XBP1 and PERK Have Distinct Roles in Aβ-Induced Pathology

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 beta-amyloid (A beta)-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 A beta 42 transgenic flies. Proteasome activity played a key role in this sequential activation. Furthermore, our study separated learning deficits from early degeneration in A beta-induced impairment by demonstrating that X-box binding protein 1 overexpression at an early stage reversed A beta-induced early death without affecting learning performance in the A beta 42 transgenic flies. PERK activation was determined to only enhance A beta 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 A beta pathogenesis and the possibility of using different ER stress effectors as reporters to indicate the status of disease progression.