3) Obesity
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.
3.1. IRS-2
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).
3.2. IGF-1
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).
Figure 3: FOXO deactivated by insulin signaling through AKT and HDAC causing autophagy as well as metabolic stress and resulting in accumulation of amyloid β leading to Alzheimer’s disease.
Transcriptional Alterations
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).
Conclusion and future perspective
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 novel paradigms of this kind.
Reference s
Abd-Elbaset M, Mansour AM, Ahmed OM, Abo-Youssef AM. The potential chemotherapeutic effect of β-ionone and/or sorafenib against hepatocellular carcinoma via its antioxidant effect, PPAR-γ, FOXO-1, Ki-67, Bax, and Bcl-2 signaling pathways. Naunyn-Schmiedeberg’s Archives of Pharmacology. 2020 Sep;393(9):1611-24. https://doi.org/10.1007/s00210-020-01863-9. AHMAD M, THARUMALAY RD, Din M, BALQIS NS. The Effects of Circadian Rhythm Disruption towards Metabolic Stress and Mental Health: A Review. Malaysian Journal of Health Sciences/Jurnal Sains Kesihatan Malaysia. 2020 Jan 1;18(1). Alam Q, Zubair Alam M, Mushtaq G, A Damanhouri G, Rasool M, Amjad Kamal M, Haque A. Inflammatory process in Alzheimer’s and Parkinson’s diseases: central role of cytokines. Current pharmaceutical design. 2016 Feb 1;22(5):541-8. Anstey KJ, Cherbuin N, Budge M, Young J. Body mass index in midlife and late‐life as a risk factor for dementia: a meta‐analysis of prospective studies. Obesity reviews. 2011 May;12(5):e426-37. https://doi.org/10.1111/j.1467-789X.2010.00825.x Audesse AJ, Dhakal S, Hassell LA, Gardell Z, Nemtsova Y, Webb AE. FOXO3 directly regulates an autophagy network to functionally regulate proteostasis in adult neural stem cells. PLoS genetics. 2019 Apr 11;15(4):e1008097. https://doi.org/10.1371/journal.pgen.1008097. Bellinger FP, He QP, Bellinger MT, Lin Y, Raman AV, White LR, Berry MJ. Association of selenoprotein p with Alzheimer’s pathology in human cortex. Journal of Alzheimer’s Disease. 2008 Jan 1;15(3):465-72. Bomfim TR, Forny-Germano L, Sathler LB, Brito-Moreira J, Houzel JC, Decker H, Silverman MA, Kazi H, Melo HM, McClean PL, Holscher C. An anti-diabetes agent protects the mouse brain from defective insulin signaling caused by Alzheimer’s disease–associated Aβ oligomers. The Journal of clinical investigation. 2012 Apr 2;122(4):1339-53. https://doi.org/10.1172/JCI57256. Bonifacino JS, Hurley JH. Retromer. Current opinion in cell biology. 2008 Aug 1;20(4):427-36. https://doi.org/10.1016/j.ceb.2008.03.009 Brewster JL, Linseman DA, Bouchard RJ, Loucks FA, Precht TA, Esch EA, Heidenreich KA. Endoplasmic reticulum stress and trophic factor withdrawal activate distinct signaling cascades that induce glycogen synthase kinase-3β and a caspase-9-dependent apoptosis in cerebellar granule neurons. Molecular and Cellular Neuroscience. 2006 Jul 1;32(3):242-53. https://doi.org/10.1016/j.mcn.2006.04.006 Burd CG. Physiology and pathology of endosome‐to‐Golgi retrograde sorting. Traffic. 2011 Aug;12(8):948-55. https://doi.org/10.1111/j.1600-0854.2011.01188.x Buxbaum JD, Ruefli AA, Parker CA, Cypess AM, Greengard P. Calcium regulates processing of the Alzheimer amyloid protein precursor in a protein kinase C-independent manner. Proceedings of the National Academy of Sciences. 