Methodology:
A systematic literature review of Bentham, Scopus, PubMed, Medline, and EMBASE (Elsevier) databases was carried out with the help of the keywords like Alzheimer’s Disease; FOXO; Liver; Diabetes; Obesity; Oxidative stress. The review was conducted using the above keywords to understand the Correlation between Metabolic Disorders and FOXO Signaling in AD: A Therapeutic Approach.
Role of FOXO Protein in Alzheimer’s Disease
The mammalian forkhead transcription factors of the O class are known as FOXOs. It has four components: FOXO1, FOXO3, FOXO4, and FOXO6, which are broadly distributed throughout the body. Nearly all tissues express FOXO1 and FOXO3, although FOXO4 is expressed in muscles, colon tissue, kidney, brain, and liver, and FOXO6 in the liver (van der Vos et al., 2011). FOXOs do the transcriptional regulation of the target genes. Apoptosis, cell division and differentiation, oxidative stress, metabolism, and lifespan are among the physiological processes that the FOXO proteins are adept at controlling (Jünger et al., 2003; Puig et al., 2003; Giannakou et al., 2004; Hwangbo et al., 2004). Since the modulation of cellular response to oxidative stress is the known function of FOXO protein, it can be related to AD because oxidative stress plays a substantial part in the pathophysiology of AD (Zhao et al., 2013). A study examined the physical interactions between FOXO and human cells that have been exposed to the domain of amyloid precursor protein (AICD) intracellularly. Following oxidative stress, AICD moved sideways with FOXO from the cytoplasm to the nucleus as well as served as a co-factor of transcription for FOXO (Hwangbo et al., 2004). Overall, this promotes the activation of the apoptotic gene Bim, which activates the machinery that causes cells to die (Wang et al., 2014). Since insulin activity is influenced by oxidative stress and the FOXO transcriptional factor, FOXO may have a connection between insulin resistance and AD. The FOXO protein may be responsible for the ongoing production of ROS brought on by hyperglycemia, which in turn impairs Wnt signaling and increases the creation of amyloid plaques and hyperphosphorylated tau. Wnt inhibition may also be responsible for the FOXO protein’s ongoing activation, which promotes apoptosis along with neuronal death (Manolopoulo et al., 2010). The treatment of neurodegenerative illnesses may benefit from targeting these transcriptional factors. Throughout AD, it may be suitable for the FOXO factor to be expressed often in the neurological system (Greer et al., 2005). FOXO3A is enormously expressed in the brain region (Shi et al., 2016) and also controls pathways of cell death of apoptosis, therefore resulting in cell survival in oxidative stress (Salih et al., 2008). It is well known that the overexpression of miR-132 and miR-212 has neuroprotective properties against oxidative stress. Additionally, a study revealed that miR-132 and miR-212 control cell viability via all important AKT components, including FOXO3A (Wong et al., 2013). It is also believed that FOXO3A controls the chemicals that fight oxidation. The FOXO target gene produces the protective brain proteins selenoprotein-P and manganese-superoxide dismutase (Bellinger et al., 2008). Another study demonstrated a correlation between the levels of serum FOXO3A and tau, and that FOXO3A declines with worsening cognitive impairment. The reduced levels of FOXO3A might be a potentially useful novel marker for the earlier detection of AD and for effective treatment intervention to stop further decline (Pradhan et al., 2020). In response to apoptosis-related stimuli, activated FOXO3A factor can upregulate some different genes. According to studies, when NGF (nerve growth factor) is deprived, the overexpression of FOXO transcription factors induces BIM expression and promotes the death of sympathetic neurons in a BIM-dependent manner (Sanphui et al., 2013). In a primary neuron culture from a mouse brain, a contrary connection between FOXO3A activation and cerebral Aβ amyloidosis was observed. Calorie restriction reduced the amyloid neuropathology associated with AD by activating the I/R signaling pathway, which causes FOXO3A to become hyperphosphorylated (Qin et al., 2008).
