Austin Alzheimers J Parkinsons Dis. 2015;2(1): 1020.
Diabetes and Cholesterol Dyshomeostasis Involve Abnormal α-Synuclein and Amyloid Beta Transport in Neurodegenerative Diseases
¹Centre of Excellence in Alzheimer's Disease Research and Care, School of Medical Sciences, Edith Cowan University, Australia
²School of Psychiatry and Clinical Neurosciences,University of Western Australia, Australia
³McCusker Alzheimer's Research Foundation, Holywood Medical Centre, Australia
*Corresponding author: Ian J Martins, School of Medical Sciences, Edith Cowan University, 270 Joondalup Drive, Joondalup, Western Australia 6027,Australia.
Received: December 14, 2014; Accepted: July 16, 2015;Published: July 18, 2015
The understanding of molecular mechanisms underlying diet and Alzheimer's disease and the cholesterol connection are important for the prevention and treatment of Alzheimer's disease linked to Type 3 diabetes and aberrant lipid metabolism. Cholesterol modulates amyloid beta generation with the ATP-binding cassette transporter 1 as a major regulator of cholesterol and phospholipids from cell membranes that are involved in amyloid beta transport from the brain to the liver for metabolism. In Parkinson's disease, the α-synuclein protein binds to cholesterol (tilted peptide 67-78/isooctyl chain) in cell membranes. Fatty acids and phospholipids such as phosphatidylinositol in membranes sensitive to amyloid beta and α-synuclein binding/aggregation indicate the involvement of lipids in the progression of Alzheimer's disease. Atherogenic diets with abnormal cell cholesterol homeostasis exist as a cellular mechanism, which is common to the aggregation of amyloid beta and α-synuclein proteins that induce both Alzheimer's disease and Parkinson's disease. Sirtuin 1,a nuclear receptor known to regulate cell functions by deacetylating both histone and non-histone targets when down regulated is associated with circadian abnormalities and with poor glucose and cholesterol metabolism linked to abnormal amyloid beta metabolism in Alzheimer's disease and increased α-synuclein aggregation in Parkinson's disease. The global obesity and Type 2 diabetes epidemic indicate that the down regulation of Sirtuin 1 with increased inflammatory processes and abnormal immune responses associated with increased plasma α-synuclein levels, has become important for the modulation of membrane ion channels and impairments in protein degradation with abnormal endoplasmic reticulummitochondrial interactions associated with disturbed peripheral amyloid beta metabolism common to both Parkinson's disease and Alzheimer's disease.
Keywords: α-synuclein; Amyloid beta; Cholesterol; Ceramide; Sirtuin 1; Lipopolysaccharide
PD: Parkinson's Disease; AD: Alzheimer's Disease; apoE: Apolipoprotein E; ABCA1: ATP-binding Cassette Transporter 1; Aβ: Amyloid Beta; APP: Amyloid Precursor Protein; Sirt1: Sirtuin1; LXR: Liver X Receptor; PPAR: Peroxisome-proliferator-activated Receptor; PGC 1 alpha: PPAR Gamma co-activator 1 α; SREBP; Sterol Regulatory element-binding proteins; LPS: Lipopolysaccharide; HDL: High Density Lipoprotein
The main constituent of senile plaques, namely amyloid beta (Aβ) , is a proteolytic product of a larger protein, the amyloid precursor protein (APP). The main protein component of Alzheimer's disease (AD) senile plaques, Aβ, was firstly purified and sequenced from cerebrovascular amyloid deposits which manifest as congophillic amyloid angiopathy . Aβare found to be peptides of 39 to 43 amino acids in length, with an approximate molecular mass of 4.2 kDa . Another study published from the same research group has linked Aβ to adult Down's syndrome and AD . The understanding of molecular mechanisms underlying the AD-cholesterol connection has become important for the possible prevention and treatment of AD and it is now linked to diabetes and poor cholesterol metabolism. Plasma cholesterol profiles such as elevated low density lipoprotein and decreased high density lipoprotein (HDL) levels have been associated with AD and are important risk factors for cardiovascular diseases. Furthermore, diets that are rich in fat and cholesterol have been associated with brain amyloidosis in rabbits and AD transgenic mice. Diabetes and dyslipidemia are linked to amyloidosis with relevance to calcium dyshomeostasis and neurodegenerative diseases . Cholesterol modulates APP processing and Aβ generation with the action of 3 proteases [5-7]. Depletion of cholesterol and inhibition of intracellular transport of cholesterol or cholesterol esterification by drugs inhibited the production of Aβ formation in hippocampal neurons [8-13]. Studies indicate that cholesteryl ester (CE) levels are correlated with Aβ levels, and that cholesterol lowering drugs such as ACAT inhibitors directly modulate Aβ generation through the control of CE generation . The ATP-binding cassette transporter 1 (ABCA1) is a major regulator of HDL with the transport of cholesterol and phospholipids from cell