Advanced Glycation End Products Modulate Amyloidogenic APP Processing and Tau Phosphorylation: A Mechanistic Link between Glycation and the Development of Alzheimer’s Disease

Abstract

Advanced glycation end products (AGEs) are implicated in the pathology of Alzheimer's disease (AD), as they induce neurodegeneration following interaction with the receptor for AGE (RAGE). This study aimed to establish a mechanistic link between AGE-RAGE signaling and AD pathology. AGE-induced changes in the neuro2a proteome were monitored by SWATH-MS. Western blotting and cell-based reporter assays were used to investigate AGE-RAGE regulated APP processing and tau phosphorylation in primary cortical neurons. Selected protein expression was validated in brain samples affected by AD. The AGE-RAGE axis altered proteome included increased expression of cathepsin B and asparagine endopeptidase (AEP), which mediated an increase in Aβ formation and tau phosphorylation, respectively. Elevated cathepsin B, AEP, RAGE, and pTau levels were found in human AD brain, coincident with enhanced AGEs. This study demonstrates that the AGE-RAGE axis regulates Aβ formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology.

Quercetin is protective against short‐term dietary advanced glycation end products intake induced cognitive dysfunction in aged ICR mice

“…Existing evidence suggest that AGEs might affect Aβ and tau pathology (Batkulwar et al, 2018). For example, more than 20 years ago, in the brains of patients with AD, AGEs has been detected to be co-localized with senile plaques or NFTs (Pappolla, Alzofon, McMahon, & Theodoropoulos, 1990;Vitek et al, 1994).…”

The Roles of the NLRP3 Inflammasome in Neurodegenerative and Metabolic Diseases and in Relevant Advanced Therapeutic Interventions

“…The aforementioned studies have provided significant insights into the role NLRP3 inflammasomes play in AD progression; therefore, detailed investigation into the mechanism of inflammasome activation and its contribution to neuroinflammation will be worthwhile. Moreover, Aβ accumulation induces microglial activation via advanced glycation end product (AGE) pathways and TLR [151,152]. All these results support the usefulness of NLRP3 inflammasomes and of their downstream regulators in the identification of protein aggregates or peptides that can drive the pathogenesis of such diseases as systemic amyloidosis, prion diseases, AD, and T2D.…”

Cognitive dysfunction: A growing link between diabetes and Alzheimer's disease

“…High blood glucose levels leads to accumulation of AGE products which is found to play a role in many microvascular & macrovascular complications of diabetes (Goldin, Beckman, Schmidt, & Creager, 2006;(Yozgatli et al, 2018). Moreover, AGE products were found to be involved in the regulation of Aβ plaque and tau phosphorylation (Batkulwar et al, 2018). To prevent AGE products induced oxidative stress and cytotoxicity, vanillin was found to be successful in an in vitro study (Iannuzzi et al, 2017).…”