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Toward the Noninvasive Diagnosis of Alzheimer's Disease: Molecular Basis for the Specificity of Curcumin for Fibrillar Amyloid-β.

ABSTRACT: Recent studies show that curcumin, a naturally fluorescent dye, can be used for the noninvasive optical imaging of retinal amyloid-β (Aβ) plaques. We investigated the molecular basis for curcumin's specificity for hierarchical Aβ structures using molecular dynamics simulations, with a focus on how curcumin is able to detect and discriminate different amyloid morphologies. Curcumin inhibits and breaks up β-sheet formation in Aβ monomers. With disordered Aβ structures, curcumin forms a coarse-grained composite structure. With an ordered fibril, curcumin's interaction is highly specific, and the curcumin molecules are deposited in the fibril groove. Curcumin tends to self-aggregate, which is finely balanced with its affinity for Aβ. This tendency concentrates curcumin molecules at Aβ deposition sites, potentially increasing the fluorescence signal. This is probably why curcumin is such an effective amyloid imaging agent.

SUBMITTER: Khurshid B

PROVIDER: S-EPMC9245119 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Toward the Noninvasive Diagnosis of Alzheimer's Disease: Molecular Basis for the Specificity of Curcumin for Fibrillar Amyloid-β.

Khurshid Beenish B Rehman Ashfaq Ur AU Muhammad Shabbir S Wadood Abdul A Anwar Jamshed J

ACS omega 20220613 25

Recent studies show that curcumin, a naturally fluorescent dye, can be used for the noninvasive optical imaging of retinal amyloid-β (Aβ) plaques. We investigated the molecular basis for curcumin's specificity for hierarchical Aβ structures using molecular dynamics simulations, with a focus on how curcumin is able to detect and discriminate different amyloid morphologies. Curcumin inhibits and breaks up β-sheet formation in Aβ monomers. With disordered Aβ structures, curcumin forms a coarse-grai ...[more]

PMID: 35785332

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Project description:Protein aggregation is common to dozens of diseases including prionoses, diabetes, Parkinson's and Alzheimer's. Over the past 15 years, there has been a paradigm shift in understanding the structural basis for these proteinopathies. Precedent for this shift has come from investigation of soluble Aβ oligomers (AβOs), toxins now widely regarded as instigating neuron damage leading to Alzheimer's dementia. Toxic AβOs accumulate in AD brain and constitute long-lived alternatives to the disease-defining Aβ fibrils deposited in amyloid plaques. Key experiments using fibril-free AβO solutions demonstrated that while Aβ is essential for memory loss, the fibrillar Aβ in amyloid deposits is not the agent. The AD-like cellular pathologies induced by AβOs suggest their impact provides a unifying mechanism for AD pathogenesis, explaining why early stage disease is specific for memory and accounting for major facets of AD neuropathology. Alternative ideas for triggering mechanisms are being actively investigated. Some research favors insertion of AβOs into membrane, while other evidence supports ligand-like accumulation at particular synapses. Over a dozen candidate toxin receptors have been proposed. AβO binding triggers a redistribution of critical synaptic proteins and induces hyperactivity in metabotropic and ionotropic glutamate receptors. This leads to Ca(2+) overload and instigates major facets of AD neuropathology, including tau hyperphosphorylation, insulin resistance, oxidative stress, and synapse loss. Because different species of AβOs have been identified, a remaining question is which oligomer is the major pathogenic culprit. The possibility has been raised that more than one species plays a role. Despite some key unknowns, the clinical relevance of AβOs has been established, and new studies are beginning to point to co-morbidities such as diabetes and hypercholesterolemia as etiological factors. Because pathogenic AβOs appear early in the disease, they offer appealing targets for therapeutics and diagnostics. Promising therapeutic strategies include use of CNS insulin signaling enhancers to protect against the presence of toxins and elimination of the toxins through use of highly specific AβO antibodies. An AD-dependent accumulation of AβOs in CSF suggests their potential use as biomarkers and new AβO probes are opening the door to brain imaging. Overall, current evidence indicates that Aβ oligomers provide a substantive molecular basis for the cause, treatment and diagnosis of Alzheimer's disease.