membranes to HDL possibly plays a central role in cholesterol flux and Aβtransport from the CNS to the periphery where it is transported to the liver for metabolism and subsequent excretion . High fat and cholesterol diets may induce both AD and PD with the indications that abnormal cholesterol homeostasis exists as the cellular mechanisms that are common to the aggregation of Aβ and α-synuclein proteins [15-17]. In PD, the movement disorder is characterized by the aggregation of α-synuclein protein (14 kda) in Lewy body inclusions with dopaminergic neuron apoptosis in the substantia-nigra [18,19]. Epidemiological studies indicate that Type 2 diabetes and PD are closely linked with shared dysregulated pathways that involve molecular genetics, cell biology and insulin resistance in the pathogenesis of these diseases [20.21]. In Parkinson's disease, the α-synuclein protein is an amyloidogenic protein and has been shown to bind to cholesterol (tilted peptide 67- 78) and α-synuclein has also been shown with binding to the isooctyl chain of cholesterol in membranes [22,23]. In recent publications, the binding of Aβ has been associated with cholesterol in membranes with the regulation of liver Aβ metabolism regulated by lipoprotein cholesterol levels . The peripheral sink abeta hypothesis  is closely associated with cholesterol regulation and possibly connected to the metabolism of Aβ and α-synuclein proteins in diabetes, AD, PD and Huntington's disease. In diabetes, circadian clock abnormalities  are central to disease progression and circadian disturbances are also found in neurodegenerative disease that involves AD and PD [25-28]. Regulation of the peripheral Aβ clearance is central to the disease of diabetes with circadian clock abnormalities now believed to be the origin of poor liver glucose, cholesterol and Aβ metabolism in diabetes . Neurons in the hypothalamus are responsible for various connections to other brain regions and one of the important functions of the hypothalamus is control of the daily light dark cycle. The suprachiasmatic nucleus (SCN) may regulate the sleepwake cycle and peripheral oscillators with effects on anxiety, stress, depression and food intake. In response to the daily sleep/wake cycle Aβ metabolism, α-synuclein metabolism is controlled by the circadian rhythm, SCN [29-32] with relevance to food intake and release of pineal gland melatonin. Disturbances in the SCN will alter energy and liver glucose and Aβ metabolism with hyperglycemia closely involved with abnormal resetting of circadian rhythms and melatonin release.
Sirt 1 and insulin resistance involve circadian dysregulation with connections to membrane lipids and protein aggregation
Sirtuin 1 (Sirt1) is one of the nuclear receptors that is known to regulate several cell functions by deacetylating both histone and nonhistone targets . Sirt1 is an NAD(+)dependent class III histone deacetylase protein that targets transcription factors to adapt gene expression to metabolic activity, insulin resistance and inflammation in chronic diseases [34-38]. Nutritional regulation (calorie restriction and high fat feeding) of Sirt1 that is involved in the hypothalamic and SCN control of food intake with regulation of the central melanocortin system via the fork head transcription factor has been reported [39-42]. Sirt1 dysregulation has been closely linked with alterations in appetite regulation and with circadian clock disorders that are associated with obesity and diabetes. In support of Sirt1's role in circadian rhythms [43-47] subjects carrying minor alleles at Sirt1 and CLOCK loci, displayed a higher resistance to weight loss as compared with homozygotes for both major alleles, suggesting links between the circadian clock and Sirt1 function. Sirt1 is involved in neuron proliferation with effects on cellular cholesterol and lipid homeostasis by the regulation of liver X receptor (LXR) proteins. Sirt1 has been closely linked to Aβ metabolism in AD (Figure 1) and α-synuclein metabolism in PD with circadian dysregulation that is associated with protein aggregation [29-32] and with implications to Sirt1 research and therapeutics in Huntington's disease .
Figure 1: Sirt 1 effect on cell cholesterol efflux determines Aβ metabolism associated with α-synuclein aggregation. 1. Sirt1 an NAD(+) dependent class III histone deacetylase (nuclear receptor) is involved in neuronal proliferation. 2. Sirt1 has been closely linked to circadian clock disorders and to A metabolism in AD and α-synuclein metabolism in PD. 3. Sirt1 effects on cellular cholesterol is by regulation of PGC 1 alpha and LXR transcription factors. LXR targets ABCA1 and SREBP-1c that are intimately involved in glial-neuron interactions associated with cholesterol, α-synuclein and Aβ metabolism. 4. Downregulation of Sirt1 decreases Aβ metabolism associated with α-synuclein aggregation and mitochondrial apoptosis with ER stress in cells. N: Nucleus; Ca2+: Calcium; apo E: Apolipoprotein E.
