key: cord-0730495-wsus5dye
authors: Maiese, Kenneth
title: Neurodegeneration, memory loss, and dementia: the impact of biological clocks and circadian rhythm
date: 2021-09-30
journal: Front Biosci (Landmark Ed)
DOI: 10.52586/4971
sha: 3217f2944b1b8ebb54e8a480952c3f746c003f80
doc_id: 730495
cord_uid: wsus5dye

INTRODUCTION: Dementia and cognitive loss impact a significant proportion of the global population and present almost insurmountable challenges for treatment since they stem from multifactorial etiologies. Innovative avenues for treatment are highly warranted. METHODS AND RESULTS: Novel work with biological clock genes that oversee circadian rhythm may meet this critical need by focusing upon the pathways of the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt pathway. These pathways are complex in nature, intimately associated with autophagy that can maintain circadian rhythm, and have an intricate relationship that can lead to beneficial outcomes that may offer neuroprotection, metabolic homeostasis, and prevention of cognitive loss. However, biological clocks and alterations in circadian rhythm also have the potential to lead to devastating effects involving tumorigenesis in conjunction with pathways involving Wnt that oversee angiogenesis and stem cell proliferation. CONCLUSIONS: Current work with biological clocks and circadian rhythm pathways provide exciting possibilities for the treating dementia and cognitive loss, but also provide powerful arguments to further comprehend the intimate and complex relationship among these pathways to fully potentiate desired clinical outcomes.

Neurodegenerative disorders pose a significant challenge for diagnosis, preventing disease progression, and providing treatment. Cognitive loss in relation to Alzheimer's disease (AD) is an excellent example since diseases that include AD are the result of multiple underlying mechanisms [1] [2] [3] [4] [5] [6] (Table 1) . For example, many pathways may lead to memory loss and involve neuronal and vascular cell injury related to metabotropic receptors, lipid dysfunction, cellular metabolic dysfunction with diabetes mellitus (DM), astrocytic cell injury, β-amyloid (Aβ), heavy metal disease, loss of access to bright light, tau, mitochondrial damage, oxidative stress, acetylcholine loss, and excitotoxicity [1, 3, .

In addition, cognitive disorders raise significant financial concerns [1, [31] [32] [33] [34] . Greater than 800 billion United States dollars (USD) per year are required to treat dementia equaling approximately 2 percent of the global Gross Domestic Product. Social and medical services by the year 2030 may possibly equal 2 trillion USD per year in the United States. Currently, greater than 5 million patients have AD and it is estimated that 4 million receive care at a yearly cost of 3.8 billion USD. Furthermore, the market revenue to provide treatments for AD may not be fully appreciated, but at minimum it may be greater than 11 billion USD. Many new social and medical services will be necessary to meet this challenge such that 60 million additional care workers will be needed [35] [36] [37] . These projections do not consider that all cases of dementia may not have been identified and diagnosed at this time [38, 39] .

Cognitive loss impacts a large spectrum of the population. Dementia in the United States affects greater than 5 million people [4] . Many of these cases, 60 percent, are diagnosed as AD [4, 6, 17, [40] [41] [42] [43] . Case of AD that are familial in origin comprise under 2% of all cases [4] . In familial AD that affects 200 families worldwide, mutations in the presenilin 1 or 2 genes occurs and an autosomal dominant mutated amyloid precursor protein (APP) gene exists. In these familial AD patients, illness can present prior to 55 years of age [44] [45] [46] . Familial AD can be the result of mutations in chromosome 21 leading to changes in APP, mutations in chromosome 14 causing changes in presenilin 1, and mutations in chromosomes 1, 14, and 21 such that mutations in chromosome 1 lead to changes in presenilin However, it is the sporadic version of AD that leads to illness in patients over age 65 and represents the cases of AD in ten percent of the population in the world. The ϵ4 allele of the apolipoprotein E (APOE) gene represents an additional risk of developing AD in the sporadic group.

Current attempts to treat dementia such as with cholinesterase inhibitors may lead to a decrease in the presenting symptoms but ultimately do not block the progression of the disease, such as in AD [27, 45, 47, 48] . Other treatments for cognitive loss can focus on metabolic disorders, such as diabetes mellitus (DM) [1, 20, 27, 41, 49, 50] , and on vascular disease [19, 45, [51] [52] [53] ]. Yet, there exist other risks for developing vascular cognitive loss that can affect the efficacy of treatments such as tobacco use, alcohol consumption, hypertension, and a low level of education [20, 39, [54] [55] [56] [57] . With reference to metabolic disease, tight glucose control in the serum in combination with early diagnosis of DM may assist to limit the progression of the disease, but complications from DM can still ensue [6, [58] [59] [60] [61] [62] [63] [64] [65] [66] [67] [68] [69] . Given the need for novel strategies directed against memory loss and dementia, exciting new avenues of development are now focusing upon biological clock mechanisms and include the pathways of the mechanistic target of rapamycin (mTOR), its associated pathways of mTOR Complex 1 (mTORC1), mTOR Complex 2 (mTORC2), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless pathway of Wnt pathway (Fig. 1) .

Biological clocks and circadian rhythm pathways are vital components in the onset of nervous system disorders, memory loss, and dementia [6, 34, 39, [70] [71] [72] [73] [74] [75] [76] (Table 1) . Changes in the function of biological clock pathways can impact cellular metabolic homeostasis [6, [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] , cancer [6, 80, 81, 84, [86] [87] [88] [89] , energy metabolism and aging [70, 74, 77, 84, 90] , mitochondrial energy maintenance [76, 81, 91, 92] , renal disease [78, 86] , and viral diseases [72, [93] [94] [95] [96] [97] [98] [99] [100] [101] . Circadian rhythm in mammals is controlled in a region over the optic chiasm that detects light with retinal photosensitive ganglion cells in the suprachiasmatic nucleus (SCN) [6, 84, 98] . With the exposure to external light, biological clock genes oversee biochemical cell transmissions, physiological process in the body, and changes in behavior. The SCN controls the temperature of the body, cortisol and melatonin release, and oxidative stress responses through a connected system among the hypothalamic nuclei, pineal gland, and vasoactive intestinal peptide [88, 102, 103] . As part of the biological clock gene group, members of the basic helix-loop-helix-PAS (Period-Arnt-Single-minded) transcription factor family, that include CLOCK and BMAL1 [104] , control gene expression of Cryptochrome (Cry1 and Cry2) and Period (Per1, Per2, and Per3) [6, 78, 84, 86, [105] [106] [107] . Modulation of these pathways and auto-feedback interactions are controlled by PER:CRY heterodimers that block transcription during nuclear translocation promoted by CLOCK:BMAL1 complexes. Other regulatory pathways that can be activated by CLOCK:BMAL1 heterodimers include RORα and retinoic acid-related orphan nuclear receptors REV-ERBα, also termed NR1D1 (nuclear receptor subfamily 1, group D, member 1). The REV-ERBα and RORα receptors attach to retinoic acid-related orphan receptor response elements (ROREs) that exist in the BMAL1 promoter to block and promote rhythmic transcription of BMAL1 by RORs and REV-ERBs, respectively. REV-ERBs can inhibit transcription to lead to circadian oscillation of BMAL1 [74, 105] .

