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

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 Aβ1–42 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 Aβ1–42 formation and tau phosphorylation
via increased cathepsin B and AEP, providing a new molecular link
between AGEs and AD pathology.