Role of Forkhead Transcription Factors of the O Class (FoxO) in Development and Progression of Alzheimer’s Disease

Shikha       Goswami; Ozaifa       Kareem; Ramesh    K.    Goyal; Sayed    M.   Mumtaz; Rajiv    K.    Tonk; Rahul       Gupta; Faheem    H.   Pottoo
doi:10.2174/1871527319666201001105553
Abstract

In the Central Nervous System (CNS), a specific loss of focal neurons leads to mental and neurological disorders like dementia, Alzheimer’s Disease (AD), Huntington’s disease, Parkinson’s disease, etc. AD is a neurological degenerative disorder, which is progressive and irreversible in nature and is the widely recognized reason for dementia in the geriatric populace. It affects 10% of people above the age of 65 and is the fourth driving reason for death in the United States. Numerous evidence suggests that the neuronal compartment is not the only genesis of AD, but transcription factors also hold significant importance in the occurrence and advancement of the disease. It is the need of the time to find the novel molecular targets and new techniques for treating or slowing down the progression of neurological disorders, especially AD. In this article, we summarised a conceivable association between transcriptional factors and their defensive measures against neurodegeneration and AD. The mammalian forkhead transcription factors of the class O (FoxO) illustrate one of the potential objectives for the development of new methodologies against AD and other neurocognitive disorders. The presence of FoxO is easily noticeable in the “cognitive centers” of the brain, specifically in the amygdala, hippocampus, and the nucleus accumbens. FoxO proteins are the prominent and necessary factors in memory formation and cognitive functions. FoxO also assumes a pertinent role in the protection of multiple cells in the brain by controlling the involving mechanism of autophagy and apoptosis and also modulates the process of phosphorylation of the targeted protein, thus FoxO must be a putative target in the mitigation of AD. This review features the role of FoxO as an important biomarker and potential new targets for the treatment of AD.
Keywords: Alzheimer`s disease, neurological disorders, transcription factors, neurodegeneration, FoxO, biomarkers.
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[1] 
Levine B, Mizushima N, Virgin HW. Autophagy in immunity and inflammation. Nature  2011; 469(7330): 323-35.
[http://dx.doi.org/10.1038/nature09782] [PMID: 21248839] 
[2] 
Sharma P, Sharma A, Fayaz F, Wakode S, Pottoo FH. Biological signatures of Alzheimer’s disease. Curr Top Med Chem  2020; 20(9): 770-81.
[http://dx.doi.org/10.2174/1568026620666200228095553] [PMID: 32108008] 
[3] 
Kim J, Basak JM, Holtzman DM. The role of apolipoprotein E in Alzheimer’s disease. Neuron  2009; 63(3): 287-303.
[4] 
Ibrahim AM, Pottoo FH, Dahiya ES, Khan FA, Kumar JBS. Neuron-glia interactions: molecular basis of Alzheimer’s disease and applications of neuroproteomics. Eur J Neurosci  2020; 52(2): 2931-43.
[http://dx.doi.org/10.1111/ejn.14838] [PMID: 32463535] 
[5] 
Campion D, Dumanchin C, Hannequin D, et al. Early-onset autosomal dominant Alzheimer disease: prevalence, genetic heterogeneity, and mutation spectrum. Am J Hum Genet  1999; 65(3): 664-70.
[http://dx.doi.org/10.1086/302553] [PMID: 10441572] 
[6] 
Mendez MF. Early-onset Alzheimer’s disease: nonamnestic subtypes and type 2 AD. Arch Med Res  2012; 43(8): 677-85.
[http://dx.doi.org/10.1016/j.arcmed.2012.11.009] [PMID: 23178565] 
[7] 
Akhter Y, Nabi J, Hamid H, Tabassum N, Pottoo FH, Sharma A. Protein quality control in neurodegeneration and neuroprotection. Quality Control of Cellular Protein in Neurodegenerative Disorders  2020; 1-24.
[http://dx.doi.org/10.4018/978-1-7998-1317-0.ch001] 
[8] 
Vargas DM, De Bastiani MA, Zimmer ER, Klamt F. Alzheimer’s disease master regulators analysis: search for potential molecular targets and drug repositioning candidates. Alzheimers Res Ther  2018; 10(1): 59.
[http://dx.doi.org/10.1186/s13195-018-0394-7] [PMID: 29935546] 
[9] 
Theuns J, Van Broeckhoven C. Transcriptional regulation of Alzheimer’s disease genes: implications for susceptibility. Hum Mol Genet  2000; 9(16): 2383-94.
[http://dx.doi.org/10.1093/hmg/9.16.2383] [PMID: 11005793] 
[10] 
Anand R, Gill K D, Mahdi A A. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology  2014; 76(Pt A): 27-50.
[http://dx.doi.org/10.1016/j.neuropharm.2013.07.004] 
[11] 
Goate A, Chartier-Harlin MC, Mullan M, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer’s disease. Nature  1991; 349(6311): 704-6.
[http://dx.doi.org/10.1038/349704a0] [PMID: 1671712] 
[12] 
Irizarry MC, Deng A, Lleo A, et al. Apolipoprotein E modulates gamma-secretase cleavage of the amyloid precursor protein. J Neurochem  2004; 90(5): 1132-43.