1994 May 10;91(10):4489-93. https://doi.org/10.1073/pnas.91.10.4489 Cai H, Cong WN, Ji S, Rothman S, Maudsley S, Martin B. Metabolic dysfunction in Alzheimer’s disease and related neurodegenerative disorders. Current Alzheimer Research. 2012 Jan 1;9(1):5-17. Cameron VA, Mocatta TJ, Pilbrow AP, Frampton CM, Troughton RW, Richards AM, Winterbourn CC. Angiotensin type-1 receptor A1166C gene polymorphism correlates with oxidative stress levels in human heart failure. Hypertension. 2006 Jun 1;47(6):1155-61. https://doi.org/10.1161/01.HYP.0000222893.85662.cd Chen XF, Zhang YW, Xu H, Bu G. Transcriptional regulation and its misregulation in Alzheimer’s disease. Molecular brain. 2013 Dec;6(1):1-9. https://doi.org/10.1186%2F1756-6606-6-44. Chen, T.L., Wu, G.J., Hsu, C.S., Fong, T.H. and Chen, R.M., 2010. Nitrosative stress induces osteoblast apoptosis through downregulating MAPK-mediated NFκB/AP-1 activation and subsequent Bcl-XL expression. Chemico-biological interactions, 184(3), pp.359-365. https://doi.org/10.1016/j.cbi.2010.01.040. Ciryam P, Kundra R, Freer R, Morimoto RI, Dobson CM, Vendruscolo M. A transcriptional signature of Alzheimer’s disease is associated with a metastable subproteome at risk for aggregation. Proceedings of the National Academy of Sciences. 2016 Apr 26;113(17):4753-8. https://doi.org/10.1073%2Fpnas.1516604113. Claeysen S, Cochet M, Donneger R, Dumuis A, Bockaert J, Giannoni P. Alzheimer culprits: cellular crossroads and interplay. Cellular signalling. 2012 Sep 1;24(9):1831-40. https://doi.org/10.1016/j.cellsig.2012.05.008 Cojocaru IM, Cojocaru M, Miu GA, Sapira V. Study of interleukin-6 production in Alzheimer’s disease. Rom J Intern Med. 2011 Jan 1;49(1):55-8. De Felice FG, Lourenco MV, Ferreira ST. How does brain insulin resistance develop in Alzheimer’s disease?. Alzheimer’s & Dementia. 2014 Feb 1;10(1):S26-32. https://doi.org/10.1016/j.jalz.2013.12.004. De Matteis MA, Luini A. Exiting the Golgi complex. Nature reviews Molecular cell biology. 2008 Apr;9(4):273-84. https://doi.org/10.1038/nrm2378 De Strooper B. Proteases and proteolysis in Alzheimer disease: a multifactorial view on the disease process. Physiological reviews. 2010 Apr;90(2):465-94. https://doi.org/10.1152/physrev.00023.2009 Ding HR, Tang ZT, Tang N, Zhu ZY, Liu HY, Pan CY, Hu AY, Lin YZ, Gou P, Yuan XW, Cai JH. Protective properties of FOXO1 inhibition in a murine model of non-alcoholic fatty liver disease are associated with attenuation of ER stress and necroptosis. Frontiers in Physiology. 2020 Mar 11;11:177. https://doi.org/10.3389/fphys.2020.00177 Dong XC. FOXO transcription factors in non-alcoholic fatty liver disease. Liver research. 2017 Sep 1;1(3):168-73. https://doi.org/10.1016/j.livres.2017.11.004 Du S, Zheng H. Role of FoxO transcription factors in aging and age-related metabolic and neurodegenerative diseases. Cell & Bioscience. 2021 Dec;11(1):1-7. https://doi.org/10.1186/s13578-021-00700-7. Fan W, Imamura T, Sonoda N, Sears DD, Patsouris D, Kim JJ, Olefsky JM. FOXO1 transrepresses peroxisome proliferator-activated receptor γ transactivation, coordinating an insulin-induced feed-forward response in adipocytes. Journal of biological chemistry. 2009 May 1;284(18):12188-97. https://doi.org/10.1074/jbc.M808915200 Garg C, Kaur A, Singh TG, Sharma VK, Singh SK. Therapeutic Implications of Sonic Hedgehog Pathway in Metabolic Disorders: Novel Target for Effective Treatment. Pharmacological Research. 