Fly study explores molecular mechanisms of A-beta-induced pathology

Cheng KC, Chiang HC. XBP1 and PERK Have Distinct Roles in Aβ-Induced Pathology. Mol Neurobiol. 2018 Sep;55(9):7523-7532. doi:10.1007/s12035-018-0942-y. PMID: 29427089.

The abstract: "Endoplasmic reticulum (ER) stress triggers multiple cellular signals to restore cellular function or induce proapoptosis that is altered in the brains of patients with Alzheimer's disease (AD). However, the role of ER stress in β-amyloid (Aβ)-induced AD pathology remains elusive, and data obtained from different animal models and under different experimental conditions are sometimes controversial. The current study conducted in vivo genetic experiments to systematically examine the distinct role of each ER stress effector during disease progression. Our results indicated that inositol-requiring enzyme 1 was activated before protein kinase RNA-like endoplasmic reticulum kinase (PERK) activation in Aβ42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in Aβ-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed Aβ-induced early death without affecting learning performance in the Aβ42 transgenic flies. PERK activation was determined to only enhance Aβ-induced learning deficits. Moreover, proteasome overactivation was determined to delay PERK activation and improve learning deficits. Altogether, the findings of this study demonstrate the complex roles of ER stress during Aβ pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression."