Elsevier

Dyes and Pigments

Review

Research progress of multi-functional fluorescent probes for Alzheimer'south disease monitoring

Abstract

The diagnosis of Alzheimer's disease (Ad) has proven to be difficult to achieve in clinical practice, despite the all-encompassing research on the field of study. In improver to traditional biomarkers such as β-amyloid and neurofibrillary tangles, which have been considered important targets for the diagnosis of AD for long time, other biomarkers of the illness in its early on stages are under investigation. Fluorescent imaging is considered a promising strategy for the early on diagnosis of Advert due to its high sensitivity, simplicity of testing, minimal-invasiveness, existent-time response, availability of probes with depression toxicity requiring low dosage, and low cost. A small-scale, simply rapidly increasing number of fluorescent probes have recently been reported in the literature for the simultaneous detection of multiple biomarkers. This review describes sixteen dissimilar dual-functional fluorescent probes developed in recent years for the simultaneous detection of Advertizement biomarkers, including β-amyloid and viscosity, β-amyloid and tau fibrils, β-amyloid and lipid droplets, β-amyloid and peroxynitrite, mitochondrial viscosity and hydrogen peroxide, mitochondrial membrane potential and viscosity, mitochondrial viscosity and hydrogen sulfide, copper and hydrogen sulfide, hydrogen peroxide and pH fluctuations.

Introduction

Alzheimer'due south Affliction (Advertising) is an irreversible neurodegenerative affliction affecting the elderly that mainly manifests as cognitive dysfunctions and progressive memory loss [one]. Due to the increasing ageing of the global population, the prevalence of dementia is continuously increasing worldwide. Equally the main form of dementia, AD has a particular high incidence in people anile 65 years or older and is characterized past poor prognosis, limited therapeutic options, which are effective merely in early stages of the disease, and a low level of cocky-care ability of the patients [two]. According to a study issued by the World Health Organisation in 2018, there are currently l million of patients affected by a form of dementia in the earth, and Advertisement patients account for almost sixty%–70% of the full. Electric current projections predict that the global number of Advertizement patients may exceed 150 million in 2050. It is worth noting that the increase in the number of patients with dementia not simply increases the number of patients and families that have to alive their lives with this burden, but has also a meaning bear upon on earth economy. In fact, the global toll of diagnosis and treatment of dementia has been steadily increasing over recent years [three] passing from an estimated US$604 billions in 2010 [iv] to US$818 billions in 2015 [5].

Although AD has received extensive attending over the past three decades from both academia and manufacture, the specific pathogenic mechanism underlying this illness has not yet been clarified and a number of hypothesis are still under evaluation by the scientific community. The most widely recognized hypotheses include the β-amyloid (Aβ) hypothesis, the tau hypothesis, the immune-inflammatory response theory, the mitochondrial dysfunction theory and the oxidative stress theory [6]. About studies have focused on the Aβ and the tau hypotheses. Aβ hypothesis [7] postulates that the uncoordinated production and clearance of Aβ peptide in the brain of AD patients is responsible for an excessive accumulation of toxic Aβ. Aβ exists in the form of monomers, oligomers and fibrils in the brain, and with the progress of the affliction, these substances eventually form senile plaques. It is currently believed that Aβ oligomers are the form responsible for most of the neuronal toxicity [8]. Tau hypothesis [9] proposes that the loss of office of tau protein caused by its hyperphosphorylation impairs the formation and stability of microtubules. The aforementioned hyperphosphorylation promotes the aggregation of tau poly peptide into insoluble neurofibrillary tangles that cause damage to nerve cells, thereby affecting cerebral functions and retentiveness. The mitochondrial dysfunction theory [x] suggests that the decrease of the number of mitochondria in the brain of Advertizement patients leads to the decrease of mitochondrial enzyme activity, causing dysfunctions in the electron transport chain and in ATP production, which eventually leads to neuronal apoptosis and aggravates the condition of Advertizing patients. The oxidative stress hypothesis [11] presumes that the consumption of a large amount of oxygen and the lack of antioxidant enzymes lead to a redox imbalance in the body, causing an excessive production of free radicals that damage neuronal cells.