2022 Mar 29:106194. https://doi.org/10.1016/j.phrs.2022.106194 Garg N, Singh TG, Khan H, Arora S, Kaur A, Mannan A. Mechanistic interventions of selected Ocimum species in management of diabetes, obesity and liver disorders: transformative developments from preclinical to clinical approaches. Biointerface Res. Appl. Chem. 2021;12(1):1304-23. Gautam S, Zhang L, Arnaoutova I, Lee C, Mansfield BC, Chou JY. The signaling pathways implicated in impairment of hepatic autophagy in glycogen storage disease type Ia. Human Molecular Genetics. 2020 Mar 1;29(5):834-44. https://doi.org/10.1093/hmg/ddaa007 Ghoneum MH, El Sayed NS. Protective effect of Biobran/MGN-3 against sporadic Alzheimer’s disease mouse model: Possible role of oxidative stress and apoptotic pathways. Oxidative Medicine and Cellular Longevity. 2021 Jan 26;2021. https://doi.org/10.1155/2021/8845064 Giannakou ME, Goss M, Junger MA, Hafen E, Leevers SJ, Partridge L. Long-lived Drosophila with overexpressed dFOXO in adult fat body. Science. 2004 Jul 16;305(5682):361. https://doi.org/10.1126/science.1098219. Gong Y, Chang L, Viola KL, Lacor PN, Lambert MP, Finch CE, Krafft GA, Klein WL. Alzheimer’s disease-affected brain: presence of oligomeric Aβ ligands (ADDLs) suggests a molecular basis for reversible memory loss. Proceedings of the National Academy of Sciences. 2003 Sep 2;100(18):10417-22. https://doi.org/10.1073/pnas.1834302100. Greer EL, Brunet A. FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene. 2005 Nov;24(50):7410-25. https://doi.org/10.1038/sj.onc.1209086. Grewal AK, Singh N, Singh TG. Effects of resveratrol postconditioning on cerebral ischemia in mice: role of the sirtuin-1 pathway. Canadian Journal of Physiology and Pharmacology. 2019;97(11):1094-101. https://www.nrcresearchpress.com/doi/abs/10.1139/cjpp-2019-0188 Gross DN, Wan M, Birnbaum MJ. The role of FOXO in the regulation of metabolism. Current diabetes reports. 2009 Jun;9(3):208-14. https://doi.org/10.1007/s11892-009-0034-5 Gudala K, Bansal D, Schifano F, Bhansali A. Diabetes mellitus and risk of dementia: A meta‐analysis of prospective observational studies. Journal of diabetes investigation. 2013 Nov;4(6):640-50. Hanyu H, Sato T, Kiuchi A, Sakurai H, Iwamoto T. Pioglitazone improved cognition in a pilot study on patients with Alzheimer’s disease and mild cognitive impairment with diabetes mellitus. Journal of the American Geriatrics Society. 2009 Jan;57(1):177-9. https://doi.org/10.1111/j.1532-5415.2009.02067.x Harder H, Nielsen L, Thi TD, Astrup A. The effect of liraglutide, a long-acting glucagon-like peptide 1 derivative, on glycemic control, body composition, and 24-h energy expenditure in patients with type 2 diabetes. Diabetes care. 2004 Aug 1;27(8):1915-21. https://doi.org/10.2337/diacare.27.8.1915 Hedrick, C.C., Thorpe, S.R., Fu, M.X., Harper, C.M., Yoo, J., Kim, S.M., Wong, H. and Peters, A.L., 2000. Glycation impairs high-density lipoprotein function. Diabetologia, 43(3), pp.312-320. https://doi.org/10.1007/s001250050049. Ho, K.K., Myatt, S.S. and Lam, E.W., 2008. Many forks in the path: cycling with FoxO. Oncogene, 27(16), pp.2300-2311. https://doi.org/10.1038/onc.2008.23. Hooper C, Killick R, Lovestone S. The GSK3 hypothesis of Alzheimer’s disease. Journal of neurochemistry. 