Sirt1 is involved in the deacetylation and ubiquitination of LXR with regulation of the expression of LXR targets that are involved in cellular cholesterol metabolism such as ABCA1 (Figure 1) and SREBP-1c [49-51]. AMP-activated protein kinase (AMPK) activation by Sirt 1 may be involved in the LXR-SREBP-1c expression involved in glial-neuron interactions that are associated with the circadian cholesterol metabolism [52-55]. Sirt1 is involved with deacetylation of peroxisome-proliferator-activated receptor (PPAR) gamma co-activator 1 α (PGC-1 α) a co-activator of the LXR involved in mitochondrial biogenesis and fatty acid beta-oxidation [56-61]. LXR involved with cell cholesterol efflux has been shown to regulate the expression of α-synuclein and the secretion of cellular Aβ [62-64]. Interests in cholesterol regulation of α-synuclein has increased with regulation of α-synuclein expression by 27 OH cholesterol . Circadian dysfunction has been found in mouse models of PD  and Sirt1dysregulation in diabetes involved with circadian rhythm  and membrane cholesterol dyshomeostasis may involve in α-synuclein aggregation and abnormal Aβ metabolism in neurons [4,67-72]. Molecular mechanisms involved with neuroendocrine diseases such as obesity and diabetes are closely related to insulin resistance and require attention since metabolic dysfunction has also been associated with neurodegeneration [4,73]. The global increase in these chronic diseases supports a role for lipids such as cholesterol, sphingomyelin and its metabolites in the pathogenesis of these diseases. Lipidomics, as a tool for the development with diagnosis of abnormal lipid metabolism as an early lipid biomarker panel, has become important to diabetes, PD and AD since its comparison and inclusion with other biomarker panels will allow sensitive detection and early diagnosis of metabolic dysfunction and its relevance to AD . Interests in proteins and their interactions with membrane lipids in neurodegenerative diseases have accelerated with the existence of Aβ and α-synuclein pathologies in individuals with neurodegeneration . In particular, α-synuclein has been linked to mitochondria and endoplasmic reticulum interactions with endoplasmic reticulum stress associated with calcium levels and α-synuclein aggregation [76- 79]. The role of diet on α-synuclein aggregation in the modulation of the Aβ cascade, has become important with Aβ oligomer or toxic fibril formation that is associated with membrane cholesterol, sphingomyelin, phospholipids and fatty acids (Figure 2). The role of cholesterol in membranes is essential for protein interactions and metabolism of lipoproteins  with the isooctyl chain in cholesterol essential as a regulator of lipid metabolism . The binding of α-synuclein to the isooctyl chain of cholesterol in membranes allows regulation of peripheral cholesterol metabolism with relevance to α-synuclein biology and the peripheral sink abeta hypothesis [15,16].
Figure 2: Membrane lipids determine and influence A oligomer formation and α-synuclein interactions with cell membranes. 1. Membranes with increased ceramide-cholesterol interactions and low PI promote Aβ oligomerization. 2. Membrane lipids such as sulfatide (101) determine the aggregation of α-synuclein with effects on Aβ oligomerization. 3. Apo E-ABCA1 interactions determine membrane cholesterol contents and regulate interactions between α-synuclein and Aβ that are influenced by various fatty acids, gangliosides, sphingolipids, ceramide and phospholipids (anionic lipids). Mechanistic links to Aβ accumulation indicate the importance of oligomers that contain both Aβ and α-synuclein that develop with unhealthy diets that are low in phosphatidylinositol (PI) and butyric acid.
Neurodegenerative diseases and abnormal protein and cholesterol interactions (isooctyl chain of cholesterol) and other membrane lipids may involve the consensus cholesterol-binding motifs CRAC, CARC or a tilted peptide [22,23]. α-synuclein has been shown to bind to specific sites on the cholesterol such as the tilted peptide [67-78] and with binding to the isooctyl chain of cholesterol. The formation of cholesterol-rich domains [81,82] in membranes may involve both α-synuclein and Aβ and the insertion of both proteins in membranes are influenced by the various fatty acids, glycosphinglipids, phospholipids (anionic lipids) and gangliosides that may determine Aβ oligomer formation and α-synuclein aggregation (Figure 2) in cells [83-92]. The oligomers that contain both Aβ and
α-synuclein have recently been reported with indications that nutrition and dietary lipids such as phosphatidylinositol  may be important in the mechanistic links between Aβ accumulation and α-synuclein pathogenesis (Figure 2) . Fatty acids such as butyric acid  have become important for nutrition and neurodegenerative diseases and the used phenyl butyric acid has been assessed for the reduction of Aβ plaques and increased α-synuclein content in the brains of transgenic mice [94,95]. Furthermore, the interactions between α-synuclein and Aβ (Figure 2) may corrupt apo E-Aβ interactions [15,96] or apo E-ABCA1 interactions  with relevance to α-synuclein's role in brain amyloidosis and neurodegeneration [98-100]. Down regulation of Sirt1 affectsLXR-ABCA1 that regulates apo E-ABCA1  interactions with effects on cholesterol efflux, α-synuclein aggregation and Aβ metabolism.
