6 research outputs found
Advanced glycation end products modulate amyloidogenic APP processing and Tau phosphorylation: a mechanistic link between glycation and the development of Alzheimerâs 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 Aβ 1-42 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 Aβ 1-42 formation and tau phosphorylation via increased cathepsin B and AEP, providing a new molecular link between AGEs and AD pathology. </p
Advanced glycation end products modulate amyloidogenic APP processing and Tau phosphorylation: a mechanistic link between glycation and the development of Alzheimerâs disease
Advanced
glycation end products (AGEs) are implicated in the pathology
of Alzheimerâs 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<sub>1â42</sub> 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<sub>1â42</sub> formation and tau phosphorylation
via increased cathepsin B and AEP, providing a new molecular link
between AGEs and AD pathology
Immune response to chemically modified proteome
Both enzymatic and nonenzymatic PTMs of proteins involve chemical modifications. Some of these modifications are prerequisite for the normal functioning of cell, while other chemical modifications render the proteins as âneoâselfâ antigens, which are recognized as ânonâselfâ leading to aberrant cellular and humoral immune responses. However, these modifications could be a secondary effect of autoimmune diseases, as in the case of type I diabetes, hyperglycemia leads to protein glycation. The enigma of chemical modifications and immune response is akin to the âchickâandâeggâ paradox. Nevertheless, chemical modifications regulate immune response. In some of the wellâknown autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis, chemically modified proteins act as autoantigens forming immune complexes. In some instances, chemical modifications are also involved in regulating immune response during pathogen infection. Further, the usefulness of proteomic analysis of immune complexes is briefly discussed