Introduction
Alzheimer’s Disease (AD) is a complex, aging-related neurological
illness that causes steady deterioration in cognitive ability and
ultimately leads to mortality (Wellen et al., 2010). In 2010, more than
30 million population was affected, and by 2050, it is expected that
number will rise to 106 million worldwide. AD is known to be the seventh
greatest reason for death in 2020 as well as 2021, affecting an
estimated 6.5 million persons aged 65 and more (Scarmeas et al., 2009).
The development of tau-mediated neurofibrillary tangles (NFTs) and the
accumulation of amyloid-beta (Aβ) plaques are the primary
pathophysiological marks of AD. The pathogenesis of AD is based on
neuroinflammation, oxidative stress, neuronal damage, loss of synapses,
and endoplasmic reticulum stress (ER) (Khan et al., 2021; Saklani et
al., 2022). Inflammation triggers the cellular stress system, which
further damages both cell function and the body’s metabolism in the
peripheral tissues (Prabhakar et al., 2022). However, these proceedings
are interconnected with Aβ oligomers and studies have shown that
oligomer enhances neuronal stress by peculiarly uplifting the tumor
necrosis factor α (TNF-α), eIF2α phosphorylation (eIF2α-P), reactive
oxygen species (ROS), and activating JNK/PKR signaling in the models of
AD (Bomfim et al., 2012; Ma et al., 2013; De Felice et al., 2014). The
prefrontal cortex and the hippocampus portion of the brain exhibit these
symptoms, which ultimately result in neuronal death along with the
deterioration of cognitive function. However, recent research has
demonstrated the involvement of metabolic dysfunction in various
neuro-degenerative illnesses, like; as AD, which worsens neurological
symptoms (Watson et al., 2005; Martin et al., 2009). Such metabolic
dysfunctions as the uncontrolled, gradual loss of weight as well as
impaired glucose tolerance are frequently seen in AD patients and have a
detrimental effect on prognosis due to a poorly understood cascade of
events (Cai et al., 2012). The transgenic mice with excessive Aβ
expression that had decreased glucose utilization demonstrated the
correlation between Aβ and metabolic dysfunction (Sharma et al., 2020).
In reaction to an unbalanced metabolic equilibrium, cells undergo a
well-defined physiological process called metabolic stress, which helps
the cells survive. For instance, the low energy level experienced during
exercise contributes to the development of harmful toxins and the
advancement of metabolic stress. These toxins promote the hormonal
release, the production of reactive oxygen species (ROS), hypoxia, as
well as cell swelling (Wellen et al., 2010). Also, metabolic stress is
allied with other diseases like obesity (Garg et al., 2021); aging (Khan
et al., 2022); circadian rhythm (Ahmad., 2020); autophagy (Kalra et al.,
2022); cardiomyopathy (Liu et al., 2017); inflammatory bowel disease
(Schoultz et al., 2011); diabetes (Garg et al., 2022); cognitive
impairment (Khan et al., 2021), etc. Numerous studies in AD suggest a
connection between Aβ oligomers and disease progression. They are also
thought to be neurotoxins that cause individuals to lose their memory
and synapse function (Gong et al., 2003; Xia et al., 2009). In this
review, we will discuss the correlation between metabolic stress and the
signaling pathway FOXO in Alzheimer’s disease for a therapeutic
approach.