands at increasing concentrations induce different conformational changes in FPR2, providing a novel mechanism by which biased allosteric modulators alter receptor conformations and generate pro- and anti-inflammatory signals.