Aging-induced Akt activation involves in aging-related pathologies and Aβ-induced toxicity

Multicellular signals are altered in the processes of both aging and neurodegenerative diseases, including Alzheimer's disease (AD). Similarities in behavioral and cellular functional changes suggest a common regulator between aging and AD that remains undetermined. Our genetics and behavioral approaches revealed the regulatory role of Akt in both aging and AD pathogenesis. In this study, we found that the activity of Akt is upregulated during aging through epidermal growth factor receptor activation by using the fruit fly as an in vivo model. Downregulation of Akt in neurons improved cell survival, locomotor activity, and starvation challenge in both aged and Aβ42-expressing flies. Interestingly, increased cAMP levels attenuated both Akt activation-induced early death and Aβ42-induced learning deficit in flies. At the molecular level, overexpression of Akt promoted Notch cleavage, suggesting that Akt is an endogenous activity regulator of γ-secretase. Taken together, this study revealed that Akt is involved in the aging process and Aβ toxicity, and manipulating Akt can restore both neuronal functions and improve behavioral activity during the processes of aging and AD pathogenesis.