2008 Mar;104(6):1433-9. Huang X, Liu G, Guo J, Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. International journal of biological sciences. 2018;14(11):1483. https://doi.org/10.7150/ijbs.27173 Huang Y, Wilkinson GF, Willars GB. Role of the signal peptide in the synthesis and processing of the glucagon‐like peptide‐1 receptor. British journal of pharmacology. 2010 Jan;159(1):237-51. https://doi.org/10.1111/j.1476-5381.2009.00517.x Hwangbo DS, Gersham B, Tu MP, Palmer M, Tatar M. Drosophila dFOXO controls lifespan and regulates insulin signalling in brain and fat body. Nature. 2004 Jun;429(6991):562-6. https://doi.org/10.1038/nature02549. Ishizawa T, Sahara N, Ishiguro K, Kersh J, McGowan E, Lewis J, Hutton M, Dickson DW, Yen SH. Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. The American journal of pathology. 2003 Sep 1;163(3):1057-67. https://doi.org/10.1016/S0002-9440(10)63465-7. Jin H, Zhang L, He J, Wu M, Jia L, Guo J. Role of FOXO3a Transcription Factor in the Regulation of Liver Oxidative Injury. Antioxidants. 2022 Dec;11(12):2478. https://doi.org/10.3390/antiox11122478 Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends in biochemical sciences. 2004 Feb 1;29(2):95-102. https://doi.org/10.1016/j.tibs.2003.12.004. Jünger MA, Rintelen F, Stocker H, Wasserman JD, Végh M, Radimerski T, Greenberg ME, Hafen E. The Drosophila forkhead transcription factor FOXO mediates the reduction in cell number associated with reduced insulin signaling. Journal of biology. 2003 Mar;2(3):1-7. https://doi.org/10.1186/1475-4924-2-20. Kalogerakis G, Baker AM, Christov S, Rowley KG, Dwyer K, Winterbourn C, Best JD, Jenkins AJ. Oxidative stress and high-density lipoprotein function in Type I diabetes and end-stage renal disease. Clinical science. 2005 Jun 1;108(6):497-506. https://doi.org/10.1042/CS20040312 Kalra P, Khan H, Kaur A, Singh TG. Mechanistic insight on autophagy modulated molecular pathways in cerebral ischemic injury: from preclinical to clinical perspective. Neurochemical Research. 2022 Jan 7:1-9. https://doi.org/10.1007/s11064-021-03500-0 Kang CH, Jayasooriya RG, Choi YH, Moon SK, Kim WJ, Kim GY. β-Ionone attenuates LPS-induced pro-inflammatory mediators such as NO, PGE2 and TNF-α in BV2 microglial cells via suppression of the NF-κB and MAPK pathway. Toxicology in Vitro. 2013 Mar 1;27(2):782-7. https://doi.org/10.1016/j.tiv.2012.12.012 Kang K, Bai J, Zhong S, Zhang R, Zhang X, Xu Y, Zhao M, Zhao C, Zhou Z. Down-Regulation of Insulin Like Growth Factor 1 Involved in Alzheimer’s Disease via MAPK, Ras, and FoxO Signaling Pathways. Oxidative medicine and cellular longevity. 2022 Jan 1;2022. https://doi.org/10.1155/2022/8169981 Khan H, Garg N, Singh TG, Kaur A, Thapa K. Calpain inhibitors as potential therapeutic modulators in neurodegenerative diseases. Neurochemical Research. 2022 Jan 4:1-25. https://doi.org/10.1007/s11064-021-03521-9 Khan H, Gupta A, Singh TG, Kaur A. Mechanistic insight on the role of leukotriene receptors in ischemic–reperfusion injury. Pharmacological Reports. 2021 Oct;73(5):1240-54. https://doi.org/10.1007/s43440-021-00258-8 Khan H, Sharma K, Kumar A, Kaur A, Singh TG. Therapeutic implications of cyclooxygenase (COX) inhibitors in ischemic injury. Inflammation Research. 2022 Feb 17:1-6. https://doi.org/10.1007/s00011-022-01546-6 Khan H, Sharma R, Kaur A, Singh TG. The endocannabioids system and their implications in various disorders. Int. J. Pharm. Sci. Rev. Res. 2018. Khan H, Tiwari P, Kaur A, Singh TG. Sirtuin acetylation and deacetylation: a complex paradigm in neurodegenerative disease. Molecular Neurobiology. 