Early Aβ42 Exposure Causes Learning Impairment in Later Life

Amyloid cascade hypothesis proposes that amyloid β (Aβ) accumulation is the initiator and major contributor to the development of Alzheimer's disease (AD). However, this hypothesis has recently been challenged by clinical studies showing that reduction of Aβ accumulation in the brain does not accompany with cognitive improvement, suggesting that therapeutically targeting Aβ in the brain may not be sufficient for restoring cognitive function. Since the molecular mechanism underlying the progressive development of cognitive impairment after Aβ clearance is largely unknown, the reason of why there is no behavioral improvement after Aβ clearance remains elusive. In the current study, we demonstrated that transient Aβ expression caused learning deficit in later life, despite the accumulated Aβ was soon being removed after the expression. Early Aβ exposure decreased the cellular expression of XBP1 and both the antioxidants, catalase, and dPrx5, which made cells more vulnerable to oxidative stress in later life. Early induction of XBP1, catalase, and dPrx5 prevented the overproduction of ROS, improved the learning performance, and preserved the viability of cells in the later life with the early Aβ induction. Treating the early Aβ exposed flies with antioxidants such as vitamin E, melatonin and lipoic acid, after the removal of Aβ also preserved the learning ability in later life. Taken together, we demonstrated that early and transient Aβ exposure can have a profound impact on animal behavior in later life and also revealed the cellular and molecular mechanism underlying the development of learning impairment by the early and transient Aβ exposure.