From Companion Diagnostics to Theranostics: A New Avenue for Alzheimer’s Disease?

Bolognesi, María Laura; Gandini, Annachiara; Prati, Federica; Uliassi, Elisa

doi:10.1021/acs.jmedchem.6b00151

Cited by 47 publications

(43 citation statements)

References 77 publications

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“…125 The term theranostic has thus been coined to characterize these new inhibitor-biomarkers, many based on scaffolds of fluorescent probes such as ThT, to detect fibril formation in vivo and alter their accumulation. 126 These new strategies have been made possible by improved understanding of the assembly mechanism of Aβ at the molecular level, which will continue to guide rational drug design against AD.…”

Section: Aβ Tau and Alzheimer’s Diseasementioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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Neurodegenerative disorders and type 2 diabetes are global epidemics compromising the quality of life of millions worldwide, with profound social and economic implications. Despite the significant differences in pathology – much of which are poorly understood – these diseases are commonly characterized by the presence of cross-β amyloid fibrils as well as the loss of neuronal or pancreatic β-cells. In this review, we document research progress on the molecular and mesoscopic self-assembly of amyloid-beta, alpha synuclein, human islet amyloid polypeptide and prions, the peptides and proteins associated with Alzheimer’s, Parkinson’s, type 2 diabetes and prions diseases. In addition, we discuss the toxicities of these amyloid proteins based on their self-assembly as well as their interactions with membranes, metal ions, small molecules and engineered nanoparticles. Through this presentation we show the remarkable similarities and differences in the structural transitions of the amyloid proteins through primary and secondary nucleation, the common evolution from disordered monomers to alpha-helices and then to β-sheets when the proteins encounter the cell membrane, and, the consensus (with a few exceptions) that off-pathway oligomers, rather than amyloid fibrils, are the toxic species regardless of the pathogenic protein sequence or physicochemical properties. In addition, we highlight the crucial role of molecular self-assembly in eliciting the biological and pathological consequences of the amyloid proteins within the context of their cellular environments and their spreading between cells and organs. Exploiting such structure-function-toxicity relationship may prove pivotal for the detection and mitigation of amyloid diseases.

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Section: Aβ Tau and Alzheimer’s Diseasementioning

confidence: 99%

Implications of peptide assemblies in amyloid diseases

et al. 2017

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“…The general statement by Cummings [162] [163] that until today some candidates entered clinical trial, but since approval of memantine in 2003 no further candidate has completed a phase 3 trial, is attenuated for the diagnostic point of view by phase 3 studies presented for florbetaben and florbetapir [65] [113] [116] [163] [164].…”

Section: Discussionmentioning

confidence: 99%

“…Presently, the tendency to separate therapeutic and diagnostic line of drug development is displaced by another trend summarized under the term theranostics [65] [66] [67]. Small molecules with new therapeutic targets at several control points of the cascade model are connected with antibodies as tool for better targeting and diagnostics of neurodegenerative alterations.…”

Section: Introductionmentioning

confidence: 99%

Small Molecule-Assisted PET: Approaches to Imaging of Conformational Diseases of the Brain

Pissarek¹

2017

WJNS

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PET (positron emission tomography) in vivo imaging of cerebral conformational diseases is essentially based on non-peptide small molecule ligands used to detect early alterations in peptide secondary structures and subsequent accumulation of aberrant oligomers and protein deposits involved in progressive neurodegeneration, cognitive and movement disorders. In this article, an overview is given about tracers currently available and lead structures of potential PET probes for detection of ß-amyloid (Aß), tau protein, α-synuclein, constitutive (PrP c ) and infectious isoforms (PrP sc ) of prions (proteinaceous infectious particles) as imaging targets. Whereas the styrylpyridine derivative florbetapir, approved for clinical applications, the stilbene derivative florbetaben and the benzoxazole derivative BF227 show high affinity binding to Aß, preclinical investigations promise improved pharmacokinetics for benzoimidazothiazoles, aryloxazoles and benzofuran derivatives. Tau protein imaging based clinically, presently, on the pyridine-pyridoindole T807 has got new incentives following identification of a series of pyrrolopyridine quinolines and pharmacokinetic improvements of fluoropropoxy quinolines including for instance THK-5351. The pyridine isoquinoline MK6240 is involved now in clinical trials. Most forward-looking efforts apply to small molecule ligands of α-synuclein, which are expected to permit a breakthrough in differential diagnostics of Parkinson-related dementia and Lewy body diseases. However, at the moment the proposed lead structures are in affinity and blood brain barrier delivery properties below the possibilities of Aß and tau protein ligands. This is the case also for potential tracers of prion proteins.