With neurodegeneration and aging studies, experimental studies with Parkinson's disease (PD) using 6-hydroxydopamine (6-OHDA) during chronic treatment with levodopa show depressed levels of BMAL1 and RORα, indicating that memory loss in PD patients also may be a result of medication that alters circadian rhythm clock genes [106] . Cognitive impairment with memory loss and neuronal injury may occur as a result of sleep fragmentation during extended space flight which alters circadian rhythm [108, 109] . Changes in the DNA methylation of biological clock genes may foster memory loss and changes in behavior since rhythmic methylation of BMAL1 has been shown in the brains of individuals with AD [70] . In experimental studies AD using mice, significant alterations have been observed in RNA clock gene expression that may suggest a dysfunction in the clock pathways during cognitive loss [110] .

Lifespan can be affected by biological clock genes. Lifespan in Drosophila melanogaster is decreased through three arrhythmic mutants involving ClkAR, cyc0 and tim0. In addition, mutations in ClkAR with increasing age can result in dysfunction with ambulation. Through the promotion of Clk function, the locomotor deficits in Drosophila were reversed. This loss of function appears linked to the absence of dopaminergic neurons instead of insults from oxidative stress [75] . Other studies in Drosophila also suggest negative effects with alterations in circadian rhythm [6, 80, 84] (Table 1) . For example, TIMELESS, a mammalian homolog of Drosophila circadian rhythm gene, can lead to cell death and has increased expression in nasopharyngeal carcinoma. During increased TIMELESS expression, cell growth pathways are fostered that involve the wingless pathway of Wnt/βcatenin and resistance against chemotherapy to lead to cell apoptosis, such as with cisplatin, is increased [89] . Wnt proteins are cysteine-rich glycosylated proteins that can affect development of neurons, immune system function, tissue fibrosis, angiogenesis, stem cell development, and cancer [111] [112] [113] [114] . Yet, detrimental effects with Wnt pathways can result to promote increased vascular growth of tumors [111, 115, 116] and tumorigenesis [40, [117] [118] [119] [120] [121] . As a result, these mechanisms may work in conjunction with TIMELESS. There also is evidence for sleep fragmentation and disruption of biological clock genes with shift work to indicate that these lighting and international travel are other examples that can lead to circadian rhythm disturbance [79] . Sleep deprivation affects circadian rhythm and can prevent the clearance of Aβ, α-synuclein, and tau that are tied to the progression of nervous system disorders that include AD and PD [34, 109] . Some work suggests that female healthcare workers with extended night shift work may be at enhanced risk for breast cancer [122] . The circadian gene hClock during increased expression also can lead to cancer and colorectal cancer metastatic disease through promotion genes that activate angiogenesis [123] .

Circadian clock genes rely upon pathways of both autophagy and the mechanistic target of rapamycin (mTOR) [6, 84, [124] [125] [126] (Table 1) . Circadian rhythm dysfunction can lead to changes in the induction of autophagy especially during cognitive loss [72, 81, 84, 92, [127] [128] [129] . Autophagy plays a vital role in multiple diseases of the nervous system and can sequester and remove intracellular deposits during AD [19, 41, 130, 131] , amyotrophic lateral sclerosis [48, 132, 133], Huntington's disease (HD) [19, 134] , traumatic brain injury [135] [136] [137] , and PD [83, 130, 135, [138] [139] [140] . This removal of toxic intracellular substances may be important to maintain memory and cognition. As part of a programmed cell death pathway, autophagy is tied to oxidative stress [2, 29, 66, 67, 71, [141] [142] [143] [144] [145] . Autophagy pathways can recycle cytoplasmic organelles and components for tissue remodeling [19, 146] and can eliminate non-functional organelles [6, 71, 142, 147] . Macroautophagy reuses organelles in cells and packages cytoplasmic proteins into cellular components termed autophagosomes. Once associated with lysosomes, the autophagosomes are degraded to begin another process for the recycling of organelles [19] . Microautophagy promotes invagination of lysosomal membranes to allow for the digestion of cell cytoplasm components. Chaperone-mediated autophagy employs cytosolic chaperones to transport cytoplasmic cell components across lysosomal membranes.

Previous studies also suggest in experimental studies with AD that a baseline cyclic circadian rhythm that controls autophagy is necessary to reduce Aβ deposition and prevent memory loss [129, 148] . Alterations in environmental homeostasis [82, 129, 149] can alter circadian rhythm that results in loss of cognitive ability [2, 19, 49, 50, 84, 150] . Sleep fragmentation also can produce changes in hippocampal autophagy proteins and decrease memory function [4, 127, [151] [152] [153] [154] . Cellular protection is dependent on the activation of autophagy with circadian clock proteins during insults with stroke, since loss in the function of the PER1 circadian clock protein can increase cerebral ischemia [128] .

