Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

Nie, Qian; Du, Xiaoguang; Geng, Meiyu

doi:10.1038/aps.2011.14

Cited by 220 publications

(195 citation statements)

References 78 publications

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“…To this end, the carboxymethyl end group of the PEG-coated MNPs was functionalized with the peptide sequence leucineproline-phenylalanine-phenylalanine-aspartic acid (LPFFD) ( Figure 3 A, estimation for degree of MNP functionalization in Figure S2, Supporting Information), which binds to a hydrophobic domain on the Aβ structure (amino acids [17][18][19][20]. [ 11,15 ] While LPFFD peptide is a β-sheet breaker that can block Aβ fi bril growth and cause disaggregation in >10-fold molar excess with respect to Aβ for extended incubation periods, [ 11,12,35 ] in this study, the ratio of LPFFD:Aβ (1:15, with the unlikely assumption of 100% conversion) is far too low to inhibit fi bril growth. [ 11 ] Structural studies indicate that the hydrophobic domain is largely confi ned to the fi bril core, [ 36,37 ] which should restrict targeting to hydrophobic moieties exposed on the periphery of aggregates.…”

Section: Targeting Mnps To Aβmentioning

confidence: 99%

“…The former can hinder Aβ aggregation at high concentrations, though with limited effi cacy due to insuffi cient steric hindrance. [ 11,12 ] Similarly, nanoparticles can prevent amyloid aggregation via protein adsorption on their surface. [ 13 ] However, the mechanism of this passive inhibition is not well understood, and depending on their concentration and surface chemistry, nanoparticles may instead accelerate protein aggregation.…”

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confidence: 99%

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Targeted Magnetic Nanoparticles for Remote Magnetothermal Disruption of Amyloid‐β Aggregates

Loynachan

Romero

Christiansen

et al. 2015

Adv Healthcare Materials

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Remotely triggered hysteretic heat dissipation by magnetic nanoparticles (MNPs) selectively attached to targeted proteins can be used to break up self-assembled aggregates. This magnetothermal approach is applied to the amyloid-β (Aβ) protein, which forms dense, insoluble plaques characteristic of Alzheimer's disease. Specific targeting of dilute MNPs to Aβ aggregates is confirmed via transmission electron microscopy (TEM) and is found to be consistent with a statistical model of MNP distribution on the Aβ substrates. MNP composition and size are selected to achieve efficient hysteretic power dissipation at physiologically safe alternating magnetic field (AMF) conditions. Dynamic light scattering, fluorescence spectroscopy, and TEM are used to characterize the morphology and size distribution of aggregates before and after exposure to AMF. A dramatic reduction in aggregate size from microns to tens of nanometers is observed, suggesting that exposure to an AMF effectively destabilizes Aβ deposits decorated with targeted MNPs. Experiments in primary hippocampal neuronal cultures indicate that the magnetothermal disruption of aggregates reduces Aβ cytotoxicity, which may enable future applications of this approach for studies of protein disaggregation in physiological environments.

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Section: Targeting Mnps To Aβmentioning

confidence: 99%

mentioning

confidence: 99%

Targeted Magnetic Nanoparticles for Remote Magnetothermal Disruption of Amyloid‐β Aggregates

Loynachan

Romero

Christiansen

et al. 2015

Adv Healthcare Materials

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“…Although the biological function of APP is still unclear, the protein has been found to be involved in multiple cellular processes, including neuronal growth and survival (Nie et al 2011;Haass et al 1993). APP cleavage by "-secretase at methionine 671 position produces a soluble APP fragment and a C-terminal fragment with 99 amino acids.…”

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confidence: 99%

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Thapa

2015

Advances in Experimental Medicine and Biology

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Flavonoids are naturally occurring phytochemicals found in a variety of fruits and vegetables and offer color, flavor, aroma, nutritional and health benefits. Flavonoids have been found to play a neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) peptide into oligomers and fibrils, which are linked to the pathogenesis of Alzheimer's disease. The neuroprotective efficacy of flavonoids has been found to strongly depend on their structure and functional groups. Flavonoids may exist in monomeric, as well as di-, tri-, tetra- or polymeric form through C-C or C-O-C linkages. It has been shown that flavonoids containing two or more units, e.g., biflavonoids, exert greater biological activity than their respective monoflavonoids. For instance, biflavonoids have the ability to distinctly alter Aβ aggregation and more effectively reduce the toxicity of Aβ oligomers compared to the monoflavonoid moieties. Although the molecular mechanisms remain to be elucidated, flavonoids have been shown to alter the Aβ aggregation pathway to yield non-toxic, unstructured Aβ aggregates, as well as directly exerting a neuroprotective effect to cells. In this chapter, we review biflavonoid-mediated Aβ aggregation and toxicity, and highlight the beneficial roles biflavonoids can potentially play in the prevention and treatment of Alzheimer's disease.

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“…Chemical substances that bind to the oligomer/protofibril ends and block the addition of intact Aβ molecules [207][208][209] , as well as substances that interfere with secondary nucleation 210 , appear to be the best candidates.…”

Section: The Vicious Cycle Of Alzheimer's Diseasementioning

confidence: 99%

Age-Related Diseases as Vicious Cycles

Belikov

2017

Preprint

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Age-related diseases (ARDs) are the leading cause of death worldwide, and contribute to 90% of mortality in developed countries. Interestingly, the mortality rates of individual ARDs increase exponentially with age. Processes described by the exponential growth function typically involve a branching chain reaction or, more generally, a positive feedback loop. Here I propose that each ARD is mediated by one or several positive feedback loops (vicious cycles). I then identify critical vicious cycles in five major ARDs: atherosclerosis, hypertension, diabetes, Alzheimer's and Parkinson's. I also propose that the progression of ARDs can be halted by selectively interrupting the vicious cycles and suggest the most promising targets. An evolutionary perspective is also offered.

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Small molecule inhibitors of amyloid β peptide aggregation as a potential therapeutic strategy for Alzheimer's disease

Cited by 220 publications

References 78 publications

Targeted Magnetic Nanoparticles for Remote Magnetothermal Disruption of Amyloid‐β Aggregates

Targeted Magnetic Nanoparticles for Remote Magnetothermal Disruption of Amyloid‐β Aggregates

Biflavonoids as Potential Small Molecule Therapeutics for Alzheimer’s Disease

Age-Related Diseases as Vicious Cycles

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