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P4‐509: SUPPRESSION OF NEUROINFLAMMATION AND AMYLOID PATHOLOGY IN 5XFAD MICE BRAIN BY GLIA MATURATION FACTOR ANTIBODY
Author(s) -
Ahmed Mohammad Ejaz,
Thangavel Ramasamy,
Selvakumar Govindhasamy Pushpavathi,
Kempuraj Duraisamy Pushpavathi,
Dubova Iuliia Pushpavathi,
Raikwar Sudhanshu P.,
Zaheer Smita P.,
Iyer Shankar S.,
Zaheer Asgar
Publication year - 2019
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2019.08.055
Subject(s) - neuroinflammation , neurodegeneration , glial fibrillary acidic protein , neuroscience , astrocyte , cerebral cortex , amyloid precursor protein , biology , alzheimer's disease , pathology , immunology , central nervous system , medicine , immunohistochemistry , inflammation , disease
Background: The self-assembly of soluble proteins into oligomeric and fibrillar amyloid structures is associated with a range of neurodegenerative disorders, including Alzheimer’s disease (AD). In AD, the pathogenic process is thought to start by binding of amyloid-b (Ab) oligomers to specific receptors at cell surface. So far, a number of cell-surface proteins have been reported to act as Ab receptors, but the molecular mechanism of the binding has remained unclear. Methods: Here, we used a multi-disciplinary approach combining super-resolution microscopy (SRM) and biochemical assays to measure the dynamics and kinetics of Ab-receptors interactions at a nanoscale level. We have used direct stochastic optical reconstruction microscopy (dSTORM) and structured illumination microscopy (SIM) to visualize directly the effect of cellular prion protein (PrP) and two other putative receptors on Ab aggregation process. SRM enabled us to distinguish oligomers, protofibrils and fibrils, and localize the receptor proteins that bind to them. Furthermore, we analyzed the effect of each of the receptors on Ab aggregation kinetics bymeasuring ThT fluorescence curves.Results: We observed a number of morphological differences between the Ab assemblies formed in presence and absence of PrP. Our data showed that Ab fibrils are shorter and more numerous when formed in presence of PrP. Moreover, our dSTORM images demonstrate that PrP binds selectively to the fast-growing end of fibrils, thereby accounting for the inhibitory effect on fibril elongation.We found that, PrP interacts with Ab oligomers and protofibril ends in a fashion similar to the fibrils ends. Amazingly, we have found that two other putative Abo receptors, Fcg receptor IIb (FcgRIIb) and Leukocyte immunoglobulin-like receptor; subfamily B2 (LilrB2), affect Ab polymerization kinetics and aggregate length in a manner very similar to PrP, while control proteins, such as calmodulin, have no effect. Conclusions: These results suggest a molecular model in which several different neuronal receptors, which are thought to transduce the neurotoxic effects of oligomeric Ab, all recognize a common structural motif that is present on the ends of elongation-competent Ab oligomers and fibrils. Blocking the interaction between Ab and its receptors may represent a viable therapeutic strategy for preventing Ab neurotoxicity.