[http://dx.doi.org/10.1111/j.1471-4159.2004.02581.x] [PMID: 15312168] 
[13] 
Corder EH, Saunders AM, Strittmatter WJ, et al. Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science  1993; 261(5123): 921-3.
[http://dx.doi.org/10.1126/science.8346443] 
[14] 
Corder EH, Saunders AM, Risch NJ, et al. Protective effect of apolipoprotein E type 2 allele for late onset Alzheimer disease. Nat Genet  1994; 7(2): 180-4.
[http://dx.doi.org/10.1038/ng0694-180] [PMID: 7920638] 
[15] 
Hiltunen M, Lu A, Thomas AV, et al. Ubiquilin 1 modulates amyloid precursor protein trafficking and Abeta secretion. J Biol Chem  2006; 281(43): 32240-53.
[http://dx.doi.org/10.1074/jbc.M603106200] [PMID: 16945923] 
[16] 
Nigar S, Pottoo F, Tabassum N, Verma S, Javed M. Molecular insights into the role of inflammation and oxidative stress in epilepsy. J Adv Med Pharm Sci  2016; 10(1): 1-9.
[http://dx.doi.org/10.9734/JAMPS/2016/24441] 
[17] 
Dal Prà I, Chiarini A, Gui L, et al. Do astrocytes collaborate with neurons in spreading the “infectious” aβ and Tau drivers of Alzheimer’s disease? Neuroscientist  2015; 21(1): 9-29.
[http://dx.doi.org/10.1177/1073858414529828] [PMID: 24740577] 
[18] 
Pandey M, Nabi J, Tabassum N, Pottoo FH, Khatik R, Ahmad N. Molecular chaperones in neurodegeneration: mechanisms of regulation in cellular proteostasis. Quality Control of Cellular Protein in Neurodegenerative  2020; 354-79.
[http://dx.doi.org/10.4018/978-1-7998-1317-0.ch014] 
[19] 
Braak H, Braak E. Frequency of stages of Alzheimer-related lesions in different age categories. Neurobiol Aging  1997; 18(4): 351-7.
[http://dx.doi.org/10.1016/S0197-4580(97)00056-0] [PMID: 9330961] 
[20] 
Pandey M, Saleem S, Nautiyal H, Pottoo FH, Javed MN. PINK1/Parkin in neurodegenerative disorders: crosstalk between mitochondrial stress and neurodegeneration. Quality Control of Cellular Protein in Neurodegenerative Disorders  2020; 282-301.
[http://dx.doi.org/10.4018/978-1-7998-1317-0.ch011] 
[21] 
Selkoe DJ. Early network dysfunction in Alzheimer’s disease. Science  2019; 365(6453): 540-1.
[22] 
Gu L, Guo Z. Alzheimer’s Aβ42 and Aβ40 peptides form interlaced amyloid fibrils. J Neurochem  2013; 126(3): 305-11.
[http://dx.doi.org/10.1111/jnc.12202] [PMID: 23406382] 
[23] 
Iwatsubo T, Odaka A, Suzuki N, Mizusawa H, Nukina N, Ihara Y. Visualization of A β 42(43) and A β 40 in senile plaques with end-specific A β monoclonals: evidence that an initially deposited species is A β 42(43). Neuron  1994; 13(1): 45-53.
[http://dx.doi.org/10.1016/0896-6273(94)90458-8] [PMID: 8043280] 
[24] 
Andreasen N, Vanmechelen E, Vanderstichele H, Davidsson P, Blennow K. Cerebrospinal fluid levels of total-tau, phospho-tau and Abeta42 predicts development of Alzheimer’s disease in patients with mild cognitive impairment. Acta Neurol Scand  2003; 107(s179): 47-51.
[http://dx.doi.org/10.1034/j.1600-0404.107.s179.9.x] 
[25] 
Bentahir M, Nyabi O, Verhamme J, et al. Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms. J Neurochem  2006; 96(3): 732-42.
[http://dx.doi.org/10.1111/j.1471-4159.2005.03578.x] [PMID: 16405513] 
[26] 
De Strooper B. Alzheimer’s disease. Closing in on γ-secretase. Nature  2000; 405(6787): 627-628, 629.
[http://dx.doi.org/10.1038/35015193] [PMID: 10864307] 
[27] 
Seubert P, Vigo-Pelfrey C, Esch F, et al. Isolation and quantification of soluble Alzheimer’s β-peptide from biological fluids. Nature  1992; 359(6393): 325-7.
[http://dx.doi.org/10.1038/359325a0] [PMID: 1406936] 
[28] 
Braak H, Braak E. Demonstration of amyloid deposits and neurofibrillary changes in whole brain sections. Brain Pathol  1991; 1(3): 213-6.
[http://dx.doi.org/10.1111/j.1750-3639.1991.tb00661.x] [PMID: 1669710] 
[29] 
Budson AE, Solomon PR. New criteria for Alzheimer disease and mild cognitive impairment: implications for the practicing clinician. Neurologist  2012; 18(6): 356-63.
[http://dx.doi.org/10.1097/NRL.0b013e31826a998d] [PMID: 23114667] 
[30] 
Sabri O, Seibyl J, Rowe C, Barthel H. Beta-amyloid imaging with florbetaben. Clin Transl Imaging  2015; 3(1): 13-26.