According to the latest diagnosis guidelines issued by the National Institute on Aging and Alzheimer'south Association (NIA-AA), Advertizement is currently divided into preclinical, mild cerebral impairment (MCI), and dementia phases [12]. The course of Advertisement is mostly long (more than eight years), and the drugs currently approved for its treatment (i.e., rivastigmine, galantamine, donepezil and memantine) [13], only relieve some of the symptoms and are more constructive if administered in the early phases. For this reasons, early diagnosis and treatment have become a popular enquiry direction for scholars. The biomarkers for the early diagnosis of Ad include senile plaques (SPs), which are formed past Aβ deposition, neurofibrillary tangles, which are caused by tau poly peptide hyperphosphorylation, glial cells inflammation-related markers, and other markers of degenerative diseases of the nervous system and oxidative stress [14]. In addition, metal ions [15], abnormal lipid metabolism [16] and lysosomal dysfunction [17] have besides been linked to the pathogenesis of Advertizing, therefore the related substances may also act as biomarkers for the early diagnosis of AD. Metal ions, such as Cu2+, tin bear upon the toxicity of Aβ through a diverseness of mechanisms, such as ane) promotion of Aβ assemblage and acceleration of senile plaques formation; 2) increment of the toxicity of Aβ oligomers upon chelation in nerve cells; iii) promotion of Fenton reaction and production of free radicals [[18], [nineteen], [20]]. On the other hand, hydrogen sulfide inhibits γ-secretase, the protease responsible for the formation of Aβ monomers from amyloid precursor protein, and has therefore anti-amyloidogenic outcome [21]. In summary, the lack of H2S and the aggregating of Cu2+ are related to the occurrence of AD and can be used as biomarkers of the disease [[22], [23], [24], [25]].

At nowadays, most of the research on biomarkers for the early diagnosis of Advertizement has focused on the Aβ peptide. In the field of fluorescent probes, many molecules have been designed for the detection of Aβ, including the near prominent probes with the archetype D-π-A architecture, cyanine derivatives, BODIPY-based probes, curcumin derivatives and thiophene derivatives [26]. For the detection of tau protein aggregates enquiry take more often than not focused on BODIPY derivatives, indocyanine greenish derivatives and curcumin derivatives [27]. A curcumin derivative has besides been recently developed as a fluorescent probe for detecting reactive oxygen species (ROS), which are biomarkers of oxidative stress [28].

The application of fluorescent probe imaging equally a diagnostic and therapeutic strategy has recently attracted attention because of its numerous positive characteristics, including high sensitivity, high efficiency, minimal-invasiveness, real-time response, availability of probes with low toxicity requiring depression dosage and low overall cost for the diagnosis of diseases [[29], [30], [31], [32]]. Probes used for extracellular, intracellular or in vivo fluorescence imaging should meet the following conditions: 1) low or no toxicity and high specificity; 2) the probe itself tin produce fluorescence or tin can amass to induce luminescence, and the fluorescence intensity is different when interacting with different substances; 3) the probe has an appropriate logP for good brain distribution kinetics, which allows high penetration through cell membranes and the blood-brain barrier (molecules with logP between 1.5 and three.0 are considered to accept a high blood-brain barrier penetration ability) [33,34]; 4) long fluorescence emission wavelength and big Stokes shifts for amend penetration depth [35].

Many fluorescent probes accept been developed over the years for the detection of unmarried AD biomarkers such equally Aβ, and have been the discipline of several review [[36], [37], [38], [39], [xl], [41]]. However, a number of fluorescent probes capable of simultaneously detecting multiple biomarkers take recently been reported and have non yet been reviewed. Here, we summarize the bifunctional probes that have been reported in recent years for the diagnosis and treatment of AD. This review focuses on the structural pattern, optical properties, chemical properties, imaging characteristics of these probes (Table ane) inside and outside cells or in vivo, as well equally on their potential applications.

