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
- 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.
- 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.
- 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).