[http://dx.doi.org/10.1007/s40336-015-0102-6] [PMID: 25741488] 
[31] 
Maies K. “FoxO Proteins in the Nervous System,” Analytical cell Patho.   2015; pp. pp. 1-15.
[32] 
Hampel H, Bürger K, Teipel SJ, Bokde ALW, Zetterberg H, Blennow K. Core candidate neurochemical and imaging biomarkers of Alzheimer’s disease. Alzheimers Dement  2008; 4(1): 38-48.
[http://dx.doi.org/10.1016/j.jalz.2007.08.006] [PMID: 18631949] 
[33] 
Koola M M, Nikiforuk A, Pillai A, Parsaik A K. Galantamine-memantine combination superior to donepezil-memantine combination in Alzheimer’s disease: critical dissection with an emphasis on kynurenic acid and mismatch negativity J Geriatr care Res  2018; 5(2): 57-67.
[34] 
Lao K, Ji N, Zhang X, Qiao W, Tang Z, Gou X. Drug development for Alzheimer’s disease.: review J Drug Target  2019; 27(2): 164-73.
[http://dx.doi.org/10.1080/1061186X.2018.1474361] [PMID: 29732929] 
[35] 
Dong H, Li J, Huang L, et al. Serum microrna profiles serve as novel biomarkers for the diagnosis of Alzheimer’s disease. Dis Markers  2015; 2015625659
[http://dx.doi.org/10.1155/2015/625659] [PMID: 26078483] 
[36] 
Auld DS, Kornecook TJ, Bastianetto S, Quirion R. Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies. Prog Neurobiol  2002; 68(3): 209-45.
[http://dx.doi.org/10.1016/S0301-0082(02)00079-5] [PMID: 12450488] 
[37] 
Bateman RJ, Xiong C, Benzinger TL, et al. Dominantly inherited Alzheimer network.clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med  2012; 367(9): 795-804.
[http://dx.doi.org/10.1056/NEJMoa1202753] [PMID: 22784036] 
[38] 
Pooler AM, Polydoro M, Wegmann S, Nicholls SB, Spires-Jones TL, Hyman BT. Propagation of tau pathology in Alzheimer’s disease: identification of novel therapeutic targets. Alzheimers Res Ther  2013; 5(5): 49.
[http://dx.doi.org/10.1186/alzrt214] [PMID: 24152385] 
[39] 
Salloway S, Sperling R, Fox NC, et al. Bapineuzumab 301 and 302 Clinical Trial Investigators. Two phase 3 trials of bapineuzumab in mild-to-moderate Alzheimer’s disease. N Engl J Med  2014; 370(4): 322-33.
[http://dx.doi.org/10.1056/NEJMoa1304839] [PMID: 24450891] 
[40] 
Doody RS, Thomas RG, Farlow M, et al. Alzheimer’s Disease Cooperative Study Steering Committee; Solanezumab Study Group.Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. N Engl J Med  2014; 370(4): 311-21.
[http://dx.doi.org/10.1056/NEJMoa1312889] [PMID: 24450890] 
[41] 
Kennedy ME, Stamford AW. Chen1 X, et al. The BACE1 inhibitor verubecestat (MK-8931) reduces CNS -amyloid in animal models and in Alzheimers disease patients. Sci Transl Med  2016; 8(363)363ra150
[http://dx.doi.org/10.1126/scitranslmed.aad9704] 
[42] 
Perry D, Sperling R, Katz R, et al. Building a roadmap for developing combination therapies for Alzheimer’s disease. Expert Rev Neurother  2015; 15(3): 327-33.
[http://dx.doi.org/10.1586/14737175.2015.996551] [PMID: 25708309] 
[43] 
Pedersen JT, Sigurdsson EM. Tau immunotherapy for Alzheimer’s disease. Trends Mol Med  2015; 21(6): 394-402.
[http://dx.doi.org/10.1016/j.molmed.2015.03.003] [PMID: 25846560] 
[44] 
Rosenmann H. Immunotherapy for targeting tau pathology in Alzheimer’s disease and tauopathies. Curr Alzheimer Res  2013; 10(3): 217-28.
[http://dx.doi.org/10.2174/1567205011310030001] [PMID: 23534533] 
[45] 
Buzsáki G, Wang X-J. Mechanisms of gamma oscillations. Annu Rev Neurosci  2012; 35(1): 203-25.
[http://dx.doi.org/10.1146/annurev-neuro-062111-150444] [PMID: 22443509] 
[46] 
Panza F, Solfrizzi V, Seripa D, et al. Tau-based therapeutics for Alzheimer’s disease: active and passive immunotherapy. Immunotherapy  2016; 8(9): 1119-34.
[http://dx.doi.org/10.2217/imt-2016-0019] [PMID: 27485083] 
[47] 
Ramirez-Bermudez J. Alzheimer’s disease: critical notes on the history of a medical concept. Arch Med Res  2012; 43(8): 595-9.
[http://dx.doi.org/10.1016/j.arcmed.2012.11.008] [PMID: 23178566] 
[48] 
Vassar R. BACE1 inhibitor drugs in clinical trials for Alzheimer’s disease. Alzheimers Res Ther  2014; 6(9): 89.
[http://dx.doi.org/10.1186/s13195-014-0089-7] [PMID: 25621019] 
[49] 
Ertekin-Taner N. Gene expression endophenotypes: a novel approach for gene discovery in Alzheimer’s disease. Mol Neurodegener  2011; 6(1): 31.