In regard to the mTOR pathway, mTOR is a 289-kDa serine/threonine protein kinase and is vital during nervous system disease and memory loss [2, 19, 20, 25, 49, [155] [156] [157] . mTOR is also known as the mammalian target of rapamycin and the FK506-binding protein 12-rapamycin complex-associated protein 1 [19, 85, 158, 159] . mTOR is the main component of the protein complexes mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) [160] [161] [162] . mTORC1 and mTORC2 are then divided into additional components [2, 107, [163] [164] [165] . mTORC1 is composed of Raptor, Deptor (DEP domaincontaining mTOR interacting protein), the proline rich Akt substrate 40 kDa (PRAS40), and mammalian lethal with Sec13 protein 8, termed mLST8 (mLST8) [20, 40, 166] . mTORC1 activity is controlled through a number of pathways that includes PRAS40 by blocking the association of p70 ribosomal S6 kinase (p70S6K) and the eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4EBP1) with Raptor [167, 168] . Rapamycin is an agent that can inhibit mTOR activity [164, [169] [170] [171] [172] . Rapamycin blocks the activity of mTORC1 through its association with immunophilin FK-506-binding protein 12 (FKBP12) that attaches to the FKBP12 -rapamycin-binding domain (FRB) at the carboxy (C) -terminal of mTOR to impede the FRB domain of mTORC1 [4] . mTORC2 is composed of Rictor, Deptor, mLST8, the mammalian stress-activated protein kinase interacting protein (mSIN1), and the protein observed with Rictor-1 (Protor-1) [167, 173, 174] . mTORC2 oversees remodeling of the cytoskeleton through PKCα and the migration of cells through the Rac guanine nucleotide exchange factors P-Rex1 and P-Rex2 and through Rho signaling [175] . Cognitive decline can be associated with the loss of mTOR activity and altered circadian rhythm during extended space flight [108] . Ischemia in the brain that leads to stroke may be altered by alteration in circadian rhythm genes and fluctuations in the activity of mTOR [124, 128] . Other studies suggest that the absence of period2 (PER2), a mammalian circadian clock protein, can increase mTOR activity and chemotherapy drug resistance [125] . mTOR also maintains a relationship with the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1). SIRT1 maintains an inverse relationship with mTOR [19, [176] [177] [178] [179] [180] . SIRT1 can also affect pathways of autophagy [49, 65, 163, 178, [181] [182] [183] [184] [185] [186] . SIRT1 activity can lead to the expansion of neurites and promote the survival of neurons during conditions that limit nutrients that involves mTOR inhibition [187] . SIRT1 can foster growth of tumors during autophagy induction that requires the blockade of mTOR, indicating that autophagy and SIRT1 can be targeted to control tumorigenesis [183] . SIRT1 is necessary to foster autophagy and mTOR inhibition during oxidative stress to preserve mitochondrial function in embryonic stem cells [188] . During periods of elevated serum glucose, SIRT1 can block mTOR to offer vascular cell protection [189] . SIRT1 with the blockade of mTOR activity can increase photoreceptor cell survival [177] and limit cell senescence [190] . It is also important to note that some pathways that lead to nerve cell injury require a relationship between mTOR and SIRT1 that is symbiotic. During the loss of dopaminergic neuronal cells, it has been observed that a balance in activities of SIRT1, mTOR, and forkhead transcription factors are required to promote neuronal cell survival [191] . It also has been demonstrated that SIRT1 and mTOR absence during obesity can suppress core circadian components CLOCK and BMAL1 and lead to loss of metabolic cellular homeostasis. The agent metformin, an inhibitor of mTOR activity [4, 65, 72] , can prevent such processes during obesity in experimental mouse models and can reverse the loss of SIRT1 function during inhibition of the circadian components CLOCK and BMAL1 [192] .

Biological clock pathways closely rely upon SIRT1 [6, 84, 85, 91, 193, 194] (Table 1) . SIRT1 is a histone deacetylase that can transfer acetyl groups from ϵ-N-acetyl lysine amino acids to the histones of deoxyribonucleic acid (DNA) to control transcription [19, 45, 48, 84, 85, 152, [195] [196] [197] [198] [199] [200] . As noted above, SIRT1 plays a critical role in nervous system diseases [164, 199, 201, 202] that also are dependent upon autophagy regulation [113, 178, 185, 186, 190, 203] . Other work focuses on SIRT1 to control the expression of clock genes through PER2 deacetylation [204] . SIRT1 its ability to control multiple biological clock gene pathways indicates that loss of SIRT can impact circadian rhythm cycles and result in memory loss and AD [110] .

Through SIRT1 pathways, the coenzyme ß-nicotinamide adenine dinucleotide (NAD + ) has an important function with clock genes that is linked to mTOR [20, 66, 72, 192, 205] . Control of circadian rhythm by SIRT1 and melatonin can impact glucose tolerance in cells [102] . Dementia onset can be dependent upon melatonin, a pineal hormone that controls circadian rhythm [81, 88, 95] , as well as mTOR through autophagy induction [90, 206] . During the process of aging, circadian rhythm cycles involving melatonin can affect infection with coronavirus disease of 2019 (COVID-19) [94] , cellular metabolism [90, 103] , mitochondrial dysfunction [81] , oxidative stress [207, 208] , and inflammatory mediators [206, 209] . In addition, SIRT1 can affect biological clock rhythm through stem cell function [210] and inflammation during obesity [91] and neurodegeneration [209] . Cellular NAD + pools fluctuate with circadian rhythmicity and with aging [72] . SIRT1 in connection with CLOCK:BMAL1 can control the circadian expression of nicotinamide phosphoribosyltransferase (NAMPT) that is required for NAD + production. SIRT1 also through the NAMPT promoter can promote the circadian synthesis of its own coenzyme [211] . Yet, NAD + cellular pools can become depleted during impairment of mitochondrial function to result in cell injury with cellular NAD + pools oscillating with free nicotinamide levels and promoting cell injury, metabolic dysfunction, and loss of cognitive function [205] . SIRT1 regulation of biological clock genes also can affect cognitive function though growth factors, such as EPO [161, 197, [212] [213] [214] . The EPO gene is present on chromosome 7

and represents a single copy in a 5.4 kb region of the genomic DNA [215, 216] . The gene encodes for a polypeptide chain protein that has 193 amino acids [64, 217] . EPO later undergoes the removal of a carboxy-terminal arginine 166 in the mature human and recombinant human EPO (rhEPO). A protein with a molecular weight of 30.4 kDa and 165 amino acids is generated as the mature protein [218] [219] [220] [221] . EPO expression occurs in the brain, uterus, and liver [64, 161, 164, 215, 216, 222, 223] , but the principal site for the production and secretion of EPO is the peritubular interstitial cells of the kidney [216, 217, [224] [225] [226] [227] . It is important to note that expression of EPO is overseen by oxygen tension changes and not by the concentration of red blood cells [64, 228, 229] .