2021 Aug;58(8):3903-17. https://doi.org/10.1007/s12035-021-02387-w Landreth G. Therapeutic use of agonists of the nuclear receptor PPARγ in Alzheimer’s disease. Current Alzheimer Research. 2007 Apr 1;4(2):159-64. https://doi.org/10.2174/156720507780362092 Li JQ, Yu JT, Jiang T, Tan L. Endoplasmic reticulum dysfunction in Alzheimer’s disease. Molecular neurobiology. 2015 Feb;51(1):383-95. https://doi.org/10.1007/s12035-014-8695-8 Li Y, Tweedie D, Mattson MP, Holloway HW, Greig NH. Enhancing the GLP‐1 receptor signaling pathway leads to proliferation and neuroprotection in human neuroblastoma cells. Journal of neurochemistry. 2010 Jun;113(6):1621-31. https://doi.org/10.1111/j.1471-4159.2010.06731.x Liu J, Wei L, Wang Z, Song S, Lin Z, Zhu J, Ren X, Kong L. Protective effect of Liraglutide on diabetic retinal neurodegeneration via inhibiting oxidative stress and endoplasmic reticulum stress. Neurochemistry International. 2020 Feb 1;133:104624. https://doi.org/10.1016/j.neuint.2019.104624 Liu W, Ruiz-Velasco A, Wang S, Khan S, Zi M, Jungmann A, Dolores Camacho-Muñoz M, Guo J, Du G, Xie L, Oceandy D. Metabolic stress-induced cardiomyopathy is caused by mitochondrial dysfunction due to attenuated Erk5 signaling. Nature communications. 2017 Sep 8;8(1):1-6. https://doi.org/10.1038/s41467-017-00664-8. Ma T, Trinh MA, Wexler AJ, Bourbon C, Gatti E, Pierre P, Cavener DR, Klann E. Suppression of eIF2α kinases alleviates AD-related synaptic plasticity and spatial memory deficits. Nature neuroscience. 2013 Sep;16(9):1299. https://doi.org/10.1038%2Fnn.3486. Mannan A, Garg N, Singh TG, Kang HK. Peroxisome proliferator-activated receptor-gamma (PPAR-ɣ): molecular effects and its importance as a novel therapeutic target for cerebral ischemic injury. Neurochemical Research. 2021 Nov;46(11):2800-31. https://doi.org/10.1007/s11064-021-03402-1 Manolopoulos KN, Klotz LO, Korsten P, Bornstein SR, Barthel A. Linking Alzheimer’s disease to insulin resistance: the FoxO response to oxidative stress. Molecular psychiatry. 2010 Nov;15(11):1046-52. https://doi.org/10.1038/mp.2010.17. Martin B, Golden E, Carlson OD, Pistell P, Zhou J, Kim W, Frank BP, Thomas S, Chadwick WA, Greig NH, Bates GP. Exendin-4 improves glycemic control, ameliorates brain and pancreatic pathologies, and extends survival in a mouse model of Huntington’s disease. Diabetes. 2009 Feb 1;58(2):318-28. https://doi.org/10.2337/db08-0799. Martin B, Mattson MP, Maudsley S. Caloric restriction and intermittent fasting: two potential diets for successful brain aging. Ageing research reviews. 2006 Aug 1;5(3):332-53. https://doi.org/10.1016/j.arr.2006.04.002 Marwarha G, Claycombe-Larson K, Lund J, Ghribi O. Palmitate-Induced SREBP1 expression and activation underlies the increased BACE 1 activity and amyloid beta genesis. Molecular neurobiology. 2019 Jul;56(7):5256-69. doi: 10.1007/s12035-018-1451-8. Matsuzaki K, Nakajima A, Guo Y, Ohizumi Y. A Narrative Review of the Effects of Citrus Peels and Extracts on Human Brain Health and Metabolism. Nutrients. 2022 Jan;14(9):1847. https://doi.org/10.3390/nu14091847 Micaroni M. The role of calcium in intracellular trafficking. Current molecular medicine. 