[http://dx.doi.org/10.1186/1750-1326-6-31] [PMID: 21569597] 
[50] 
Eckert A, Schulz KL, Rhein V, Götz J. 
                       Convergence of amyloid-beta and tau pathologies on mitochondria 
                        
                           in vivo
                        
                       .
                     Mol Neurobiol  2010; 41(2-3): 107-14.
[http://dx.doi.org/10.1007/s12035-010-8109-5] [PMID: 20217279] 
[51] 
Theuns J, Brouwers N, Engelborghs S, et al. Promoter mutations that increase amyloid precursor-protein expression are associated with Alzheimer disease. Am J Hum Genet  2006; 78(6): 936-46.
[http://dx.doi.org/10.1086/504044] [PMID: 16685645] 
[52] 
Lv H, Jia L, Jia J. Promoter polymorphisms which modulate APP expression may increase susceptibility to Alzheimer’s disease. Neurobiol Aging  2008; 29(2): 194-202.
[http://dx.doi.org/10.1016/j.neurobiolaging.2006.10.001] [PMID: 17112637] 
[53] 
De Strooper B, Saftig P, Craessaerts K, et al. Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein. Nature  1998; 391(6665): 387-90.
[http://dx.doi.org/10.1038/34910] [PMID: 9450754] 
[54] 
Das HK. Transcriptional regulation of the presenilin-1 gene: implication in Alzheimer’s disease. Front Biosci  2008; 13(13): 822-32.
[http://dx.doi.org/10.2741/2723] [PMID: 17981591] 
[55] 
Chen X-F, Zhang YW, Xu H, Bu G. Transcriptional regulation and its misregulation in Alzheimer’s disease. Mol Brain  2013; 6(1): 44.
[http://dx.doi.org/10.1186/1756-6606-6-44] [PMID: 24144318] 
[56] 
Jonsson T, Stefansson H, Steinberg S, et al. Variant of TREM2 associated with the risk of Alzheimer’s disease. N Engl J Med  2013; 368(2): 107-16.
[http://dx.doi.org/10.1056/NEJMoa1211103] [PMID: 23150908] 
[57] 
Turnbull IR, Gilfillan S, Cella M, et al. Cutting edge: TREM-2 attenuates macrophage activation. J Immunol  2006; 177(6): 3520-4.
[http://dx.doi.org/10.4049/jimmunol.177.6.3520] [PMID: 16951310] 
[58] 
Llorens-Marítin M, Jurado J, Hernández F, Ávila J. GSK-3β, a pivotal kinase in Alzheimer disease. Front Mol Neurosci  2014; 77169337
[http://dx.doi.org/10.3389/fnmol.2014.00046] 
[59] 
Milano J, McKay J, Dagenais C, et al. Modulation of notch processing by γ-secretase inhibitors causes intestinal goblet cell metaplasia and induction of genes known to specify gut secretory lineage differentiation. Toxicol Sci  2004; 82(1): 341-58.
[http://dx.doi.org/10.1093/toxsci/kfh254] [PMID: 15319485] 
[60] 
Leroy K, Brion J-P. Developmental expression and localization of glycogen synthase kinase-3β in rat brain. J Chem Neuroanat  1999; 16(4): 279-93.
[http://dx.doi.org/10.1016/S0891-0618(99)00012-5] [PMID: 10450875] 
[61] 
Frame S, Cohen P, Biondi RM. A common phosphate binding site explains the unique substrate specificity of GSK3 and its inactivation by phosphorylation. Mol Cell  2001; 7(6): 1321-7.
[http://dx.doi.org/10.1016/S1097-2765(01)00253-2] [PMID: 11430833] 
[62] 
Dudek H. Regulation of neuronal survival by the serine-threonine protein kinase akt. Science  1997; 25(5300): 661-5.
[http://dx.doi.org/10.1126/science.275.5300.661] 
[63] 
Clark KL, Halay ED, Lai E, Burley SK. Co-crystal structure of the HNF-3/fork head DNA-recognition motif resembles histone H5. Nature  1993; 364(6436): 412-20.
[http://dx.doi.org/10.1038/364412a0] [PMID: 8332212] 
[64] 
Maiese K, Chong ZZ, Shang YC. OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins. Trends Mol Med  2008; 14(5): 219-27.
[http://dx.doi.org/10.1016/j.molmed.2008.03.002] [PMID: 18403263] 
[65] 
Huang H, Tindall DJ. Dynamic FoxO transcription factors. J Cell Sci  2007; 120(Pt 15): 2479-87.
[http://dx.doi.org/10.1242/jcs.001222] [PMID: 17646672] 
[66] 
Maiese K, Chong ZZ, Shang YC, Wang S. Targeting disease through novel pathways of apoptosis and autophagy. Expert Opin Ther Targets  2012; 16(12): 1203-14.
[http://dx.doi.org/10.1517/14728222.2012.719499] [PMID: 22924465] 
[67] 
Park Y, Nnamani MC, Maziarz J, Wagner GP. Cis-regulatory evolution of forkhead box O1 (FOXO1), a terminal selector gene for decidual stromal cell identity. Mol Biol Evol  2016; 33(12): 3161-9.