In relation to SIRT1, EPO prevents metabolic dysfunction by modulating adipose energy homeostasis in adipocytes through the combined activation of peroxisome proliferatoractivated receptor-α (PPAR-α) and SIRT1 [213] (Table 1) . EPO promotes vascular cell protection in the brain through SIRT1 nuclear subcellular trafficking and blocks mitochondrial depolarization, cytochrome c release, BCL2 associated agonist of cell death (Bad) activity, and caspase activation [212] . EPO can increase human cardiomyocyte survival through SIRT1 activation during chemotherapy toxicity [197] and prevent brain neuronal cell loss through the up-regulation of SIRT1 [214] . EPO can block memory loss during AD [5, 43] , control metabolic pathways [230, 231] , and block mitochondrial dysfunction [197, 216, 222, [232] [233] [234] . However, control of biological clock gene pathways appear to be necessary for EPO and SIRT1 to offer cellular protection. Some studies indicate that during hypoxia specific clock genes, that include BMAL1 and PER2, are required for the production of EPO [235] .

EPO also relies upon mTOR to affect cellular survival. EPO employs mTOR to foster neuronal regeneration through autophagy and apoptotic pathways [20, 203, [236] [237] [238] [239] . EPO prevents apoptosis during Aβ exposure with mTOR activation to prevent caspase activation [240] . EPO can increase the survival of microglia during oxidative stress through mTOR signaling pathways [241] . EPO oversees mTOR, protein kinase B (Akt) [232, 242, 243] , and proline rich Akt substrate 40 kDa (PRAS40) to promote the survival of neurons during oxygen-glucose deprivation [244] .

Mammalian FOXO proteins of the O class are transcription factors and play a significant role in the nervous system. FoxO family members include FOXO1, FOXO3, FOXO4, and FOXO6 [67, 164, [245] [246] [247] (Table 1) . FoxO proteins bind to deoxyribonucleic acid (DNA) through the FoxO-recognized element in the C-terminal basic region of the forkhead DNA binding domain. With the binding to DNA by FoxOs, target gene expression is blocked or promoted through fourteen protein-DNA contacts with the primary recognition site located at α-helix H3. Phosphorylation or acetylation of FoxOs can change the binding of the C-terminal basic region to DNA to inhibit FoxO transcriptional activity [48, 152, 199, 248] . FoxOs are intimately connected circadian rhythm since they are linked to SIRT1 [4, 34, 48, 85, [248] [249] [250] [251] [252] . For example, insulin-phosphatidylinositol 3-kinase (PI3K) signaling that occurs in the liver is overseen by FoxO3 control of circadian rhythmicity through modulation of Clock. Loss of FoxO3 impairs the circadian amplitude and rhythmicity [253] . Autophagy induction also is dependent on mammalian FOXO proteins of the O class [12, 164, 202, 254, 255] . FoxO1 transcription factors [256] oversee the myelination of nerves that requires oligodendrocyte progenitor cells and determine the progression of disorders that include multiple sclerosis [257] . Additional studies indicate that epigenetic changes in DNA methylation and genetic variations of FoxO3a and FoxO1 also can affect demyelinating disorders [258] . Yet, it is important to state that a fine balance in FoxO activity is necessary to lead to the protection of cells since activation of FoxOs with autophagy can be beneficial. Sequestering and clearance of detrimental intracellular accumulations by FoxOs and autophagy can lead to increased survival of neurons [246, 259, 260] .

In regard to SIRT1, blockade of the activity of FoxOs by SIRT1 can promote cell survival [19, 67, [249] [250] [251] . However, FoxOs can attach to the SIRT1 promoter region to further change forkhead transcription [181] . This mechanism permits FoxOs to use auto-feedback mechanisms to regulate the activity of SIRT1. FoxO proteins, including FoxO1, can oversee SIRT1 transcription and increase the expression of SIRT1 [261] . These studies suggest an intimate relationship between SIRT1 and FoxOs. Interestingly, SIRT1 and FoxOs can synergistically increase cell survival. SIRT1 and FoxO3a can work in unison to block memory loss and Aβ brain toxicity, mitochondrial dysfunction, and oxidative stress [5, 152, 262, 263] .

Neurodegenerative disorders that involve cognitive loss and dementia impact a significant proportion of the world's population and lead to a large financial burden for all nations. Adding to these concerns is the knowledge that cognitive disorders present almost insurmountable challenges for treatment since they are multifactorial in origin and can result from multiple pathways that involve Aβ, tau, metabotropic receptors, excitotoxicity, lipid dysfunction, mitochondrial damage, astrocyte injury, loss of access to bright light, heavy metal disease, acetylcholine loss, oxidative stress, and metabolic dysfunction that involves DM. Novel new therapeutic strategies are desperately warranted. New investigations may meet this need with work that highlights biological clock genes that oversee circadian rhythm and involve the pathways of mTOR, SIRT1, FoxOs, EPO, and the Wnt/β-catenin pathway (Fig. 1) . These pathways are complex in nature and intimately tied to autophagy induction that can sequester intracellular accumulations and potentially reduce cognitive loss under some conditions. Dysfunctional changes in biological clock genes and circadian rhythm can result in motor deficits, memory impairment, and the progression of dementia. Even chronic treatment regimens that occur during PD can alter circadian rhythm function and foster dementia. The pathways of autophagy may be one mechanism to oversee circadian rhythm homeostasis that can become lost during conditions of chronic sleep fragmentation.