2010 Nov 1;10(8):763-73. https://doi.org/10.2174/156652410793384204 Moll L, Schubert M. The role of insulin and insulin-like growth factor-1/FoxO-mediated transcription for the pathogenesis of obesity-associated dementia. Current Gerontology and Geriatrics Research. 2012 Jan 1;2012. doi: 10.1155/2012/384094. Nagashima T, Shigematsu N, Maruki R, Urano Y, Tanaka H, Shimaya A, Shimokawa T, Shibasaki M. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. Molecular pharmacology. 2010 Nov 1;78(5):961-70. doi: 10.1124/mol.110.065714. O’brien RJ, Wong PC. Amyloid precursor protein processing and Alzheimer’s disease. Annual review of neuroscience. 2011 Jul 21;34:185-204. https://doi.org/10.1146/annurev-neuro-061010-113613 Omata Y, Lim YM, Akao Y, Tsuda L. Age-induced reduction of autophagy-related gene expression is associated with onset of Alzheimer’s disease. American journal of neurodegenerative disease. 2014;3(3):134. Pan X, Zhang Y, Kim HG, Liangpunsakul S, Dong XC. FOXO transcription factors protect against the diet-induced fatty liver disease. Scientific reports. 2017 Mar 16;7(1):1-2. https://doi.org/10.1038/srep44597. Phiel CJ, Wilson CA, Lee VM, Klein PS. GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature. 2003 May;423(6938):435-9. https://doi.org/10.1038/nature01640. Picone P, Di Carlo M, Nuzzo D. Obesity and Alzheimer’s disease: Molecular bases. European Journal of Neuroscience. 2020 Oct;52(8):3944-50. https://doi.org/10.1111/ejn.14758 Ponugoti B, Dong G, Graves DT. Role of forkhead transcription factors in diabetes-induced oxidative stress. Experimental diabetes research. 2012;2012. Prabhakar NK, Khan H, Grewal AK, Singh TG. Intervention of neuroinflammation in the traumatic brain injury trajectory: In vivo and clinical approaches. International Immunopharmacology. 2022 Jul 1;108:108902. https://doi.org/10.1007/s11033-022-07594-9 Pradhan R, Yadav SK, Prem NN, Bhagel V, Pathak M, Shekhar S, Gaikwad S, Dwivedi SN, Bal CS, Dey AB, Dey S. Serum FOXO3A: A ray of hope for early diagnosis of Alzheimer’s disease. Mechanisms of Ageing and Development. 2020 Sep 1;190:111290. https://doi.org/10.1016/j.mad.2020.111290. Puig O, Marr MT, Ruhf ML, Tjian R. Control of cell number by Drosophila FOXO: downstream and feedback regulation of the insulin receptor pathway. Genes & development. 2003 Aug 15;17(16):2006-20. Qin W, Zhao W, Ho L, Wang J, Walsh K, Gandy S, Pasinetti GM. Regulation of forkhead transcription factor FoxO3a contributes to calorie restriction‐induced prevention of Alzheimer’s disease‐type amyloid neuropathology and spatial memory deterioration. Annals of the New York Academy of Sciences. 2008 Dec;1147(1):335-47. https://doi.org/10.1196/annals.1427.024. Rajendran L, Annaert W. Membrane trafficking pathways in Alzheimer’s disease. Traffic. 2012 Jun;13(6):759-70. https://doi.org/10.1111/j.1600-0854.2012.01332.x Rehni, A.K., Singh, T.G., Jaggi, A.S. and Singh, N., 2008. Pharmacological preconditioning of the brain: a possible interplay between opioid and calcitonin gene related peptide transduction systems. Pharmacological Reports60(6), p.904. Rehni, A.K., Singh, T.G., Singh, N. and Arora, S., 2010. Tramadol-induced seizurogenic effect: a possible role of opioid-dependent histamine (H1) receptor activation-linked mechanism. Naunyn-Schmiedeberg’s archives of pharmacology381(1), pp.11-19. https://doi.org/10.1007/s00210-009-0476-y Saklani P, Khan H, Singh TG, Gupta S, Grewal AK. Demethyleneberberine, a potential therapeutic agent in neurodegenerative disorders: a proposed mechanistic insight. Molecular Biology Reports. 