Section snippets

Fluorescent probes for the simultaneous detection of Aβ peptide and viscosity

The NIR fluorescence probe MC-one [42], which was obtained by replacing the cationic moiety of IR-780 [43,44] with a neutral group, was reported by Yan and colleagues for Aβ peptide detection. However, MC-1 was establish to be also sensitive to environmental viscosity, enabling the possibility to image viscosity at the cellular level. In 2019, the aforementioned group designed MC-Northward-2 [45], a probe for the simultaneous detection of Aβ peptide and viscosity, by introducing different amine chains to MC-1 as

Conclusions

Due to the complex pathogenesis of Advertizing and the current lack of constructive diagnostic tools, fluorescent probes that can detect multiple biomarkers are of great promise for the early on diagnosis of this disease. In this article, nosotros introduced the research progress on multifunctional fluorescent probes directed at recognized biomarkers such equally Aβ aggregates and NFTs, and other promising biomarkers such every bit ROS, RNS, mitochondrial and lysosomal viscosity, Cu2+, HtwoDue south, BACE1 and CatD. The use of these

Announcement of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could take appeared to influence the work reported in this paper.

Acknowledgements

This work was financially supported by the supported by the Natural Science Foundation of Guangdong Province, China (2019A1515010137), the Fundamental Research Funds for the Central Universities (D2191260) and the Medical Scientific Research Foundation of Guangdong Province, Prc (A2018080 and A2019029).

References (84)

  • et al.

    Plough-on chemiluminescence probes and dual-amplification of signal for detection of amyloid beta species in vivo

    Nat Commun

    (13 Aug. 2020)
  • Y. Chen et al.

    A nontoxic, photostable and high bespeak-to-noise ratio mitochondrial probe with mitochondrial membrane potential and viscosity detectivity

    Spectrochim Acta Mol Biomol Spectrosc

    (2018 Jan 15)
  • Yard. Qu et al.

    Hydrogen sulfide: neurochemistry and neurobiology - ScienceDirect

    Neurochem Int

    (2008)
  • A.I. Bush et al.

    Therapeutics for Alzheimer's disease based on the metal hypothesis

    Neurotherapeutics

    (2008)
  • Y. Wang et al.

    Dual-functional AIE fluorescent probes for imaging β-amyloid plaques and lipid droplets

    Anal. Chem. Acta.

    (2020)
  • Y. Wang et al.

    Preferential accumulation of the near infrared heptamethine dye IR-780 in the mitochondria of drug-resistant lung cancer cells

    Biomaterials

    (2014)
  • A. Jamerlan et al.

    Advances in amyloid beta oligomer detection applications in Alzheimer's disease

    Trac Trends Anal Chem

    (2020)
  • H. Zhou et al.

    H2S2-triggered off-on fluorescent indicator with endoplasmic reticulum targeting for imaging in cells and zebrafishes

    Sensor Actuator

    (2019)
  • Y.I. Gyasi et al.

    Biological applications of near infrared fluorescence dye probes in monitoring Alzheimer's disease

    Eur J Med Chem

    (2020)
  • Due south. Palanisamy et al.

    A h2o soluble and fast response fluorescent turn-on copper complex probe for H2S detection in zebra fish

    Talanta

    (2016)
  • O. Bandmann et al.

    Wilson's disease and other neurological copper disorders

    Lancet Neurol

    (2015)
  • B. Olsson et al.

    CSF and blood biomarkers for the diagnosis of Alzheimer's disease: a systematic review and meta-assay

    Lancet Neurol

    (2016)
  • G. McKhann et al.

    The diagnosis of dementia due to Alzheimer'southward disease: recommendations from the National Plant on Crumbling-Alzheimer'due south Clan workgroups on diagnostic guidelines for Alzheimer's illness

    Alzheimer's Dementia

    (2011)
  • Southward. Hauptmann et al.

    Mitochondrial dysfunction: an early outcome in Alzheimer pathology accumulates with age in Advertizing transgenic mice

    Neurobiol Crumbling

    (2009)
  • J. Hardy et al.

    Amyloid deposition as the cardinal issue in the aetiology of Alzheimer'southward disease

    Trends Pharmacal Sci

    (1991)
  • P. Sharma et al.

    Comprehensive review of mechanisms of pathogenesis involved in Alzheimer's disease and potential therapeutic strategies

    Prog Neurobiol

    (2019)
  • C.L. Masters et al.