[http://dx.doi.org/10.1093/molbev/msw193] [PMID: 27634871] 
[68] 
Maiese K, Chong ZZ, Hou J, Shang YC. The “O” class: crafting clinical care with FoxO transcription factors. Adv Exp Med Biol  2009; 665: 242-60.
[http://dx.doi.org/10.1007/978-1-4419-1599-3_18] [PMID: 20429429] 
[69] 
van der Heide LP, Jacobs FMJ, Burbach JPH, Hoekman MFM, Smidt MP. FoxO6 transcriptional activity is regulated by Thr26 and Ser184, independent of nucleo-cytoplasmic shuttling. Biochem J  2005; 391(Pt 3): 623-9.
[http://dx.doi.org/10.1042/BJ20050525] [PMID: 15987244] 
[70] 
Salih DAM, Rashid AJ, Colas D, et al. FoxO6 regulates memory consolidation and synaptic function. Genes Dev  2012; 26(24): 2780-801.
[http://dx.doi.org/10.1101/gad.208926.112] [PMID: 23222102] 
[71] 
Hou J, Wang S, Shang YC, Chong ZZ, Maiese K. Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress. Curr Neurovasc Res  2011; 8(3): 220-35.
[http://dx.doi.org/10.2174/156720211796558069] [PMID: 21722091] 
[72] 
Peng S, Zhao S, Yan F, et al. HDAC2 selectively regulates FOXO3a-mediated gene transcription during oxidative stress-induced neuronal cell death. J Neurosci  2015; 35(3): 1250-9.
[http://dx.doi.org/10.1523/JNEUROSCI.2444-14.2015] [PMID: 25609639] 
[73] 
Chamorro ME, Wenker SD, Vota DM, Vittori DC, Nesse AB. Signaling pathways of cell proliferation are involved in the differential effect of erythropoietin and its carbamylated derivative. Biochim Biophys Acta  2013; 1833(8): 1960-8.
[http://dx.doi.org/10.1016/j.bbamcr.2013.04.006] [PMID: 23602701] 
[74] 
Zeldich E, Chen CD, Colvin TA, et al. 
                       The neuroprotective effect of Klotho is mediated 
                        
                           via 
                        
                       regulation of members of the redox system.
                     J Biol Chem  2014; 289(35): 24700-15.
[http://dx.doi.org/10.1074/jbc.M114.567321] [PMID: 25037225] 
[75] 
Rong Z, Pan R, Xu Y, Zhang C, Cao Y, Liu D. Hesperidin pretreatment protects hypoxia-ischemic brain injury in neonatal rat. Neuroscience  2013; 255: 292-9.
[http://dx.doi.org/10.1016/j.neuroscience.2013.09.030] [PMID: 24076349] 
[76] 
Neri C. Role and therapeutic potential of the pro-longevity factor FOXO and its regulators in neurodegenerative disease. Front Pharmacol  2012; 3: 15.
[77] 
Hoekman MFM, Jacobs FMJ, Smidt MP, Burbach JPH. Spatial and temporal expression of FoxO transcription factors in the developing and adult murine brain. Gene Expr Patterns  2006; 6(2): 134-40.
[http://dx.doi.org/10.1016/j.modgep.2005.07.003] [PMID: 16326148] 
[78] 
Glenner GG, Wong CW, Quaranta V, Eanes ED. The amyloid deposits in Alzheimer’s disease: their nature and pathogenesis. Appl Pathol  1984; 2(6): 357-69.
[PMID: 6242724] 
[79] 
Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: past, present and future. Neuropharmacology  2014; 76(Pt A): 27-50.
[http://dx.doi.org/10.1016/j.neuropharm.2013.07.004] [PMID: 23891641] 
[80] 
Lucas JJ, Hernández F, Gómez-Ramos P, Morán MA, Hen R, Avila J. Decreased nuclear beta-catenin, tau hyperphosphorylation and neurodegeneration in GSK-3beta conditional transgenic mice. EMBO J  2001; 20(1-2): 27-39.
[http://dx.doi.org/10.1093/emboj/20.1.27] [PMID: 11226152] 
[81] 
Bullock BP, Habener JF. Phosphorylation of the cAMP response element binding protein CREB by cAMP-dependent protein kinase A and glycogen synthase kinase-3 alters DNA-binding affinity, conformation, and increases net charge. Biochemistry  1998; 37(11): 3795-809.
[http://dx.doi.org/10.1021/bi970982t] [PMID: 9521699] 
[82] 
Bijur GN, Jope RS. Proapoptotic stimuli induce nuclear accumulation of glycogen synthase kinase-3 β. J Biol Chem  2001; 276(40): 37436-42.
[http://dx.doi.org/10.1074/jbc.M105725200] [PMID: 11495916] 
[83] 
Qian W, Shi J, Yin X, et al. PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3beta. J Alzheimers Dis  2010; 19(4): 1221-9.
[http://dx.doi.org/10.3233/JAD-2010-1317] [PMID: 20308788] 
[84] 
Alikhani M, Roy S, Graves DT. FOXO1 plays an essential role in apoptosis of retinal pericytes. Mol Vis  2010; 16: 408-15.
[PMID: 20300563] 
[85] 
Alikhani M, Maclellan CM, Raptis M, Vora S, Trackman PC, Graves DT. Advanced glycation end products induce apoptosis in fibroblasts through activation of ROS, MAP kinases, and the FOXO1 transcription factor. Am J Physiol Cell Physiol  2007; 292(2): C850-6.
