Abstract

OBJECTIVES:TTP488, an antagonist of the receptor for advanced glycation end-products, was evaluated as a potential treatment for patients with mild-to-moderate Alzheimer’s disease (AD). However, the mechanism underlying the protective action of TTP488 against AD has not yet been fully explored.METHODS:Healthy male rats were exposed to aberrant amyloid β (Aβ) 1-42. Lipopolysaccharide (LPS) and the NOD-like receptor family pyrin domain containing 1 (NLRP1) overexpression lentivirus were injected to activate the NLRP1 inflammasome and exacerbate AD. TTP488 was administered to reverse AD injury. Finally, tofacitinib and fludarabine were used to inhibit the activity of Janus tyrosine kinase (JAK) and signal transducer and activator of transcription (STAT) to prove the relationship between the JAK/STAT signaling pathway and TTP488.RESULTS:LPS and NLRP1 overexpression significantly increased the NLRP1 levels, reduced neurological function, and aggravated neuronal damage, as demonstrated by the impact latency time of, time spent by, and length of the platform covered by, the mice in the Morris water maze assay, Nissl staining, and immunofluorescence staining in rats with AD.CONCLUSIONS:TTP488 administration successfully reduced AD injury and reversed the aforementioned processes. Additionally, tofacitinib and fludarabine administration could further reverse AD injury after the TTP488 intervention. These results suggest a new potential mechanism underlying the TTP488-mediated alleviation of AD injury.

Highlights

  • Alzheimer’s disease (AD), largely considered to be caused by aberrant amyloid b (Ab) accumulation and the most common cause of dementia, is clinically characterized by a progressive and irreversible loss of cognitive functions and is pathologically characterized by the loss of synapses and neuronal death [1,2]

  • Ab is known to bind to the receptor for advanced glycation end-products (RAGE), an immunoglobulin supergene family member expressed on multiple cell types in the brain and periphery, which leads to sustained inflammatory states that play a crucial role in AD [3,4]

  • We focused on the TTP488-mediated alleviation of AD injury, which occurs via the inhibition of NOD-like receptor family pyrin domain containing 1 (NLRP1) inflammasome activation, using lipopolysaccharide (LPS) and an NLRP1 overexpression lentivirus to suppress the effects of TTP488

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Summary

Introduction

Alzheimer’s disease (AD), largely considered to be caused by aberrant amyloid b (Ab) accumulation and the most common cause of dementia, is clinically characterized by a progressive and irreversible loss of cognitive functions and is pathologically characterized by the loss of synapses and neuronal death [1,2]. Neuroinflammation plays an important role in the development and progression of AD. Received for publication on August 19, 2020. Accepted for publication on November 5, 2020

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