The pathways that impact circadian rhythm have an intricate relationship that can lead to both beneficial as well as detrimental clinical effects. For example, blockade of mTOR activity can change circadian rhythm, affect memory function, and increase neuronal cell injury such as during stroke. SIRT1 can oversee the production of NAD + pools that have been tied to circadian rhythmicity and if these cellular pools become depleted, cell injury and metabolic dysfunction can ensue with cognitive loss. Furthermore, without circadian rhythm control, the protective capability of EPO and SIRT1 may become absent and lead to mitochondrial dysfunction and the loss of cognition. In regard to FoxOs, SIRT1 and FoxOs may be required to work in unison to limit cognitive loss, mitochondrial dysfunction, and oxidative stress. Yet, it is important to remember that Wnt pathways that function in conjunction with circadian clock gene pathways, such as TIMELESS, may promote new angiogenesis and tumorigenesis. In addition, other circadian genes that include hClock also may promote metastatic colorectal cancer through the promotion of angiogenesis-related gene activity and vascular cell growth.

These observations serve to form a strong foundation for the further investigation of biological clock genes and circadian rhythm in regards to their significant role in neurodegenerative disorders such as dementia. The circadian pathways involving mTOR, SIRT1, FoxOs, EPO, and the Wnt can offer considerable potential for the understanding and treatment of memory loss and neurodegnerative disorders. Yet, it is the intimate and complex relationship among these pathways that is most intriguing and potentially offers the greatest insight to harness this knowledge for the innovative treatment of dementia.

We appreciate the reviewers for their opinions and suggestions.

This research was supported by the following grants to Kenneth Maiese: American Diabetes Association, American Heart Association, NIH NIEHS, NIH NIA, NIH NINDS, NS053956, and NIH ARRA.

Alzheimer's disease The circadian biological clock gene pathways are intricately related but complex in nature. The pathways of the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt/β-catenin pathway can lead to beneficial outcomes and employ autophagy induction that may provide cellular protection, metabolic homeostasis, and prevent dementia and cognitive loss. Yet, biological clocks and alterations in circadian rhythm, such as during sleep disruption and fragmentation, also have the potential to lead to devastating effects involving tumorigenesis in conjunction with pathways involving Wnt that oversee angiogenesis and stem cell proliferation. Circadian rhythm disruption can result from shift work, exposure to artificial lighting, and from sleep fragmentation. A fine balance in the oversight of circadian biological clock gene pathways is required to foster safe and efficacious clinical outcomes for the treatment of dementia and cognitive loss. 

• Cognitive loss in relation to Alzheimer's disease is an excellent example of complex disorders that are multi-factorial in origin and may involve several mechanisms as etiologies that include cellular injury from β-amyloid, tau, metabotropic receptors, excitotoxicity, lipid dysfunction, mitochondrial damage, loss of access to bright light, acetylcholine loss, oxidative stress, and metabolic dysfunction with diabetes mellitus.

• Current strategies to treat cognitive loss are limited and do not adequately address disease onset and progression. Innovative work with biological clock genes that oversee circadian rhythm can offer new strategies for the treatment of dementia that employ the pathways of the mechanistic target of rapamycin (mTOR), the silent mating type information regulation 2 homolog 1 (Saccharomyces cerevisiae) (SIRT1), mammalian forkhead transcription factors (FoxOs), the growth factor erythropoietin (EPO), and the wingless Wnt/β-catenin pathway.

• Autophagy in combination with biological clock gene pathways are dependent upon mTOR. Studies suggest that a basal circadian rhythm that modulates autophagy and mTOR pathways involving mTOR Complex 1 (mTORC1) and mTOR Complex 2 (mTORC2) may be necessary to prevent cognitive decline and cellular toxicity with amyloid deposition. mTOR also holds an inverse relationship with SIRT1 and these pathways may be necessary to support core circadian components CLOCK and BMAL1 and prevent cellular metabolic dysfunction.

• SIRT1,a histone deacetylase, regulates ß-nicotinamide adenine dinucleotide (NAD + ) cellular NAD + pools that fluctuate with circadian rhythmicity and can impact cell function, metabolism, and loss of cognitive function. Oversight with SIRT1 of circadian rhythm pathways may be required for growth factor EPO cellular production and protection.

• FoxOs that can control circadian rhythmicity, such as through the modulation of Clock, can also bind to SIRT1 promoter regions to function through autofeedback mechanisms to regulate SIRT1 activity. SIRT1 and FoxOs can work in unison to block cognitive loss and prevent amyloid toxicity, mitochondrial dysfunction, and oxidative stress injury.

• Wnt proteins are cysteine-rich glycosylated proteins that can affect neuronal development, immunity, tissue fibrosis, angiogenesis, stem cell proliferation, and cancer. Wnt pathways that function in conjunction with circadian clock gene pathways, such as TIMELESS, may promote new angiogenesis and tumorigenesis. Furthermore, disruption of circadian rhythms with sleep fragmentation may increase the risk for developing cancer and other circadian genes that include hClock also may promote the metastasis of colorectal cancer through the enhanced expression of angiogenesis-related genes.

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Maiese K Nicotinamide as a Foundation for Treating Neurodegenerative Disease and Metabolic Disorders

Metformin-induced suppression of IFN-alpha via mTORC1 signalling following seasonal vaccination is associated with impaired antibody responses in type 2 diabetes

Intake of ω−6 Polyunsaturated Fatty Acid-Rich Vegetable Oils and Risk of Lifestyle Diseases

Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1

Guidelines for the use and interpretation of assays for monitoring autophagy

Oversight of Metabolic Dysfunction through SIRT1, mTOR, and Clock Genes

Hardeland R Neuroprotection by radical avoidance: search for suitable agents

Neurodegeneration and the Circadian Clock

Drosophila Clock is Required in Brain Pacemaker Neurons to Prevent Premature Locomotor Aging Independently of its Circadian Function

Do not neglect the role of circadian rhythm in muscle atrophy

Resetting the Aging Clock: Implications for Managing Age-Related Diseases

Circadian rhythms of mineral metabolism in chronic kidney disease-mineral bone disorder

Mammalian circadian systems: Organization and modern life challenges

PER2 inhibits proliferation and stemness of glioma stem cells via the Wnt/β-catenin signaling pathway

Daily and seasonal mitochondrial protection: Unraveling common possible mechanisms involving vitamin D and melatonin

Diurnal Rhythmicity of Autophagy Is Impaired in the Diabetic Retina

Exosomes from Human Periapical Cyst-MSCs: Theranostic Application in Parkinson's Disease