[http://dx.doi.org/10.1152/ajpcell.00356.2006] [PMID: 17005604] 
[86] 
Speckmann B, Walter PL, Alili L, et al. Selenoprotein P expression is controlled through interaction of the coactivator PGC-1alpha with FoxO1a and hepatocyte nuclear factor 4alpha transcription factors. Hepatology  2008; 48(6): 1998-2006.
[http://dx.doi.org/10.1002/hep.22526] [PMID: 18972406] 
[87] 
Lu Q, Zhai Y, Cheng Q, et al. The Akt-FoxO3a-manganese superoxide dismutase pathway is involved in the regulation of oxidative stress in diabetic nephropathy. Exp Physiol  2013; 98(4): 934-45.
[http://dx.doi.org/10.1113/expphysiol.2012.068361] [PMID: 23159718] 
[88] 
Smith WW, Norton DD, Gorospe M, et al. Phosphorylation of p66Shc and forkhead proteins mediates Abeta toxicity. J Cell Biol  2005; 169(2): 331-9.
[http://dx.doi.org/10.1083/jcb.200410041] [PMID: 15837797] 
[89] 
Shang YC, Chong ZZ, Hou J, Maiese K. The forkhead transcription factor FOXO3a controls microglial inflammatory activation and eventual apoptotic injury through Caspase 3. Curr Neurovasc Res  2009; 6(1): 20-31.
[http://dx.doi.org/10.2174/156720209787466064]] 
[90] 
Chuang PY, Dai Y, Liu R, et al. Alteration of forkhead box O (foxo4) acetylation mediates apoptosis of podocytes in diabetes mellitus. PLoS One  2011; 6(8)e23566
[http://dx.doi.org/10.1371/journal.pone.0023566] [PMID: 21858169] 
[91] 
Li H, Liang J, Castrillon DH, DePinho RA, Olson EN, Liu Z-P. FoxO4 regulates tumor necrosis factor alpha-directed smooth muscle cell migration by activating matrix metalloproteinase 9 gene transcription. Mol Cell Biol  2007; 27(7): 2676-86.
[http://dx.doi.org/10.1128/MCB.01748-06] [PMID: 17242183] 
[92] 
Yang H, Zhao R, Yang H-Y, Lee M-H. Constitutively active FOXO4 inhibits Akt activity, regulates p27 Kip1 stability, and suppresses HER2-mediated tumorigenicity. Oncogene  2005; 24(11): 1924-35.
[http://dx.doi.org/10.1038/sj.onc.1208352] [PMID: 15688030] 
[93] 
de la Torre-Ubieta L, Gaudillière B, Yang Y, et al. A FOXO-Pak1 transcriptional pathway controls neuronal polarity. Genes Dev  2010; 24(8): 799-813.
[http://dx.doi.org/10.1101/gad.1880510] [PMID: 20395366] 
[94] 
Kim DH, Perdomo G, Zhang T, et al. FoxO6 integrates insulin signaling with gluconeogenesis in the liver. Diabetes  2011; 60(11): 2763-74.
[http://dx.doi.org/10.2337/db11-0548] [PMID: 21940782] 
[95] 
Hong M, Lee VM-Y. Insulin and insulin-like growth factor-1 regulate tau phosphorylation in cultured human neurons. J Biol Chem  1997; 272(31): 19547-53.
[http://dx.doi.org/10.1074/jbc.272.31.19547] [PMID: 9235959] 
[96] 
Hu W, Yang Z, Yang W, et al. Roles of forkhead box O (FoxO) transcription factors in neurodegenerative diseases: a panoramic view. Prog Neurobiol  2019; 181101645
[http://dx.doi.org/10.1016/j.pneurobio.2019.101645] [PMID: 31229499] 
[97] 
Hong YK, Lee S, Park SH, et al. Inhibition of JNK/dFOXO pathway and caspases rescues neurological impairments in Drosophila Alzheimer’s disease model. Biochem Biophys Res Commun  2012; 419(1): 49-53.
[http://dx.doi.org/10.1016/j.bbrc.2012.01.122] [PMID: 22326868] 
[98] 
Perez FP, Bose D, Maloney B, Nho K, Shah K, Lahiri DK. Late-onset Alzheimer’s disease, heating up and foxed by several proteins: pathomolecular effects of the aging process. J Alzheimers Dis  2014; 40(1): 1-17.
[http://dx.doi.org/10.3233/JAD-131544] [PMID: 24326519] 
[99] 
Wang H, Quirion R, Little PJ, et al. Forkhead box O transcription factors as possible mediators in the development of major depression. Neuropharmacology  2015; 99: 527-37.
[http://dx.doi.org/10.1016/j.neuropharm.2015.08.020] [PMID: 26279492] 
[100] 
Akhter R, Sanphui P, Biswas SC. The essential role of p53-up-regulated modulator of apoptosis (Puma) and its regulation by FoxO3a transcription factor in β-amyloid-induced neuron death. J Biol Chem  2014; 289(15): 10812-22.
[http://dx.doi.org/10.1074/jbc.M113.519355] [PMID: 24567336] 
[101] 
Saleem S, Biswas SC. Tribbles pseudokinase 3 induces both apoptosis and autophagy in amyloid-β-induced neuronal death. J Biol Chem  2017; 292(7): 2571-85.