2022 Jun 3:1-3. https://doi.org/10.1007/s11033-022-07594-9 Salih DA, Brunet A. FoxO transcription factors in the maintenance of cellular homeostasis during aging. Current opinion in cell biology. 2008 Apr 1;20(2):126-36. https://doi.org/10.1016/j.ceb.2008.02.005. Salminen A, Kauppinen A, Suuronen T, Kaarniranta K, Ojala J. ER stress in Alzheimer’s disease: a novel neuronal trigger for inflammation and Alzheimer’s pathology. Journal of neuroinflammation. 2009 Dec;6(1):1-3. https://doi.org/10.1186/1742-2094-6-41. Sanphui P, Biswas SC. FoxO3a is activated and executes neuron death via Bim in response to β-amyloid. Cell death & disease. 2013 May;4(5):e625-. https://doi.org/10.1038/cddis.2013.148. Scarmeas N, Luchsinger JA, Schupf N, Brickman AM, Cosentino S, Tang MX, Stern Y. Physical activity, diet, and risk of Alzheimer disease. Jama. 2009 Aug 12;302(6):627-37. 10.1001/jama.2009.1144. Schoultz I, Söderholm JD, McKay DM. Is metabolic stress a common denominator in inflammatory bowel disease?. Inflammatory bowel diseases. 2011 Sep 1;17(9):2008-18. https://doi.org/10.1002/ibd.21556. Seaman MN. Endosome protein sorting: motifs and machinery. Cellular and molecular life sciences: CMLS. 2008 Sep 1;65(18):2842-58. https://doi.org/10.1007/s00018-008-8354-1 Sharma VK, Singh TG. CREB: a multifaceted target for Alzheimer’s disease. Current Alzheimer Research. 2020 Mar 1;17(14):1280-93. https://doi.org/10.2174/1567205018666210218152253 Shi C, Viccaro K, Lee HG, Shah K. Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer’s disease models. Journal of cell science. 2016 May 1;129(9):1815-30. https://doi.org/10.1242/jcs.185009. Shi C, Viccaro K, Lee HG, Shah K. Cdk5–Foxo3 axis: initially neuroprotective, eventually neurodegenerative in Alzheimer’s disease models. Journal of cell science. 2016 May 1;129(9):1815-30. https://doi.org/10.1242%2Fjcs.185009. Small SA, Kent K, Pierce A, Leung C, Kang MS, Okada H, Honig L, Vonsattel JP, Kim TW. Model‐guided microarray implicates the retromer complex in Alzheimer’s disease. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2005 Dec;58(6):909-19. https://doi.org/10.1002/ana.20667 Smith WW, Norton DD, Gorospe M, Jiang H, Nemoto S, Holbrook NJ, Finkel T, Kusiak JW. Phosphorylation of p66Shc and forkhead proteins mediates Aβ toxicity. The Journal of cell biology. 2005 Apr 25;169(2):331-9. https://doi.org/10.1083/jcb.200410041 Sullivan CP, Jay AG, Stack EC, Pakaluk M, Wadlinger E, Fine RE, Wells JM, Morin PJ. Retromer disruption promotes amyloidogenic APP processing. Neurobiology of disease. 2011 Aug 1;43(2):338-45. https://doi.org/10.1016/j.nbd.2011.04.002 Tan J, Evin G. β‐Site APP‐cleaving enzyme 1 trafficking and Alzheimer’s disease pathogenesis. Journal of neurochemistry. 2012 Mar;120(6):869-80. https://doi.org/10.1111/j.1471-4159.2011.07623.x Valenti L, Rametta R, Dongiovanni P, Maggioni M, Ludovica Fracanzani A, Zappa M, Lattuada E, Roviaro G, Fargion S. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes. 2008 May 1;57(5):1355-62. https://doi.org/10.2337/db07-0714 van der Vos KE, Coffer PJ. The extending network of FOXO transcriptional target genes. Antioxidants & redox signaling. 