Maiese K Moving to the Rhythm with Clock (Circadian) Genes, Autophagy, mTOR, and SIRT1 in Degenerative Disease and Cancer

Maiese K Novel Treatment Strategies for the Nervous System: Circadian Clock Genes, Noncoding RNAs, and Forkhead Transcription Factors

Clock genes and cancer development in particular in endocrine tissues

The expression of the circadian gene TIMELESS in non-small-cell lung cancer and its clinical significance

Melatonin and Cancer: A Polyhedral Network Where the Source Matters

TIMELESS confers cisplatin resistance in nasopharyngeal carcinoma by activating the Wnt/beta-catenin signaling pathway and promoting the epithelial mesenchymal transition

Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways

Melatonin alleviates adipose inflammation through elevating alpha-ketoglutarate and diverting adipose-derived exosomes to macrophages in mice

Disruptions to the limb muscle core molecular clock coincide with changes in mitochondrial quality control following androgen depletion

Pharmacological activation of the circadian component REV-ERB inhibits HIV-1 replication

Elderly as a High-risk Group during COVID-19 Pandemic: Effect of Circadian Misalignment

Melatonin modulates mitophagy, innate immunity and circadian clocks in a model of viralinduced fulminant hepatic failure

Are night shift workers at an increased risk for COVID-19?

Clock Genes: Targeting Innate Immunity for Antiviral Strategies Against COVID-19

The Circadian Clock, the Immune System, and Viral Infections: The Intricate Relationship Between Biological Time and Host-Virus Interaction

Sleep and circadian rhythm in response to the COVID-19 pandemic

The case for chronotherapy in Covid-19-induced acute respiratory distress syndrome

Mechanistic Target of Rapamycin (mTOR): Novel Considerations as an Antiviral Treatment

Hardeland R Melatonin and the pathologies of weakened or dysregulated circadian oscillators

Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway

Over-expression of circadian clock gene Bmal1 affects proliferation and the canonical Wnt pathway in NIH-3T3 cells

Circadian dysregulation of clock genes: clues to rapid treatments in major depressive disorder

Long-term Levodopa Treatment Accelerates the Circadian Rhythm Dysfunction in a 6-hydroxydopamine Rat Model of Parkinson's Disease

Key Signaling Pathways in Aging and Potential Interventions for Healthy Aging

Dammarane Sapogenins Ameliorates Neurocognitive Functional Impairment Induced by Simulated Long-Duration Spaceflight

Glymphatic Pathways, and Circadian Rhythm Disruption

Alterations of Clock Gene RNA Expression in Brain Regions of a Triple Transgenic Model of Alzheimer's Disease

Clinical Insights for a Proliferative and Restorative Member of the CCN Family

Maiese K The bright side of reactive oxygen species: lifespan extension without cellular demise

Maiese K Prospects and Perspectives for WISP1 (CCN4) in Diabetes Mellitus

The Wnt signaling pathway: aging gracefully as a protectionist?

The administration of erythropoietin attenuates kidney injury induced by ischemia/reperfusion with increased activation of Wnt/beta-catenin signaling

Cardiovascular disease and mTOR signaling

Association of Wnt1-inducible signaling pathway protein-1 with the proliferation, migration and invasion in gastric cancer cells

Maiese K Stem cell guidance through the mechanistic target of rapamycin

Cracking the Code for Clinical Disease

WISP-1 positively regulates angiogenesis by controlling VEGF-a expression in human osteosarcoma

Βeta-Catenin promotes cell proliferation, migration, and invasion but induces apoptosis in renal cell carcinoma

Rotating Night Shift Work and Risk of Breast Cancer in The Nurses' Health Studies

Upregulation of circadian gene 'hClock' contribution to metastasis of colorectal cancer

Time-of-Day Dependent Neuronal Injury after Ischemic Stroke: Implication of Circadian Clock Transcriptional Factor Bmal1 and Survival Kinase AKT

Per2 participates in AKT-mediated drug resistance in a549/DDP lung adenocarcinoma cells

mTOR signaling regulates central and peripheral circadian clock function

Circadian rhythm of autophagy proteins in hippocampus is blunted by sleep fragmentation

The Hippocampal Autophagic Machinery is Depressed in the Absence of the Circadian Clock Protein per1 that may Lead to Vulnerability during Cerebral Ischemia

Rheostatic Balance of Circadian Rhythm and Autophagy in Metabolism and Disease

Caffeic acid reduces A53T alpha-synuclein by activating JNK/Bcl-2-mediated autophagy in vitro and improves behaviour and protects dopaminergic neurons in a mouse model of Parkinson's disease

Glaucocalyxin A as a natural product increases amyloid beta clearance and decreases tau phosphorylation involving the mammalian target of rapamycin signaling pathway

Impairment of autophagy in the central nervous system during lipopolysaccharide-induced inflammatory stress in mice

The ALS/FTLD associated protein C9orf72 associates with SMCR8 and WDR41 to regulate the autophagylysosome pathway

Reinstating Aberrant mTORC1 Activity in Huntington's Disease Mice Improves Disease Phenotypes

Maiese K Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders

The Effect of Pyrroloquinoline Quinone on the Expression of WISP1 in Traumatic Brain Injury

The Effect of Pyrroloquinoline Quinone on Apoptosis and Autophagy in Traumatic Brain Injury

Autophagy in neurodegeneration: New insights underpinning therapy for neurological diseases

Targeting Alpha-Synuclein as a Therapy for Parkinson's Disease

Molecular targets for modulating the protein translation vital to proteostasis and neuron degeneration in Parkinson's disease

Valeric Acid Protects Dopaminergic Neurons by Suppressing Oxidative Stress, Neuroinflammation and Modulating Autophagy Pathways

Targeting disease through novel pathways of apoptosis and autophagy

Regulatory effects of ghrelin on endoplasmic reticulum stress, oxidative stress, and autophagy: Therapeutic potential

The Emerging Key Role of Klotho in the Hypothalamus-Pituitary-Ovarian Axis

Targeting PRAS40: a novel therapeutic strategy for human diseases

A Systems Biology Roadmap to Decode mTOR Control System in Cancer

Protein recycling and limb muscle recovery after critical illness in slow-and fast-twitch limb muscle