[http://dx.doi.org/10.1074/jbc.M116.744730] [PMID: 28011637] 
[102] 
Fluteau A, Ince PG, Minett T, et al. MRC Cognitive Function Ageing Neuropathology Study Group. The nuclear retention of transcription factor FOXO3a correlates with a DNA damage response and increased glutamine synthetase expression by astrocytes suggesting a neuroprotective role in the ageing brain. Neurosci Lett  2015; 609: 11-7.
[http://dx.doi.org/10.1016/j.neulet.2015.10.001] [PMID: 26455863] 
[103] 
Kuang X, Chen YS, Wang LF, et al. Klotho upregulation contributes to the neuroprotection of ligustilide in an Alzheimer’s disease mouse model. Neurobiol Aging  2014; 35(1): 169-78.
[http://dx.doi.org/10.1016/j.neurobiolaging.2013.07.019] [PMID: 23973442] 
[104] 
Ciechanover A, Brundin P. The ubiquitin proteasome system in neurodegenerative diseases: sometimes the chicken, sometimes the egg. Neuron  2003; 40(2): 427-46.
[http://dx.doi.org/10.1016/S0896-6273(03)00606-8] [PMID: 14556719] 
[105] 
Pickford F, Masliah E, Britschgi M, et al. The autophagy-related protein beclin 1 shows reduced expression in early Alzheimer disease and regulates amyloid β accumulation in mice. J Clin Invest  2008; 118(6): 2190-9.
[http://dx.doi.org/10.1172/JCI33585] [PMID: 18497889] 
[106] 
Hara T, Nakamura K, Matsui M, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature  2006; 441(7095): 885-9.
[http://dx.doi.org/10.1038/nature04724] [PMID: 16625204] 
[107] 
Demontis F, Perrimon N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell  2010; 143(5): 813-25.
[http://dx.doi.org/10.1016/j.cell.2010.10.007] [PMID: 21111239] 
[108] 
Sengupta A, Molkentin JD, Yutzey KE. FoxO transcription factors promote autophagy in cardiomyocytes. J Biol Chem  2009; 284(41): 28319-31.
[http://dx.doi.org/10.1074/jbc.M109.024406] [PMID: 19696026] 
[109] 
Webb AE, Brunet A. FOXO transcription factors: key regulators of cellular quality control. Trends Biochem Sci  2014; 39(4): 159-69.
[PMID: 24630600] 
[110] 
Husom AD, Peters EA, Kolling EA, Fugere NA, Thompson LV, Ferrington DA. Altered proteasome function and subunit composition in aged muscle. Arch Biochem Biophys  2004; 421(1): 67-76.
[PMID: 14678786] 
[111] 
Vilchez D, Boyer L, Morantte I, et al. Increased proteasome activity in human embryonic stem cells is regulated by PSMD11. Nature  2012; 489(7415): 304-8.
[http://dx.doi.org/10.1038/nature11468] [PMID: 22972301] 
[112] 
Kaestner KH, Kno W, Martı DE. Unified nomenclature for the winged helix: forkhead transcription factors. Genes Dev  2000; 14(2): 142-6.
[113] 
Van Der Heide LP, Hoekman FM, Smidt MP. The ins and outs of FoxO shuttling: mechanisms of FoxO translocation and transcriptional regulation. Biochem J  2004; 380(2): 297-309.
[114] 
Nakae J, Park B-C, Accili D. Insulin stimulates phosphorylation of the forkhead transcription factor FKHR on serine 253 through a Wortmannin-sensitive pathway. J Biol Chem  1999; 274(23): 15982-5.
[http://dx.doi.org/10.1074/jbc.274.23.15982] [PMID: 10347145] 
[115] 
Rena G, Woods YL, Prescott AR, et al. Two novel phosphorylation sites on FKHR that are critical for its nuclear exclusion. EMBO J  2002; 21(9): 2263-71.
[http://dx.doi.org/10.1093/emboj/21.9.2263] [PMID: 11980723] 
[116] 
Rena G, Prescott AR, Guo S, Cohen P, Unterman TG. Roles of the forkhead in rhabdomyosarcoma (FKHR) phosphorylation sites in regulating 14-3-3 binding, transactivation and nuclear targetting. Biochem J  2001; 354(Pt 3): 605-12.
[http://dx.doi.org/10.1042/bj3540605] [PMID: 11237865] 
[117] 
Huang H, Regan KM, Wang F, et al. Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation. Proc Natl Acad Sci USA  2005; 102(5): 1649-54.
[http://dx.doi.org/10.1073/pnas.0406789102] [PMID: 15668399] 
[118] 
Matsuzaki H, Daitoku H, Hatta M, Tanaka K, Fukamizu A. Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation. Proc Natl Acad Sci USA  2003; 100(20): 11285-90.
[http://dx.doi.org/10.1073/pnas.1934283100] [PMID: 13679577] 
[119] 
Calabuig-Navarro V, Yamauchi J, Lee S, et al. Forkhead box O6 (FoxO6) depletion attenuates hepatic gluconeogenesis and protects against fat-induced glucose disorder in mice. J Biol Chem  2015; 290(25): 15581-94.
[http://dx.doi.org/10.1074/jbc.M115.650994] [PMID: 25944898] 
[120] 
Greer EL, Brunet A. FOXO transcription factors in ageing and cancer. Acta Physiol (Oxf)  2008; 192(1): 19-28.
