Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits

Bansal, Seema; Agrawal, Madhunika; Mahendiratta, Saniya; Kumar, Subodh; Arora, Sangeeta; Joshi, Rupa; Prajapat, Manisha; Sarma, Phulen; Prakash, Ajay; Chopra, Kanwaljit; Medhi, Bikash

doi:10.1111/fcp.12677

Cited by 4 publications

(4 citation statements)

References 52 publications

(54 reference statements)

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“…STZ injected into an animal through the intraperitoneal and intracerebroventricular routes was able to reduce the cognitive behavior and increase the aggregation and deposition of amyloid beta oligomers, as well as increase the total tau protein and change the phosphorylation/total tau level ratio. Other alterations, such as a neuroinflammation, oxidative stress, and biochemical changes, have also been observed in the brain ( Kamat, 2015 ; Sun et al, 2018 ; Bagaméry et al, 2020 ; Bansal et al, 2021 ; Figure 4 ).…”

Section: Different Agents Used For Induction Of Alzheimer Diseasementioning

confidence: 83%

“…Indeed, activation of this receptor leads to the production of different inflammatory mediators. LPS-induced inflammation exacerbates tau pathology through cdk5 kinase activity ( Sun et al, 2006 ), resulting in amyloid beta deposition, as observed in both in vitro and in vivo studies ( Bansal et al, 2021 ). Astrocytes are major players in the development of diverse neurodegenerative diseases.…”

Section: Different Agents Used For Induction Of Alzheimer Diseasementioning

confidence: 99%

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A systematic review for the development of Alzheimer’s disease in in vitro models: a focus on different inducing agents

Prajapat,

Kaur,

Choudhary

et al. 2023

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is the most common progressive neurodegenerative disease and is associated with dementia. Presently, various chemical and environmental agents are used to induce in-vitro models of Alzheimer disease to investigate the efficacy of different therapeutic drugs. We screened literature from databases such as PubMed, ScienceDirect, and Google scholar, emphasizing the diverse targeting mechanisms of neuro degeneration explored in in-vitro models. The results revealed studies in which different types of chemicals and environmental agents were used for in-vitro development of Alzheimer-targeting mechanisms of neurodegeneration. Studies using chemically induced in-vitro AD models included in this systematic review will contribute to a deeper understanding of AD. However, none of these models can reproduce all the characteristics of disease progression seen in the majority of Alzheimer’s disease subtypes. Additional modifications would be required to replicate the complex conditions of human AD in an exact manner. In-vitro models of Alzheimer’s disease developed using chemicals and environmental agents are instrumental in providing insights into the disease’s pathophysiology; therefore, chemical-induced in-vitro AD models will continue to play vital role in future AD research. This systematic screening revealed the pivotal role of chemical-induced in-vitro AD models in advancing our understanding of AD pathophysiology and is therefore important to understand the potential of these chemicals in AD pathogenesis.

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Section: Different Agents Used For Induction Of Alzheimer Diseasementioning

confidence: 83%

Section: Different Agents Used For Induction Of Alzheimer Diseasementioning

confidence: 99%

A systematic review for the development of Alzheimer’s disease in in vitro models: a focus on different inducing agents

Prajapat,

Kaur,

Choudhary

et al. 2023

Front. Aging Neurosci.

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View full text Add to dashboard Cite

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“…Several studies show that antioxidative effect of estrogen does not depend on receptor binding; thus, it is intrinsic (Thomas et al, 2001). It is believed that the potential neuroprotective effects of estrogen replacement therapy could lower the risk of AD by inhibiting oxidative stress‐induced injury (Bansal et al, 2021; Chopra et al, 2016; Hu et al, 2023).…”

Section: Investigation Of Potential Neuroprotective Properties Of Est...mentioning

