The correlation between obesity and cognitive decline went unstudied for
a very long period. These days, growing epidemiological evidence
supports a significant connection between these illnesses. Many
metabolic pathways in skeletal muscle are linked to obesity and result
in insulin resistance. Thus, aberrant PI3K/AKT-mediated glucose
transport and glycogen synthesis contribute significantly to obesity.
FoxO proteins, notably FoxO1, are the primary target of Akt and regulate
the body’s energy homeostasis. FoxO1 and PGC1α coordinately promote
fatty acid oxidation and gluconeogenesis through regulating gene
expression (Gudala et al., 2013). FoxO1 simultaneously activates AKT to
boost energy production while inhibiting mTORC1 to limit protein and
lipid production. The PI3K/AKT signalling pathway encourages lipid
production and suppresses lipolysis. Moreover, an AKT-independent,
PI3K-dependent mechanism regulates adipocyte lipolysis by directly
controlling PKA, whereas AKT regulate the FoxO1 pathway (Huang et al.,
2018). In reality, people with obesity or other metabolic illnesses have
almost a two-fold increased chance of getting AD, according to research
using a meta-analysis method (Gudala et al., 2013). Having a midlife
weight problem raises the chance of AD and dementia by 35, 33, as well
as 26%, respectively; obesity is associated with an even higher risk
(Anstey et al., 2011). More research is still needed because molecular
processes causing this co-morbidity along with the impact of fats
buildup on neurodegenerative progression are not understood well.
Obesity may cause AD through a variety of mechanisms, such as 1)
increased cleaving of amyloid precursor protein (APP) as well as Aβ
generation, 2) formation of pro-inflammatory cytokines along with
adipokines, 3) additional oxidative stress formation as well as
dysfunction of mitochondria, 4) insulin resistance via FOXO inhibition,
5) breakdown of the BBB, and 6) production of ceramides.
Obesity and AD are linked by a complicated, multifaceted process (Picone
et al., 2020). According to an investigation of FOXO expression in the
mouse brain’s various regions till 100 weeks of age, FOXO1 is primarily
present in the hippocampal region relative to total brain expression,
whereas FOXO3a is expressed in the cerebellum in a high amount.
Furthermore, a diet with a high amount of fat dramatically affects the
expression of FOXOs in C57BL/6 mice, at least if fed for 46 weeks.
Surprisingly, FOXO3a mRNA levels dropped massively in various regions of
the brain like the cerebellum along with the occipital cortex whereas
FOXO1 mRNA levels modestly elevated in the CNS of these animals (Zemva
et al., 2012). According to in vivo findings, FOXO3a is
downregulated by chronic elevation of IR/IGF-1R signalings in neurons
both in vivo as well as in vitro . This is established by
SH-SY5Y neuroblastoma cells of humans that firmly overexpress Insulin
receptor substrate 2 (IRS-2) and exhibit phosphorylated AKT at Ser473
along with significantly reduced FOXO3a expression. Research is still
being done to determine the precise chemical mechanism by which this
signaling cascades control the various expressed FOXOs. Data collected
from the line of cells, however, may not accurately represent in
vivo environment. Lowered expression of FOXOs found in high-fat diet
mice is implicated in the etiology of intellectual impairment related to
obesity appears logical or else given that a reduction in the signaling
of IRS-2 causes FOXO-facilitated transcriptions. Therefore,
transcription which is controlled by insulin receptor (IR) or
insulin-like growth factor 1 (IGF-1) may contribute to the
pathophysiology of at least AD. It is not yet apparent, nevertheless,
whether alterations in the signaling pathway IR/IGF-1 associated with
neurons directly cause neurodegeneration or a form of counter-regulation
(Moll et al., 2012).
One of the main processes driving Aβ-induced cell death of people with
recognized AD is oxidative stress-facilitated stimulation of FOXO.
Particularly, Aβ promotes the production of ROS along with the proteins
which are oxidized, leading to the liberation of H2O2 which is
neurotoxic. Curiously, uprooted expression of p66ShcS36A lowers the
phosphorylation of FOXOs, avoiding the death of cells by oxidation in
response to the toxicity of Aβ. Whereas, FOXO transcription factors are
connected to IGF1, which encodes hormones either paracrine or autocrine.
Deleting the FOXO homolog DAF-16 improves the developmental, lifespan,
and metabolic abnormalities caused by mutating the homolog DAF-2 of the
IGF1 receptor in Caenorhabditis worms (Matsuzaki et al., 2022). Further
evidence that IGF1 regulates the FOXO signaling pathway comes from the
fact that FOXOs are the targets for transcription and the rapid
initiation of gluconeogenesis mediated by IGF1, which is inhibited by
nuclear rejection stimulated by insulin. Additionally, these results are
in line with our findings that FOXO signalings are drawn in the
pathophysiology of AD and that low IGF1 expression is a contributing
factor. Conversely, if FOXO transcriptional factor is enhanced, it may
be a viable target for reducing obesity linked to AD (Kang et al.,
2020).
