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A? plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies.

ABSTRACT: Selective detection and staining of toxic amyloid plaques, a potential biomarker present in the Alzheimer's disease (AD) brain is crucial for both clinical diagnosis and monitoring AD disease progression. Herein, we report a coumarin-quinoline (CQ) conjugate-based turn-on near-infrared (NIR) fluorescence probe for specific detection of ?-amyloid (A?) aggregates. CQ probe is highly sensitive and exhibits ~100-fold fluorescence enhancement in vitro upon binding A? aggregates with enhanced quantum yield. Furthermore, the probe has ~10-fold higher binding affinity towards A? aggregates (86nM) compared to commonly used Thioflavin T. Most importantly, CQ probe displays unambiguous selectivity towards A? aggregates compared to other toxic protein aggregates such as tau, ?-synuclein (?-Syn) and islet amyloid polypeptide (IAPP). In addition, CQ is nontoxic to neuronal cells and shows significant blood brain barrier permeability. Remarkably, CQ stains A? plaques in human brain tissue over co-existing tau aggregates and neurofibrillary tangles (NFTs), which are associated in AD and tauopathies. This is a highly desirable attribute to distinguish AD from tau pathology and mixed dementia.

SUBMITTER: Rajasekhar K

PROVIDER: S-EPMC6370041 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Aβ plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies.

Rajasekhar K K Narayanaswamy Nagarjun N Murugan N Arul NA Viccaro Keith K Lee Hyoung-Gon HG Shah Kavita K Govindaraju Thimmaiah T

Biosensors & bioelectronics 20170617

Selective detection and staining of toxic amyloid plaques, a potential biomarker present in the Alzheimer's disease (AD) brain is crucial for both clinical diagnosis and monitoring AD disease progression. Herein, we report a coumarin-quinoline (CQ) conjugate-based turn-on near-infrared (NIR) fluorescence probe for specific detection of β-amyloid (Aβ) aggregates. CQ probe is highly sensitive and exhibits ~100-fold fluorescence enhancement in vitro upon binding Aβ aggregates with enhanced quantum ...[more]

PMID: 28649025

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Project description:Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) deposits, which come in myriad morphologies with varying clinical relevance. Previously, we observed an atypical Aβ deposit, referred to as the coarse-grained plaque. In this study, we evaluate the plaque's association with clinical disease and perform in-depth immunohistochemical and morphological characterization. The coarse-grained plaque, a relatively large (Ø ≈ 80 µm) deposit, characterized as having multiple cores and Aβ-devoid pores, was prominent in the neocortex. The plaque was semi-quantitatively scored in the middle frontal gyrus of Aβ-positive cases (n = 74), including non-demented cases (n = 15), early-onset (EO)AD (n = 38), and late-onset (LO)AD cases (n = 21). The coarse-grained plaque was only observed in cases with clinical dementia and more frequently present in EOAD compared to LOAD. This plaque was associated with a homozygous APOE ε4 status and cerebral amyloid angiopathy (CAA). In-depth characterization was done by studying the coarse-grained plaque's neuritic component (pTau, APP, PrPC), Aβ isoform composition (Aβ40, Aβ42, AβN3pE, pSer8Aβ), its neuroinflammatory component (C4b, CD68, MHC-II, GFAP), and its vascular attribution (laminin, collagen IV, norrin). The plaque was compared to the classic cored plaque, cotton wool plaque, and CAA. Similar to CAA but different from classic cored plaques, the coarse-grained plaque was predominantly composed of Aβ40. Furthermore, the coarse-grained plaque was distinctly associated with both intense neuroinflammation and vascular (capillary) pathology. Confocal laser scanning microscopy (CLSM) and 3D analysis revealed for most coarse-grained plaques a particular Aβ40 shell structure and a direct relation with vessels. Based on its morphological and biochemical characteristics, we conclude that the coarse-grained plaque is a divergent Aβ plaque-type associated with EOAD. Differences in Aβ processing and aggregation, neuroinflammatory response, and vascular clearance may presumably underlie the difference between coarse-grained plaques and other Aβ deposits. Disentangling specific Aβ deposits between AD subgroups may be important in the search for disease-mechanistic-based therapies.

Dataset Information

A? plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies.

Publications

Aβ plaque-selective NIR fluorescence probe to differentiate Alzheimer's disease from tauopathies.

Similar Datasets

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