confidence: 99%

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

Rishabh,

Rohilla,

Bansal

et al. 2024

Eur J of Neuroscience

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In females, Alzheimer's disease (AD) incidences increases as compared to males due to estrogen deficiency after menopause. Estrogen therapy is the mainstay therapy for menopause and associated complications. Estrogen, a hormone with multifaceted physiological functions, has been implicated in AD pathophysiology. Estrogen plays a crucial role in amyloid precursor protein (APP) processing and overall neuronal health by regulating various factors such as brain‐derived neurotrophic factor (BDNF), intracellular calcium signalling, death domain‐associated protein (Daxx) translocation, glutamatergic excitotoxicity, Voltage‐Dependent Anion Channel, Insulin‐Like Growth Factor 1 Receptor, estrogen‐metabolising enzymes and apolipoprotein E (ApoE) protein polymorphisms. All these factors impact the physiology of postmenopausal women. Estrogen replacement therapies play an important treatment strategy to prevent AD after menopause. However, use of these therapies may lead to increased risks of breast cancer, venous thromboembolism and cardiovascular disease. Various therapeutic approaches have been used to mitigate the effects of estrogen on AD. These include hormone replacement therapy, Selective Estrogen Receptor Modulators (SERMs), Estrogen Receptor Beta (ERβ)‐Selective Agonists, Transdermal Estrogen Delivery, Localised Estrogen Delivery, Combination Therapies, Estrogen Metabolism Modulation and Alternative Estrogenic Compounds like genistein from soy, a notable phytoestrogen from plant sources. However, mechanism via which these approaches modulate AD in postmenopausal women has not been explained earlier thoroughly. Present review will enlighten all the molecular mechanisms of estrogen and estrogen replacement therapies in AD. Along‐with this, the association between estrogen, estrogen‐metabolising enzymes and ApoE protein polymorphisms will also be discussed in postmenopausal AD.

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“…Improvement of cognitive functions and reduction of cortical Aβ levels were found in hAPP(J20) mice after rapamycin (canonical mTOR inhibitor) treatment, along with restoration of neurovascular coupling ( Van Skike et al, 2021 ). Increased hippocampal expression of p-mTOR was reported in the STZ-icv model of AD ( El Sayed et al, 2021 ), while mTOR inhibition by everolimus showed improvements in cognition, as well as lowered TNFα levels in the brain accompanied by increases of insulin and IGF-1 levels and correction of STZ-icv-induced alterations of mRNA expression of PI3K/Akt/mTOR pathway genes ( Bansal et al, 2021 ).…”

Section: Wnt/mtor Pathways Evidence In Alzheimer’s Disease and Attent...mentioning

confidence: 99%

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

et al. 2023

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Alzheimer’s disease (AD) is the most common neurodegenerative disorder with the majority of patients classified as sporadic AD (sAD), in which etiopathogenesis remains unresolved. Though sAD is argued to be a polygenic disorder, apolipoprotein E (APOE) ε4, was found three decades ago to pose the strongest genetic risk for sAD. Currently, the only clinically approved disease-modifying drugs for AD are aducanumab (Aduhelm) and lecanemab (Leqembi). All other AD treatment options are purely symptomatic with modest benefits. Similarly, attention-deficit hyperactivity disorder (ADHD), is one of the most common neurodevelopmental mental disorders in children and adolescents, acknowledged to persist in adulthood in over 60% of the patients. Moreover, for ADHD whose etiopathogenesis is not completely understood, a large proportion of patients respond well to treatment (first-line psychostimulants, e.g., methylphenidate/MPH), however, no disease-modifying therapy exists. Interestingly, cognitive impairments, executive, and memory deficits seem to be common in ADHD, but also in early stages of mild cognitive impairment (MCI), and dementia, including sAD. Therefore, one of many hypotheses is that ADHD and sAD might have similar origins or that they intercalate with one another, as shown recently that ADHD may be considered a risk factor for sAD. Intriguingly, several overlaps have been shown between the two disorders, e.g., inflammatory activation, oxidative stress, glucose and insulin pathways, wingless-INT/mammalian target of rapamycin (Wnt/mTOR) signaling, and altered lipid metabolism. Indeed, Wnt/mTOR activities were found to be modified by MPH in several ADHD studies. Wnt/mTOR was also found to play a role in sAD and in animal models of the disorder. Moreover, MPH treatment in the MCI phase was shown to be successful for apathy including some improvement in cognition, according to a recent meta-analysis. In several AD animal models, ADHD-like behavioral phenotypes have been observed indicating a possible interconnection between ADHD and AD. In this concept paper, we will discuss the various evidence in human and animal models supporting the hypothesis in which ADHD might increase the risk for sAD, with common involvement of the Wnt/mTOR-pathway leading to lifespan alteration at the neuronal levels.

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Everolimus: A potential therapeutic agent targeting PI3K/Akt pathway in brain insulin system dysfunction and associated neurobehavioral deficits

Cited by 4 publications

References 52 publications

A systematic review for the development of Alzheimer’s disease in in vitro models: a focus on different inducing agents

A systematic review for the development of Alzheimer’s disease in in vitro models: a focus on different inducing agents

Estrogen signalling and Alzheimer's disease: Decoding molecular mechanisms for therapeutic breakthrough

From attention-deficit hyperactivity disorder to sporadic Alzheimer’s disease—Wnt/mTOR pathways hypothesis

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