Project description:PurposeAmyloid PET tracers have been developed for in vivo detection of brain fibrillar amyloid deposition in Alzheimer's disease (AD). To serve as an early biomarker in AD the amyloid PET tracers need to be analysed in multicentre clinical studies.MethodsIn this study 238 [(11)C]Pittsburgh compound-B (PIB) datasets from five different European centres were pooled. Of these 238 datasets, 18 were excluded, leaving [(11)C]PIB datasets from 97 patients with clinically diagnosed AD (mean age 69?±?8 years), 72 patients with mild cognitive impairment (MCI; mean age 67.5?±?8 years) and 51 healthy controls (mean age 67.4?±?6 years) available for analysis. Of the MCI patients, 64 were longitudinally followed for 28?±?15 months. Most participants (175 out of 220) were also tested for apolipoprotein E (ApoE) genotype.Results[(11)C]PIB retention in the neocortical and subcortical brain regions was significantly higher in AD patients than in age-matched controls. Intermediate [(11)C]PIB retention was observed in MCI patients, with a bimodal distribution (64 % MCI PIB-positive and 36 % MCI PIB-negative), which was significantly different the pattern in both the AD patients and controls. Higher [(11)C]PIB retention was observed in MCI ApoE ?4 carriers compared to non-ApoE ?4 carriers (p?<?0.005). Of the MCI PIB-positive patients, 67 % had converted to AD at follow-up while none of the MCI PIB-negative patients converted.ConclusionThis study demonstrated the robustness of [(11)C]PIB PET as a marker of neocortical fibrillar amyloid deposition in brain when assessed in a multicentre setting. MCI PIB-positive patients showed more severe memory impairment than MCI PIB-negative patients and progressed to AD at an estimated rate of 25 % per year. None of the MCI PIB-negative patients converted to AD, and thus PIB negativity had a 100 % negative predictive value for progression to AD. This supports the notion that PIB-positive scans in MCI patients are an indicator of prodromal AD.

Project description:BackgroundReactive microglia are associated with ?-amyloid (A?) deposit and clearance in Alzhiemer's Disease (AD). Paradoxically, entocranial resident microglia fail to trigger an effective phagocytic response to clear A? deposits although they mainly exist in an "activated" state. Oligomeric A? (oA?), a recent target in the pathogenesis of AD, can induce more potent neurotoxicity when compared with fibrillar A? (fA?). However, the role of the different A? forms in microglial phagocytosis, induction of inflammation and oxidation, and subsequent regulation of phagocytic receptor system, remain unclear.ResultsWe demonstrated that A?(1-42) fibrils, not A?(1-42) oligomers, increased the microglial phagocytosis. Intriguingly, the pretreatment of microglia with oA?(1-42) not only attenuated fA?(1-42)-triggered classical phagocytic response to fluorescent microspheres but also significantly inhibited phagocytosis of fluorescent labeled fA?(1-42). Compared with the fA?(1-42) treatment, the oA?(1-42) treatment resulted in a rapid and transient increase in interleukin 1? (IL-1?) level and produced higher levels of tumor necrosis factor-? (TNF-?), nitric oxide (NO), prostaglandin E2 (PGE2) and intracellular superoxide anion (SOA). The further results demonstrated that microglial phagocytosis was negatively correlated with inflammatory mediators in this process and that the capacity of phagocytosis in fA?(1-42)-induced microglia was decreased by IL-1?, lippolysaccharide (LPS) and tert-butyl hydroperoxide (t-BHP). The decreased phagocytosis could be relieved by pyrrolidone dithiocarbamate (PDTC), a nuclear factor-?B (NF-?B) inhibitor, and N-acetyl-L-cysteine (NAC), a free radical scavenger. These results suggest that the oA?-impaired phagocytosis is mediated through inflammation and oxidative stress-mediated mechanism in microglial cells. Furthermore, oA?(1-42) stimulation reduced the mRNA expression of CD36, integrin ?1 (Itgb1), and Ig receptor Fc?RIII, and significantly increased that of formyl peptide receptor 2 (FPR2) and scavenger receptor class B1 (SRB1), compared with the basal level. Interestingly, the pre-stimulation with oA?(1-42) or the inflammatory and oxidative milieu (IL-1?, LPS or t-BHP) significantly downregulated the fA?(1-42)-induced mRNA over-expression of CD36, CD47 and Itgb1 receptors in microglial cells.ConclusionThese results imply that A? oligomers induce a potent inflammatory response and subsequently disturb microglial phagocytosis and clearance of A? fibrils, thereby contributing to an initial neurodegenerative characteristic of AD. Antiinflammatory and antioxidative therapies may indeed prove beneficial to delay the progression of AD.

Dataset Information

Toward the Noninvasive Diagnosis of Alzheimer's Disease: Molecular Basis for the Specificity of Curcumin for Fibrillar Amyloid-β.

Publications

Toward the Noninvasive Diagnosis of Alzheimer's Disease: Molecular Basis for the Specificity of Curcumin for Fibrillar Amyloid-β.

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