[http://dx.doi.org/10.1111/j.1748-1716.2007.01780.x] [PMID: 18171426] 
[121] 
Schinner S, Scherbaum WA, Bornstein SR, Barthel A. Molecular mechanisms of insulin resistance. Diabet Med  2005; 22(6): 674-82.
[http://dx.doi.org/10.1111/j.1464-5491.2005.01566.x] [PMID: 15910615] 
[122] 
Bellinger FP, He QP, Bellinger MT, et al. Association of selenoprotein p with Alzheimer’s pathology in human cortex. J Alzheimers Dis  2008; 15(3): 465-72.
[http://dx.doi.org/10.3233/JAD-2008-15313] [PMID: 18997300] 
[123] 
Sompol P, Ittarat W, Tangpong J, et al. A neuronal model of Alzheimer’s disease: an insight into the mechanisms of oxidative stress-mediated mitochondrial injury. Neuroscience  2008; 153(1): 120-30.
[http://dx.doi.org/10.1016/j.neuroscience.2008.01.044] [PMID: 18353561] 
[124] 
Jope RS, Johnson GV. The glamour and gloom of glycogen synthase kinase-3. Trends Biochem Sci  2004; 29(2): 95-102.
[http://dx.doi.org/10.1016/j.tibs.2003.12.004] [PMID: 15102436] 
[125] 
Liang M-H, Chuang D-M. Differential roles of glycogen synthase kinase-3 isoforms in the regulation of transcriptional activation. J Biol Chem  2006; 281(41): 30479-84.
[http://dx.doi.org/10.1074/jbc.M607468200] [PMID: 16912034] 
[126] 
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-3 β and cyclin-dependent kinase 5, a component of TPK II. Acta Neuropathol  1996; 92(3): 232-41.
[http://dx.doi.org/10.1007/s004010050513] [PMID: 8870824] 
[127] 
Ishizawa T, Sahara N, Ishiguro K, et al. Co-localization of glycogen synthase kinase-3 with neurofibrillary tangles and granulovacuolar degeneration in transgenic mice. Am J Pathol  2003; 163(3): 1057-67.
[http://dx.doi.org/10.1016/S0002-9440(10)63465-7] [PMID: 12937146] 
[128] 
Phiel CJ, Wilson CA, Lee VM-Y, Klein PS. GSK-3α regulates production of Alzheimer’s disease amyloid-β peptides. Nature  2003; 423(6938): 435-9.
[http://dx.doi.org/10.1038/nature01640] [PMID: 12761548] 
[129] 
Kareem O. Ghulam Nabi Bader, Faheem Hyder Pottoo, Mohd Amir, Md. Abul Barkat, Mukesh Pandey. Beclin 1 complex and neurodegenerative disorders. Quality Control of Cellular Protein in Neurodegenerative Disorders  2020; 236-60.
[http://dx.doi.org/10.4018/978-1-7998-1317-0.ch009] 
[130] 
Shi Y. Mechanisms of caspase activation and inhibition during apoptosis. Mol Cell  2002; 9(3): 459-70.
[http://dx.doi.org/10.1016/S1097-2765(02)00482-3] [PMID: 11931755] 
[131] 
Guo H, Albrecht S, Bourdeau M, Petzke T, Bergeron C, LeBlanc AC. Active caspase-6 and caspase-6-cleaved tau in neuropil threads, neuritic plaques, and neurofibrillary tangles of Alzheimer’s disease. Am J Pathol  2004; 165(2): 523-31.
[http://dx.doi.org/10.1016/S0002-9440(10)63317-2] [PMID: 15277226] 
[132] 
Rissman RA, Poon WW, Blurton-Jones M, et al. Caspase-cleavage of tau is an early event in Alzheimer disease tangle pathology. J Clin Invest  2004; 114(1): 121-30.
[http://dx.doi.org/10.1172/JCI200420640] [PMID: 15232619] 
[133] 
Oddo S, Caccamo A, Shepherd JD, et al. Triple-transgenic model of Alzheimer’s disease with plaques and tangles: intracellular Abeta and synaptic dysfunction. Neuron  2003; 39(3): 409-21.
[PMID: 12895417] 
[134] 
Buteau J, Accili D. Regulation of pancreatic beta-cell function by the forkhead protein FoxO1. Diabetes Obes Metab  2007; 9(s2)(Suppl. 2): 140-6.
[http://dx.doi.org/10.1111/j.1463-1326.2007.00782.x] [PMID: 17919188] 
[135] 
Martinez SC, Tanabe K, Cras-Méneur C, Abumrad NA, Bernal-Mizrachi E, Permutt MA. Inhibition of Foxo1 protects pancreatic islet beta-cells against fatty acid and endoplasmic reticulum stress-induced apoptosis. Diabetes  2008; 57(4): 846-59.
[http://dx.doi.org/10.2337/db07-0595] [PMID: 18174526] 
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DOI https://dx.doi.org/10.2174/1871527319666201001105553	Print ISSN 1871-5273
Publisher Name Bentham Science Publisher	Online ISSN 1996-3181
CNS & Neurological Disorders - Drug Targets

Role of Forkhead Transcription Factors of the O Class (FoxO) in Development and Progression of Alzheimer’s Disease

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