2011 Feb 15;14(4):579-92. https://doi.org/10.1089/ars.2010.3419. Viollet B, Foretz M, Guigas B, Horman S, Dentin R, Bertrand L, Hue L, Andreelli F. Activation of AMP‐activated protein kinase in the liver: a new strategy for the management of metabolic hepatic disorders. The Journal of physiology. 2006 Jul 1;574(1):41-53. https://doi.org/10.1113/jphysiol.2006.108506 Wang L, Zhu X, Sun X, Yang X, Chang X, Xia M, Lu Y, Xia P, Yan H, Bian H, Gao X. FoxO3 regulates hepatic triglyceride metabolism via modulation of the expression of sterol regulatory-element binding protein 1c. Lipids in health and disease. 2019 Dec;18(1):1-2. https://doi.org/10.1186/s12944-019-1132-2. Wang S, Xia P, Huang G, Zhu P, Liu J, Ye B, Du Y, Fan Z. FoxO1-mediated autophagy is required for NK cell development and innate immunity. Nature communications. 2016 Mar 24;7(1):1-5. https://doi.org/10.1038/ncomms11023 Wang X, Wang Z, Chen Y, Huang X, Hu Y, Zhang R, Ho MS, Xue L. FoxO mediates APP-induced AICD-dependent cell death. Cell death & disease. 2014 May;5(5):e1233-. https://doi.org/10.1038/cddis.2014.196. Wang Y, Lin Y, Wang L, Zhan H, Luo X, Zeng Y, Wu W, Zhang X, Wang F. TREM2 ameliorates neuroinflammatory response and cognitive impairment via PI3K/AKT/FoxO3a signaling pathway in Alzheimer’s disease mice. Aging (Albany NY). 2020 Oct 10;12(20):20862. doi: 10.18632/aging.104104. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. The American journal of geriatric psychiatry. 2005 Nov 1;13(11):950-8. https://doi.org/10.1097/00019442-200511000-00005. Watson GS, Cholerton BA, Reger MA, Baker LD, Plymate SR, Asthana S, Fishel MA, Kulstad JJ, Green PS, Cook DG, Kahn SE. Preserved cognition in patients with early Alzheimer disease and amnestic mild cognitive impairment during treatment with rosiglitazone: a preliminary study. The American journal of geriatric psychiatry. 2005 Nov 1;13(11):950-8. https://doi.org/10.1097/00019442-200511000-00005 Wellen KE, Thompson CB. Cellular metabolic stress: considering how cells respond to nutrient excess. Molecular cell. 2010 Oct 22;40(2):323-32.https://doi.org/10.1016/j.molcel.2010.10.004 Wong HK, Veremeyko T, Patel N, Lemere CA, Walsh DM, Esau C, Vanderburg C, Krichevsky AM. De-repression of FOXO3a death axis by microRNA-132 and-212 causes neuronal apoptosis in Alzheimer’s disease. Human molecular genetics. 2013 Aug 1;22(15):3077-92. https://doi.org/10.1093/hmg/ddt164. Xia W, Yang T, Shankar G, Smith IM, Shen Y, Walsh DM, Selkoe DJ. A specific enzyme-linked immunosorbent assay for measuring β-amyloid protein oligomers in human plasma and brain tissue of patients with Alzheimer disease. Archives of neurology. 2009 Feb 1;66(2):190-9. 10.1001/archneurol.2008.565. Yamaguchi H, Ishiguro K, Uchida T, Takashima A, Lemere CA, Imahori K. Preferential labeling of Alzheimer neurofibrillary tangles with antisera for tau protein kinase (TPK) I/glycogen synthase kinase-3β and cyclin-dependent kinase 5, a component of TPK II. Acta neuropathologica. 1996 Aug;92(3):232-41. https://doi.org/10.1007/s004010050513. Zemva J, Schilbach K, Stöhr O, Moll L, Franko A, Krone W, Wiesner RJ, Schubert M. Central FoxO3a and FoxO6 expression is downregulated in obesity induced diabetes but not in aging. Experimental and clinical endocrinology & diabetes. 2012 Jun;120(06):340-50. 10.1055/s-0031-1297970 Zhao Y, Zhao B. Oxidative stress and the pathogenesis of Alzheimer’s disease. Oxidative medicine and cellular longevity. 2013 Oct;2013. https://doi.org/10.1155/2013/316523.