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- W2010230275 abstract "Pathological accumulations of amyloid beta peptide (Abeta) and tau aggregates are critically implicated in Alzheimer's disease (AD) as initiators of the neurodegenerative cascade, while it is yet to be elucidated how these amyloidoses and downstream key processes interplay to be embodied in a self-perpetuating cycle leading to neurotoxicities. We here employed in vivo molecular imaging techniques for genetically engineered mice modeling AD to identify neurotoxic subspecies of Abeta and tau assemblies and their reciprocal links to neuroinflammation and other intermediate events in the cascade. Depositions of Abeta and tau fribrils in transgenic (Tg) mice expressing mutant amyloid precursor protein (APP) and tau were assayed by positron emission tomography (PET) with specific radioligands. Neurotoxic inflammation was visualized in these animals using PET tracers for 18-kDa translocator protein (TSPO). Formation of extracellular amyloid lesions enriched with N-terminally truncated and cyclyzed Abeta, AbetaN3pE, in APP Tg mice induced amyloid PET signals characteristic of AD brains, and was enhanced by knock-down of an Abeta-degrading endopeptidase, neprilysin. Meanwhile, Abeta aggregates in hippocampal neurons undetectable by amyloid PET strongly provoked TSPO-positive microgliosis and neuronal loss. Similarly, tau fibrillogenesis prior to the emergence of PET-positive inclusions in the hippocampus of tau Tg mice gave rise to massive TSPO signals and neuronal death. This TSPO-positive neuroinflammation was accompanied by upregulation of an AbetaN3pE-producing enzyme, glutaminyl cyclase (QC), indicating interlinks among Abeta and tau depositions and toxic inflammation mediated by QC. Circumvention of excessive TSPO rises led to effective removals of Abeta and tau assemblies in immunological treatments of Tg mice with cloned microglial implants and immunizations for these molecules. Among diverse amyloid-associated events investigated here, activation of calcium-dependent proteases, calpains, was demonstrated to influence the Abeta deposition and concurrent TSPO-positive gliosis by genetically manipulating levels of a natural calpain inhibitor, calpastatin, in APP Tg mice. Our data illustrate crucial roles of specific proteolytic pathways in the mutual crosstalk among amyloidogenesis, neurotoxic glia and disrupted calcium homeostasis in animal models. Low-order multimerization of Abeta and tau may trigger neurodegenerative deteriorations, and this notion would be tested in humans with the aid of radiotracers utilized in the present study." @default.
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- W2010230275 date "2010-07-01" @default.
- W2010230275 modified "2023-09-27" @default.
- W2010230275 title "S2-03-05: In vivo targeting of Abeta and tau amyloidogeneses, neuroinflammation, calcium-mediated neurotoxicity and their interplays" @default.
- W2010230275 doi "https://doi.org/10.1016/j.jalz.2010.05.289" @default.
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