    Alzheimer'southward disease

    Nat. Rev. Dis. Primers

    (2015)
  • D. Harman

    Alzheimer's disease pathogenesis: part of crumbling

    Ann Ny Acad Sci

    (2006)

  • The Earth Alzheimer Report 2018, the state of the art of dementia research: new frontiers[R]

    London: Alzheimer's Affliction International (ADI)

    (2018)
  • Livingston G, Sommerlad A, Orgeta 5, et al Dementia prevention, intervention, and care. Lancet (London, England),...
  • G. Shankar et al.

    Amyloid-beta protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory

    Nat Med

    (2008)
  • H. Fukumoto et al.

    High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients

    Faseb J

    (2010)
  • J. Teixeira et al.

    Future therapeutic perspectives into the Alzheimer'southward disease targeting the oxidative stress hypothesis

    Molecules

    (2019)
  • T. Chase et al.

    Donepezil plus solifenacin (CPC-201) treatment for Alzheimer'south affliction

    Neurotherapeutics

    (2017)
  • Y.W. Jun et al.

    Frontiers in probing Alzheimer's illness biomarkers with fluorescent pocket-sized molecules

    ACS Cent Sci

    (2019)
  • Y. Xiang et al.

    What tin can lipidomics tell united states well-nigh the pathogenesis of Alzheimer disease

    J Biol Chem

    (2015)
  • R. Nixon et al.

    Lysosomal system pathways: genes to neurodegeneration in Alzheimer's disease

    J Alzheimers Dis

    (2006)
  • Thousand.One thousand. Savelieff et al.

    Untangling amyloid-β, tau, and metals in Alzheimer's disease

    ACS Chem Biol

    (2013)
  • P. Faller et al.

    Bioinorganic chemical science of copper and zinc ions coordinated to amyloid-β peptide

    ChemInform

    (2009)
  • S Pithadia Amit et al.

    Metal-associated amyloid-β species in Alzheimer's disease[J]

    Curr Opin Chen Biol

    (2012)
  • F.L. Zhao et al.

    Hydrogen sulfide selectively inhibits γ-secretase activity and decreases mitochondrial Aβ production in neurons from APP/PS1 transgenic mice

    Neurochem Res

    (2016 May)
  • V.S. Lin et al.

    Chemical probes for molecular imaging and detection of hydrogen sulfide and reactive sulfur species in biological systems

    Chemsocrev

    (2015)
  • R.Due east. Tanzi et al.

    The Wilson disease gene is a copper transporting ATPase with homology to the Menkes affliction gene

    Nat Genet

    (1993)
  • A. Jamerlan et al.

    Advances in amyloid beta oligomer detection applications in Alzheimer's disease

    Trac Trends Anal Chem

    (2020)
  • J. Yang et al.

    Development of near-infrared fluorescent probes for use in Alzheimer's affliction diagnosis

    Bioconjugate Chem

    (2020)
  • C. Peng et al.

    Versatile fluorescent probes for near-infrared imaging of amyloid-β species in Alzheimer's disease mouse model

    J Mater Chem B

    (2019 Mar 28)
  • B. Iravani et al.

    Non-invasive recording from the man olfactory bulb

    Nat Commun

    (2020 Jan 31)
  • C. Zhang et al.

    A new mitochondrion targetable fluorescent probe for carbon monoxide-specific detection and live jail cell imaging

    Chem Commun

    (2019 Aug 7)
  • X. Zhang et al.

    Design and synthesis of curcumin analogues for in vivo fluorescence imaging and inhibiting copper-induced cross-linking of amyloid beta species in Alzheimer'south illness

    J Appl Comput Sci

    (2009)
  • J.Y. Xie et al.

    Well-nigh-infrared fluorescent probe with high quantum yield and its application in the selective detection of glutathione in living cells and tissues

    Anal Chem

    (2016)
  • T. Liu et al.

    Quantitatively mapping cellular viscosity with detailed organelle information via a iesigned PET fluorescent probe

    Sci Rep

    (2014)

    • Cited past (9)

    View total text

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