Pathological Impact of Endoplasmic Reticulum Stress on Neuronal Degeneration in Alzheimer’s and Parkinson’s Disease Models
Background: Alzheimer's disease (AD) and Parkinson's disease (PD) are distinct neurodegenerative disorders characterized by the accumulation of misfolded proteins—amyloid-beta (Aβ) and α-synuclein, respectively. Emerging evidence suggests that endoplasmic reticulum (ER) stress and the subsequent Unfolded Protein Response (UPR) may represent a common pathogenic pathway. However, a direct comparative analysis of the temporal progression and pathological contribution of ER stress in both diseases is lacking. Methodology: We used the 5xFAD transgenic mouse model for AD and the neurotoxin-based MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) model for PD. Brain tissues from the hippocampus (AD) and substantia nigra (PD) were collected at progressive disease stages (3, 6, and 9 months for 5xFAD; 1, 3, and 7 days post-MPTP injection) alongside age-matched wild-type controls. Key UPR markers (GRP78, p-PERK, XBP1s, CHOP) and neuronal degeneration markers (NeuN, Tyrosine Hydroxylase [TH]) were quantified using Western blotting and immunohistochemistry. Apoptosis was assessed via TUNEL staining. Results: In both 5xFAD and MPTP models, the ER chaperone GRP78 and the UPR initiator p-PERK were significantly elevated at the earliest time points, preceding significant neuronal loss. As the diseases progressed, downstream pro-apoptotic UPR marker CHOP became robustly upregulated. Critically, a strong positive correlation was found between CHOP expression levels and the degree of neuronal loss (loss of NeuN-positive cells in hippocampus, r = 0.89, p < 0.001; loss of TH-positive cells in substantia nigra, r = 0.92, p < 0.001). Immunohistochemical analysis confirmed the co-localization of CHOP in degenerating neurons. Conclusions: Our findings demonstrate that ER stress is not only an early and sustained pathological feature in both AD and PD models but also that its pro-apoptotic signaling directly correlates with the severity of neuronal degeneration. This positions the UPR, particularly the PERK-CHOP axis, as a critical, convergent mechanism of neurotoxicity, suggesting that therapeutic strategies targeting ER stress may have broad applicability across multiple proteinopathies.