Receptor for advanced glycation endproduct modulators: a new therapeutic target in Alzheimer’s disease

Abstract

Introduction: Reduction in the deposition of amyloid β (Aβ) has been the primary target for Alzheimer’s disease (AD) therapeutics recently, but in clinical trials this approach has generally been unsuccessful. A common feature of AD pathology is a complex inflammatory component that could be a target for treatment. One feature of this inflammation has been the involvement of the receptor for advanced glycation endproducts (RAGE), whose ligands include advanced glycation-endproduct-modified proteins as well as lipids and Aβ, which are found at elevated levels in AD brains.

Areas covered: In this article, the authors describe the key features of RAGE and how it could have a role in AD pathogenesis. They also summarize experimental animal and clinical data that demonstrate the therapeutic effect of RAGE inhibition and consider what these findings mean for human disease.

Expert opinion: RAGE has multiple ligands, including Aβ, that are increased in AD brains. Inhibiting RAGE-ligand interactions without activating receptor signaling can reduce multiple pathological pathways relevant for AD. Several RAGE inhibitors and modulators are now being tested as therapeutics for AD. Recent Phase II studies have established the good safety and tolerability of TTP448 with some evidence of positive benefit at lower dose. This suggests that further studies are required.

Keywords:

• Alzheimer’s disease
• β amyloid
• clinical trials
• inflammation
• receptor for advanced glycation endproducts

Declaration of interest

The authors are supported by the Banner Sun Health Research Institute and the National Institutes of Aging grant AG 019610. M Sabbagh is on the advisory board for Eli Lilly & Co., Piramal, Muses Laboratory and Biogen Idec. They also have clinical trial contracts from Avid, Eli Lilly & Co., Genentech, Roche, Merck & Co., Functional Neuromodulation, AstraZeneca, Neuronix, Navidea, DART and Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Notes

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