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“…Although chemiluminescence has been intensively explored in many diseases such as cancers and diabetes, its applications in brain disorders including Alzheimer's disease (AD) is scarce. Ab plaques and neurofibrillary Tau tangles are the most pronounced and characteristic hallmarks of Alzheimer's disease (AD) [21][22][23] , and several imaging methods been widely applied in preclinical and clinical studies [24][25][26][27][28][29][30][31][32][33][34][35][36][37] . Optical imaging, including NIRF imaging and two-photon imaging, are the most used methods for preclinical investigations of fundamental pathological questions and for therapy monitoring in drug development.…”

Section: Introductionmentioning

confidence: 99%

Smart Chemiluminescence Probes and Dual-Amplification of Signal for Detection of Amyloid Beta Species in Alzheimer’s Disease Model

Yang¹,

Yin²,

Van³

et al. 2020

Preprint

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<div>Fluorescence and chemiluminescence imaging are the most widely applied optical emissive imaging</div><div>methods in biomedical research. “Smart” (turn-on) fluorescence imaging has been routinely used for in</div><div>vitro, cellular, and in vivo imaging; however, smart chemiluminescence imaging has been rarely explored.</div><div>In this report, we designed chemiluminescence probe ADLumin-1 and validated that ADLumin-1 was a</div><div>smart chemiluminescence probe for amyloid beta (Ab) species, evidenced by a 216-fold amplification of</div><div>chemiluminescence intensity upon mixing with Abs in vitro. In vivo two photon imaging indicated that</div><div>ADLumin-1 could efficiently cross blood-brain- barrier (BBB) and provided excellent contrast both for Ab</div><div>plaques and cerebral amyloid angiopathy (CAA). In vivo whole brain imaging showed that the</div><div>chemiluminescence signal of ADLumin-1 from 5-month-old transgenic AD (5xFAD) mice was 1.80-fold</div><div>higher than that from the age-matched wild-type mice. Moreover, we demonstrated that it was feasible to</div><div>further dually-amplify signal via chemiluminescence resonance energy transfer (DAS-CRET) using two</div><div>non-conjugated smart probes (ADLumin-1 and CRANAD-3) in solutions, brain homogenates, and in vivo</div><div>whole brain imaging. Our results showed that DAS-CRET could provide a 2.25-fold margin between 5-</div><div>month-old 5xFAD mice and wild type mice. To our knowledge, this is the first report that a</div><div>chemiluminescence probe could be used for detecting Ab species both in vitro and in vivo. Although</div><div>ADLumin-1 was designed for Abs, we believe that our strategy could be potentially extended to a wide</div><div>range of targets, including other aggregating-prone proteins. Notably, our results suggested that the</div><div>strategies for turning-on fluorescence could be used for amplifying chemiluminescence, and we believe that</div><div>our studies could inspire considerably more research on chemiluminescence imaging</div>

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From Companion Diagnostics to Theranostics: A New Avenue for Alzheimer’s Disease?

Cited by 47 publications

References 77 publications

Implications of peptide assemblies in amyloid diseases

Implications of peptide assemblies in amyloid diseases

Small Molecule-Assisted PET: Approaches to Imaging of Conformational Diseases of the Brain

Smart Chemiluminescence Probes and Dual-Amplification of Signal for Detection of Amyloid Beta Species in Alzheimer’s Disease Model

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