Abstract:
Endoplasmic reticulum (ER) dysfunction has an imperative role in numerous
neurological disorders, including, multiple sclerosis, amyotrophic lateral sclerosis, prion
diseases and Alzheimer's disease. In disease state, protein misfolding in the endoplasmic
reticulum (ER) initiates a stress response, the unfolded protein response (UPR) in
neurons due to a rise in proteotoxicity. Although there is an immense effort to explore the
pathogenesis of ER dysfunction, unfortunately the exact mechanism is still unclear.
Therefore as a preliminary initiative the present study was conducted to investigate one
of the aspects of this complex molecular event. The study elucidates the molecular
relationship between the unfolded protein response (UPR) during ER stress and
aggregation of Amyloid beta that ultimately results in neuronal toxicity leading to
neurodegeneration. The experimental animals, Balb/c mice were divided into 4 groups
(n=15, each). Dithiothreitol (DTT) was used to induce UPR following ER stress. An
optimum dose of DTT (75 mg/kg) was administered after every 24 hours. Histological
examination showed a marked formation of amyloid beta plaques in the cortex and
hippocampus sections of mice brain along with atrophied neuronal morphology, after 48
to 72 hours of treatment. Differential proteomic analysis was carried out using SDSPAGE
followed by ESI-QTOFMS/MS identification. The analysis revealed 10
differentially expressed cortical and hippocampal proteins, involved in various cellular
and metabolic pathways. The gene expression analysis performed by Real-Time PCR
determined the transcriptional expression of Activating Transcription Factor 6 (ATF6), a
UPR regulating protein, and Amyloid Precursor Protein (APP) isoforms (common, 695
770). Furthermore, the immunohistochemical analysis also revealed the nuclear
localization of ATF6 during ER stress. In conclusion, the findings of the present work
may contributes to the existing pool of knowledge and provide a better understanding of
complex molecular association of UPR with AB neurotoxicty that may help in further