Fasting activates macroautophagy in neurons of Alzheimer's disease mouse model but is insufficient to degrade amyloid-beta

The host mTOR pathway and parasitic diseases pathogenesis

Accumulation of beta-synuclein in cortical neurons is associated with autophagy attenuation in the brains of dementia with Lewy body patients

Influence of age-related learning and memory capacity of mice: different effects of a high and low caloric diet

Forkhead transcription factors: new considerations for alzheimer's disease and dementia

Protective effect of Dl-3n-butylphthalide on learning and memory impairment induced by chronic intermittent hypoxia-hypercapnia exposure

Selenomethionine Mitigates Cognitive Decline by Targeting both Tau Hyperphosphorylation and Autophagic Clearance in an Alzheimer's Disease Mouse Model

Everolimus (RAD001) ameliorates vascular cognitive impairment by regulating microglial function via the mTORC1 signaling pathway

Topical rapamycin reduces markers of senescence and aging in human skin: an exploratory, prospective, randomized trial

Temporal changes in mammalian target of rapamycin (mTOR) and phosphorylated-mTOR expressions in the hippocampal CA1 region of rat with vascular dementia

Role of BDNF-mTORC1 Signaling Pathway in Female Depression

Phytocannabinoid-dependent mTORC1 regulation is dependent upon inositol polyphosphate multikinase activity

The functions of mTOR in ischemic diseases

one-Two Punch" for Aging-Related Disorders Accompanied by Enhanced Life Expectancy

Hypothalamic mTOR: the rookie energy sensor

Sirtuin Biology in Cancer and Metabolic Disease

Maiese K Targeting the core of neurodegeneration: FoxO, mTOR, and SIRT1. Neural Regeneration Research

The mTOR/NF-κB Pathway Mediates Neuroinflammation and Synaptic Plasticity in Diabetic Encephalopathy

mTORC1 restricts hepatitis C virus RNA replication through ULK1-mediated suppression of miR-122 and facilitates post-replication events

Maiese K Driving neural regeneration through the mammalian target of rapamycin. Neural Regeneration Research

Proline-rich AKT substrate of 40-kDa (PRAS40) in the pathophysiology of cancer

Effect of Calcineurin Inhibitors and Mammalian Target of Rapamycin Inhibitors on the Course of COVID-19 in Kidney Transplant Recipients

Rapamycin: Drug Repurposing in SARS-CoV-2 Infection

Pharmacological Modulators of Autophagy as a Potential Strategy for the Treatment of COVID-19

Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

Shedding new light on neurodegenerative diseases through the mammalian target of rapamycin

Role of mTOR complex in IGF-1 induced neural differentiation of DPSCs

Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive

Cross-talk between CD38 and TTP is Essential for Resolution of Inflammation during Microbial Sepsis

MTOR may interact with PARP-1 to regulate visible light-induced parthanatos in photoreceptors

Exploration of age-related mitochondrial dysfunction and the antiaging effects of resveratrol in zebrafish retina

Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance

Effect of lycopene on pain facilitation and the SIRT1/mTOR pathway in the dorsal horn of burn injury rats

Maiese K Novel Treatment Strategies for Neurodegenerative Disease with Sirtuins

Strategy for Stem Cell Renewal and Clinical Development

Inhibition of SIRT1/2 upregulates HSPA5 acetylation and induces pro-survival autophagy via ATF4-DDIT4-mTORC1 axis in human lung cancer cells

Nicotinamide protects hepatocytes against palmitate-induced lipotoxicity via SIRT1-dependent autophagy induction

A Novel PDE4D Inhibitor BPN14770 Reverses Scopolamine-Induced Cognitive Deficits via cAMP/SIRT1/Akt

Protective role of mitoquinone against impaired mitochondrial homeostasis in metabolic syndrome

Sirt1 overexpression in neurons promotes neurite outgrowth and cell survival through inhibition of the mTOR signaling

SIRT1 positively regulates autophagy and mitochondria function in embryonic stem cells under oxidative stress

Aldose reductase regulates hyperglycemia-induced HUVEC death via SIRT1/AMPK-alpha1/mTOR pathway

Genistein protects against ox-LDL-induced senescence through enhancing SIRT1/LKB1/AMPK-mediated autophagy flux in HUVECs

Hormetic effect of panaxatriol saponins confers neuroprotection in PC12 cells and zebrafish through PI3K/AKT/mTOR and AMPK/ SIRT1/FOXO3 pathways

Metformin opposes impaired AMPK and SIRT1 function and deleterious changes in core clock protein expression in white adipose tissue of genetically-obese db/db mice

Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamineinduced hepatocellular carcinoma

Circadian Reprogramming in the Liver Identifies Metabolic Pathways of

Caveolin1/protein arginine methyltransferase1/sirtuin1 axis as a potential target against endothelial dysfunction

SIRT1: new avenues of discovery for disorders of oxidative stress

Erythropoietin activates SIRT1 to protect human cardiomyocytes against doxorubicin-induced mitochondrial dysfunction and toxicity

Retinoic acid ameliorates high-fat diet-induced liver steatosis through sirt1

Maiese K SIRT1 and stem cells: in the forefront with cardiovascular disease, neurodegeneration and cancer

Maiese K Harnessing the Power of SIRT1 and Non-coding RNAs in Vascular Disease

Sir-2.1 mediated attenuation of alpha-synuclein expression by Alaskan bog blueberry polyphenols in a transgenic model of Caenorhabditis elegans

Synthesis and neuroprotective effects of novel chalcone-triazole hybrids

Novel directions for diabetes mellitus drug discovery

SIRT1 regulates circadian clock gene expression through per2 deacetylation

The evolving role of the NAD+/nicotinamide metabolome in skin homeostasis, cellular bioenergetics, and aging

Melatonin and Rapamycin Attenuate Isoflurane-Induced Cognitive Impairment Through Inhibition of Neuroinflammation by Suppressing the mTOR Signaling in the Hippocampus of Aged Mice

Metallothionein attenuates 3-morpholinosydnonimine (SIN-1)-induced oxidative stress in dopaminergic neurons