Pathophysiological Mechanisms of FOXO in Alzheimer’s Disease
  1. Oxidative stress: It is a significant contributor to insulin resistance (InsRes), diabetes complications, and the etiology of AD. There may be a connection between AD and FOXO transcription factors because they are involved in the physiological response to oxidative stress (Manolopoulos et al., 2010). In the pathogenesis of InsRes, AD, and other metabolic illnesses, oxidative stress is frequently present (Fig 1). Additionally, FOXO proteins are essential for controlling oxidative stress, apoptosis, and the regulation of glucose and energy homeostasis in insulin-sensitive tissues. Oxidative stress causes FOXO activation, which, for instance, increases β-catenin co-binding and blocks Wnt to increase the transcription of antioxidant enzymes (Rehni et al., 2008; 2010). However, GSK-3 (Glycogen synthase kinase 3) gets activated as a result of Wnt inhibition (Jope et al., 2004). Accordingly, neuronal degeneration and neurofibrillary tangles (NFT) are connected to increased levels of GSK-3 (Yamaguchi et al., 1996; Ishizawa et al., 2003). Increased GSK-3 activity raised Aβ production (Phiel et al., 2003), neuronal death (Hooper et al., 2008), and increased tau protein phosphorylation (Brewster et al., 2006). Prolonged FOXO activation may increase the system’s susceptibility to apoptosis rather than improve its ability to create antioxidants. In humans, higher JNK activity is connected to FOXO activity which would activate various receptors and might increase the amount of intracellular ROS produced. Due to the vicious cycle, this causes, oxidative stress-induced apoptosis is induced and prolonged FOXO activity is encouraged (Valenti et al., 2008; Martin et al., 2006).Figure 1: FOXO response to oxidative stress a) under normal conditions, wingless proteins (Wnt) inactivate GSK-3 through disheveled (dvl) and promote β-catenin accumulation in the nucleus, thus activating transcription factors of the T-cell factor family (TCF). (b) in the status of oxidative stress, Wnt is inhibited leading to the disinhibition of GSK-3, which in turn, promotes τ protein phosphorylation. The available β catenin now preferably binds to FOXO proteins, thus upregulating the transcription of genes. In the case of prolonged FOXO activity, apoptosis is initiated and leads to neuronal degeneration.
  2. Impaired Autophagy and processing of amyloid precursor protein (APP) : The produced type 1 integral membrane protein, known as APP, is first elated to the cell surface, where it can also be taken up by early endosomes or sliced by the sheddase-secretase Disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) (Claeysen et al., 2012). The APP protein can then be delivered in one of three ways: (i) by recycling back to the cell surface; (ii) through the retrograde endosome-to-Golgi pathway; or (iii) to the late endosome-lysosome degradation pathway (O’Brien and Wong, 2011; Claeysen et al., 2012; Rajendran and Annaert, 2012; Seaman, 2012). It’s fascinating to note that beta-site APP cleaving enzyme 1 (BACE1) and presenilin (PS)/γ-secretase, two APP processing enzymes, are likewise transported through the trans-Golgi network (TGN), early endosomes, and late endosomes (Claeysen et al., 2012; Tan and Evin, 2012). It is currently believed that the TGN and the acidic endosomal compartments are where amyloid peptides are generated (De Strooper, 2010). In the affected regions of AD brains, Vacuolar protein sorting ortholog 35 (VPS35) and Vacuolar protein sorting-associated protein (VPS26) had considerably decreased protein levels (Small et al., 2005). The generation of amyloid is increased by any deficiency in the carrier proteins along the endosome-TGN route (Bonifacino and Hurley, 2008; Burd, 2011). This demonstrates that APP and its cleaving enzymes may relocate to acidic endosomal compartments, boosting the synthesis of amyloid- and subsequently its exocytosis, if the capacity to transport from the endosomes to the TGN is compromised (Sullivan et al., 2011). Numerous studies have shown that different types of transcription factors under different signaling pathways, such as the FOXO signaling, the insulin/growth factor pathway, as well as nutrient-sensing signaling through the mTOR- and Akt-dependent pathways, tightly regulate the expression levels of genes related to autophagy (Omata et al., 2014; De Matteis and Luini, 2008). But Sirt1 is a sensor of caloric restriction to promote autophagy by deacetylation of FOXO and also control the activation of autophagy through the suppression of insulin signaling, which results in TOR inhibition. (Buxbaum et al., 1994; Grewal et al., 2019). The expression of autophagy-related genes is tightly regulated by many factors, including aging, FOXO signaling, sirtuin signaling, TOR signaling, APP processing, and autophagy activity itself (Micaroni, 2010).Figure 2: FOXO role in autophagy. AMPK, AKT, MAPK, and SIRT1 are activated via hypoxia, insulin receptor, and ROS respectively which phosphorylates FOXO and causes autophagy and eventually Alzheimer’s disease.
  3. Inflammation
In AD, neuroinflammation is seen as a powerful propeller. Growing data suggested that activated microglia are accountable for the advancement of AD because they can generate proinflammatory cytokines such as IL-1β, IL-6, and TNF-α as well as harm the neurons (Khan et al., 2022). Microglia are classified as having a ”homostatic function molecule” (M0), ”pro-inflammation effects” (M1), and ”anti-inflammatory effects” (M2) (Khan et al., 2022; Khan et al., 2018). The interactions of M1 and M2 microglia in the CNS control inflammation (Fig 2). While the PI3K/AKT/FOXO3a signaling pathway may have a significant role in the inflammatory response. The progression of AD is marked by an inflammatory response caused by numerous variables, including FOXO (Wang et al., 2020).