Rac1 and Akt Exhibit Distinct Roles in Mediating Aβ-Induced Memory Damage and Learning Impairment

Accumulated beta-amyloid (A beta) in the brain is the hallmark of Alzheimer's disease (AD). Despite A beta accumulation is known to trigger cellular dysfunctions and learning and memory damage, the detailed molecular mechanism remains elusive. Recent studies have shown that the onset of memory impairment and learning damage in the AD animal is different, suggesting that the underlying mechanism of the development of memory impairment and learning damage may not be the same. In the current study, with the use of A beta 42 transgenic flies as models, we found that A beta induces memory damage and learning impairment via differential molecular signaling pathways. In early stage, A beta activates both Ras and PI3K to regulate Rac1 activity, which affects mostly on memory performance. In later stage, PI3K-Akt is strongly activated by A beta, which leads to learning damage. Moreover, reduced Akt, but not Rac1, activity promotes cell viability in the A beta 42 transgenic flies, indicating that Akt and Rac1 exhibit differential roles in A beta regulating toxicity. Taken together, different molecular and cellular mechanisms are involved in A beta-induced learning damage and memory decline; thus, caution should be taken during the development of therapeutic intervention in the future.

Automated summary

Accumulated beta-amyloid in the brain is the hallmark of Alzheimer's disease, and recent studies have shown that it triggers memory impairment and learning damage through different molecular signaling pathways at different stages. Caution should be taken in future therapeutic interventions due to the involvement of different molecular and cellular mechanisms in A beta-induced learning damage and memory decline.