There are numerous types of pathological changes in human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND), including apoptosis of neurons. HIV-1 transactivator of transcription (Tat) protein, which is encoded by HIV-1, may promote apoptosis in HAND. Forkhead box O3 (FOXO3) is a multispecific transcription factor that has roles in many biological processes, including cellular apoptosis. The aim of this study was to determine whether FOXO3 is activated by HIV-1 Tat and to investigate its role in neuronal apoptosis in HAND. We employed tissue staining and related molecular biological experimental methods to confirm our hypothesis. The in vivo experimental results demonstrated that the expression of nuclear FOXO3 increased in the apoptotic neurons of the cerebral cortexes of rhesus macaques infected with simian human immunodeficiency virus (SHIV). The in vitro investigation showed that HIV-1 Tat activated FOXO3, causing it to move from the cytoplasm to the nucleus via the c-Jun N-terminal kinase (JNK) signaling pathway in SH-SY5Y cells. Moreover, FOXO3 down-regulated expression of the anti-apoptosis gene B-cell lymphoma 2 (Bcl-2) and up-regulated the expression of the pro-apoptosis gene Bcl-2-like 11 (Bim) after entering the nucleus, eventually causing cellular apoptosis. Finally, reduction of nuclear FOXO3 reversed cellular apoptosis. Our results suggest that HIV-1 Tat induces FOXO3 to translocate from the cytoplasm to the nucleus via the JNK signaling pathway, leading to neuronal apoptosis. Agents targeting FOXO3 may provide approaches for restoring neuronal function in HAND.

Alzheimer's disease (AD) and type 2 diabetes (T2D) are among the most prevalent chronic diseases affecting the aging population. Extensive research evidence indicates that T2D is a well-established risk factor for AD; however, the molecular mechanisms underlying this association have not been fully elucidated. Furthermore, how T2D may contribute to the progression of AD is a subject of extensive investigation. In this study, we compared the blood transcriptome of patients with mild cognitive impairment (MCI), AD, and advanced AD to those afflicted with T2D to unveil shared and unique pathways and potential therapeutic targets. Blood transcriptomic analyses revealed a positive correlation between gene expression profiles of MCI, AD, and T2D in seven independent microarrays. Interestingly, gene expression profiles from women with advanced AD correlated negatively with T2D, suggesting sex-specific differences in T2D as a risk factor for AD. Network and pathway analysis revealed that shared molecular networks between MCI and T2D were predominantly enriched in inflammation and infectious diseases whereas those networks shared between overt AD and T2D were involved in the phosphatidylinositol 3-kinase and protein kinase B/Akt (PI3K-AKT) signaling pathway, a major mediator of insulin signaling in the body. The PI3K-AKT signaling pathway became more significantly dysregulated in the advanced AD and T2D shared network. Furthermore, endocrine resistance and atherosclerosis pathways emerged as dysregulated pathways in the advanced AD and T2D shared network. Interestingly, network analysis of shared differentially expressed genes between children with T2D and MCI subjects identified forkhead box O3 (FOXO3) as a central transcriptional regulator, suggesting that it may be a potential therapeutic target for early intervention in AD. Collectively, these results suggest that T2D may be implicated at different stages of AD through different molecular pathways disrupted during the preclinical phase of AD and more advanced stages of the disease.