Accumulation of the Aβ peptide is a significant neuropathological event
in AD. Numerous genes control the synthesis and elimination of Aβ in the
brain. It is necessary to fine-tune the expression levels of these genes
in the brain to maintain a balanced level of Aβ under physiological
circumstances (Chen et al., 2013). It has been discovered that AD gene
dysregulation either raises the risk of AD or quickens the progression
of the disease. Discovering the regulatory components and
transcriptional factors that control the expression of these genes has
advanced significantly in recent years (Chen et al., 2013). It is well
known that the beginning and development of AD are accompanied by
pervasive transcriptional alterations. It is still unclear, however,
whether such changes are the result of nonspecific dysregulation and
multisystem failure or rather are part of a coordinated response to
cellular dysfunction because of the multifactorial nature of this
neurodegenerative disorder and its complicated relationship with aging.
A study on the identification of transcriptional alterations associated
with aging and AD was conducted on a meta-analysis of over 1,600
microarrays from human central nervous system tissues. Their method of
identifying a transcriptional signature of AD identified a collection of
genes that were down-regulated and encoded proteins that were metastable
to aggregation (Ciryam et al., 2016). They found a modest number of
biochemical pathways using this method, most notably oxidative
phosphorylation, which were enhanced in proteins prone to aggregation in
control brains and encoded by genes down-regulated in AD. The findings
revealed that when protein homeostasis is harmed in AD, the
down-regulation of a metastable subproteome may assist prevent abnormal
protein aggregation (Ciryam et al., 2016). Through the Foxo3
transcriptional factor, deregulated Cdk5 results in neurotoxic A peptide
processing and cell death, two characteristics of AD, in hippocampus
cells, primary neurons, and an AD mouse model. In lysates from brain
tissue, Foxo3 was discovered to be a direct substrate of
Cyclin-dependent kinase 5 (Cdk5) by a study using a novel chemical
genetic screen. Foxo3 is immediately phosphorylated by Cdk5, increasing
its concentration and nuclear translocation. Cells were initially
protected from the resulting oxidative stress by nuclear Foxo3 by
upregulating MnSOD. Foxo3, on the other hand, elevated Bim and FasL
after prolonged exposure, leading to cell death. Their levels were
similarly elevated by active Foxo3 in a phosphorylation-dependent
fashion. By producing phosphorylation-resistant Foxo3 or by depleting
either Cdk5 or Foxo3, these events were fully suppressed, demonstrating
a critical function for Cdk5 in controlling Foxo3 (Shi et al., 2016).
These findings were corroborated by an AD animal model, which showed
elevated levels and nuclear localization of Foxo3 in hippocampus neurons
before neurodegeneration and the development of A plaques, showing that
this phenomenon is a very early stage in the pathogenesis of AD. These
findings reveal that the phospho-regulation of Foxo3 by Cdk5 can
activate several genes that promote neuronal death and abnormal A
processing, accelerating the development of neurodegenerative diseases.
Consequently, one potential target for the neuroprotective effects could
be the control of foxo3 (Shi et al., 2016). Cellular homeostasis depends
on maintaining a balanced proteome, and proteostasis loss is linked to
tissue malfunction and neurodegenerative diseases. A program of
autophagy genes regulated by the transcription factor FOXO3 was found in
a study that examined the transcriptional programs necessary for neural
stem and progenitor cell (NSPC) activity. By using genomic techniques,
it was discovered that FOXO3 functionally controls the induction of
autophagy in adult NSPCs by directly binding a network of
autophagy-related target genes. Interestingly, aggregates build up in
NSPCs when FOXO activity is absent, and TOR (target of rapamycin)
inhibition reverses this effect. Unexpectedly, increasing FOXO3 induces
protein aggregates to form but does not speed up their breakdown. The
findings revealed a genetic network that is crucial for maintaining a
healthy mammalian stem cell pool to sustain lifelong neurogenesis and is
directly regulated by a significant transcriptional regulator of aging
(Audesse et al., 2019).
The underlying cause of morbidity, as well as mortality in the aging
population, is AD (Salminen et al., 2009). Regulating metabolic
disturbances may lessen the impact of metabolic stress and related
diseases including diabetes, obesity, and liver injury on AD, as these
pathologies can be effectively treated via FOXO signaling (Shi et al.,
2016). The FOXO protein controls the oxidative stress response, tissue
metabolism, glucose homeostasis, and autophagy—all of which are
included in AD’s pathophysiology associated with metabolic ailments. An
underlying biological relationship between AD and metabolic disorders
may exist since FOXOs are important in these conditions (Kang et al.,
2020). To comprehend the part played by FOXO proteins in AD, and
metabolic illnesses and also to guide the development of new treatments,
a thorough knowledge of these proteins under various situations of the
anatomy along with pathology at molecular extent is necessary. Since AD
linked with metabolic disorders currently lacks a curative treatment,
researchers and clinicians must continue to develop
innovative strategies to enhance
clinical outcomes based on the recently identified associations and
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