Improvement of oxidative stress and immunity by melatonin: an age dependent study in golden hamster

Sirtuins and intervertebral disc degeneration: Roles in inflammation, oxidative stress, and mitochondrial function

Melatonin Rescues the Ti Particle-Impaired Osteogenic Potential of Bone Marrow Mesenchymal Stem Cells via the SIRT1/SOD2

Signaling Pathway

Circadian Control of the NAD+ Salvage Pathway by CLOCK-SIRT1

Erythropoietin employs cell longevity pathways of SIRT1 to foster endothelial vascular integrity during oxidant stress

PPARalpha and Sirt1 mediate erythropoietin action in increasing metabolic activity and browning of white adipocytes to protect against obesity and metabolic disorders

RhEPO affects apoptosis in hippocampus of aging rats by upregulating SIRT1

Avenues of Exploration for Erythropoietin

Maiese K Regeneration in the nervous system with erythropoietin

Raves and risks for erythropoietin

Impact of Erythropoietin in the management of Hypoxic Ischaemic Encephalopathy in resource-constrained settings: protocol for a randomized control trial

An effective erythropoietin dose regimen protects against severe nerve injury-induced pathophysiological changes with improved neural gene expression and enhances functional recovery

Current Evidence on the Protective Effects of Recombinant Human Erythropoietin and Its Molecular Variants against Pathological Hallmarks of Alzheimer's Disease

Mitochondrial Metabolism as Target of the Neuroprotective Role of Erythropoietin in Parkinson's Disease

Erythropoietin and derivatives: Potential beneficial effects on the brain

GSK3beta: a plausible mechanism of cognitive and hippocampal changes induced by erythropoietin treatment in mood disorders? Translational psychiatry

Erythropoietin Signaling in the Microenvironment of Tumors and Healthy Tissues

Endothelial TRPV1 as an Emerging Molecular Target to Promote Therapeutic Angiogenesis

AKT/GSK-3β/β-catenin signaling pathway participates in erythropoietin-promoted glioma proliferation

From oxygen to erythropoietin: relevance of hypoxia for retinal development, health and disease

Triple play: promoting neurovascular longevity with nicotinamide, WNT, and erythropoietin in diabetes mellitus

Combination of intravitreal bevacizumab and erythropoietin versus intravitreal bevacizumab alone for refractory diabetic macular edema: a randomized double-blind clinical trial. Graefe's Archive for

Erythropoietin (EPO) haplotype associated with all-cause mortality in a cohort of Italian patients with Type-2 Diabetes

Erythropoietin is a novel vascular protectant through activation of Akt1 and mitochondrial modulation of cysteine proteases

Erythropoietin fosters both intrinsic and extrinsic neuronal protection through modulation of microglia, Akt1, Bad, and caspase-mediated pathways

Prevention of betaamyloid degeneration of microglia by erythropoietin depends on Wnt1, the PI 3-K/mTOR pathway, Bad, and Bcl-xL

Pathophysiological significance of clock genes BMAL1 and per2 as erythropoietin-controlling factors in acute blood hemorrhage

The AKT/mTOR pathway mediates neuronal protective effects of erythropoietin in sepsis

The Neuroprotective Effect of Erythropoietin on Rotenone-Induced Neurotoxicity in SH-SY5Y Cells through the Induction of Autophagy

Maiese K Warming up to New Possibilities with the Capsaicin Receptor TRPV1: mTOR, AMPK, and Erythropoietin

Erythropoietin protects epithelial cells from excessive autophagy and apoptosis in experimental neonatal necrotizing enterocolitis

WNT1 Inducible Signaling Pathway Protein 1 (WISP1) Targets PRAS40 to Govern beta-Amyloid Apoptotic Injury of Microglia

Erythropoietin and Wnt1 govern pathways of mTOR, Apaf-1, and XIAP in inflammatory microglia

Erythropoietin prevents early and late neuronal demise through modulation of Akt1 and induction of caspase 1, 3, and 8

Erythropoietin exerts cell protective effect by activating PI3K/Akt and MAPK pathways in C6 Cells

PRAS40 Is an Integral Regulatory Component of Erythropoietin mTOR Signaling and Cytoprotection

Exploring the therapeutic potential of forkhead box O for outfoxing COVID-19

Expression of FOXO transcription factors in the brain following traumatic brain injury

Elucidating the Possible Role of FoxO in Depression

OutFOXOing disease and disability: the therapeutic potential of targeting FoxO proteins

Kaempferol suppresses acetaminophen-induced liver damage by upregulation/activation of SIRT1

Resveratrol Suppresses Severe Acute Pancreatitis-Induced Microcirculation Disturbance through Targeting SIRT1-FOXO1 Axis

Acylated ghrelin protects against Doxorubicin-induced nephropathy by activating SIRT1. Basic and Clinical Pharmacology and Toxicology

Evaluation of silent information regulator T (SIRT) 1 and Forkhead Box O (FOXO) transcription factor 1 and 3a genes in glaucoma

Insulin-FOXO3 signaling modulates circadian rhythms via regulation of clock transcription

FoxO proteins: cunning concepts and considerations for the cardiovascular system

FoxO3a requires BAF57, a subunit of chromatin remodeler SWI/SNF complex for induction of PUMA in a model of Parkinson's disease

TGFbeta signaling regulates the timing of CNS myelination by modulating oligodendrocyte progenitor cell cycle exit through SMAD3/4/FoxO1/ Sp1

Maiese K Novel Insights for Multiple Sclerosis and Demyelinating Disorders with Apoptosis, Autophagy, FoxO, and mTOR

The effect of FOXO gene family variants and global DNA metylation on RRMS disease

Tribbles Pseudokinase 3 Induces Both Apoptosis and Autophagy in Amyloid-beta-induced Neuronal Death

Signaling pathways and effectors of aging

FoxO1 Mediates an Autofeedback Loop Regulating SIRT1 Expression

Hydrogen-rich water attenuates amyloid beta-induced cytotoxicity through upregulation of Sirt1-FoxO3a by stimulation of AMPactivated protein kinase in SK-N-MC cells

Effect and mechanism of fuzhisan and donepezil on the sirtuin 1 pathway and amyloid precursor protein metabolism in PC12 cells