The global increase in chronic diseases such as obesity and diabetes supports a role for lipids such as ceramide and their metabolites in the pathogenesis of these diseases . The link between the cholesterolceramide connections to diabetes and AD [102-104] has indicated the role of ceramide in the pathogenesis of PD and AD that is also referred to as Type 3 diabetes . The cholesterol-ceramide connection linked with aging, diabetes and AD, is associated with increased α-synuclein-Aβ interactions in membranes that are associated with conformational Aβ transitions to benign or toxic amyloid assembly states . Aβ intermediates modulated by α-synuclein (Figure 2) possibly determine the role of calcium channels [4,77-79,107] with relevance to membrane biology and neurodegeneration. α-syunclein is found in peripheral tissues and plasma with release of the protein from the gastrointestinal tract, macrophages, glands and skin that has been measured [108-113]. Macrophages may overexpress α-synuclein [109,111,112] and implications for the rise in plasma α-synuclein in human plasma, are sensitive to beta-cell function and insulin secretion . α-synuclein and its role in inflammatory responses is closely linked to obesity and diabetes  with the γ-synuclein  regulation of lipid and Aβ metabolism in adipose tissue controlled by Sirt1 . Effects of lipopolysaccharide (LPS) on the induction of α-synuclein and ceramide synthesis in macrophages [117,118] and α-synuclein release from the intestine  increased the α-synuclein levels in human plasma. LPS has been shown to effect cholesterol efflux by the modulation of the LXR-ABCA1 [120,121] pathways via Sirt1/LXR-ABCA1 interactions and lowering LPS has become important to reduce metabolic diseases with LPS models now reported for PD [122,123]. LPS effects macrophage SREBP expression and inhibits liver PGC 1 α expression linked to abnormal Sirt1 cell regulation [124-126]. LPS mediated corruption of cholesterol efflux in macrophages that has been reported with the importance of cholesterol-rich lipoprotein interactions for the neutralization of LPS in metabolic diseases and diabetes [127-133]. Close connections between ceramide and LPS, have been reported in cells [134,135] with disturbed cellular cholesterol efflux in diabetes, AD and PD.
Diets with low calorie contents (high fibre), nutritional interventions, appropriate protein contents (low to moderate), xenobiotic free and activators of Sirt1 nuclear receptor and transcription factors [4,15,16,73] have been shown to improve the cell and lipoprotein metabolism of cholesterol and ceramide  with implications for α-synuclein and abeta metabolism in obesity, diabetes and neurodegenerative diseases. Effects of exercise on ceramide metabolism have been measured with the increased ceramide or normal ceramide levels in the muscle and heart [136- 138]. Adiponectin has been shown to suppress α-synucleopathies in animal models with systemic effects of adiponectin on ceramide metabolism [139-141]. Nutritional interventions to increase plasma adiponectin levels require lifestyle and dietary changes to prevent stroke, PD and AD . Increases in ceramide levels in cells displace cholesterol with effects on α-synuclein and Aβ interactions [143,144]. Polyanions and polycations have an important electrostatic role in α-synuclein aggregation with drugs such as suramin (polyanionic) that are used to inhibit LPS inflammatory effects and shown to increase ceramide levels [145-148] in cells with effects of suramin on Sirt1 inhibition . Suraminhas been shown to bind to low density lipoproteins and to the low density lipoprotein receptor and to block LDL uptake [150,151]. Coumarins [152-154] and adiponectin [155- 156] have been used to inhibit LPS effects and modulate the activation of Sirt1 with therapeutic effects in the treatment of PD. LPS [157,158] and Sirt1 [159,160] are linked to food intake and appetite regulation. Nutritional diets that contain phytosterols and butyric acid may control glucose homeostasis and stabilize membrane cholesterol-ceramide interactions . However, butyric acid effects on T cell apoptosis have been reported and induced by an increase in cellular ceramide [161,162]. High fibre diets that control membrane cholesterol and cellular ceramide contents [74,102-104] are particularly relevant to activate the liver and brain nuclear receptors and stabilize membrane α-synuclein and Aβ transport in neurodegenerative diseases.
In the current global obesity and diabetes epidemic chronic diseases such as NAFLD, cardiovascular disease, kidney disease and neurodegenerative diseases such as PD and AD have increased in the developing and developed world. Links between metabolic diseases and AD indicate that Type 3 diabetes is on the increase in various countries. The Type 2 diabetes epidemic is linked to PD and associated with the Type 3 diabetes in AD. Unhealthy nutrigenomic diets down-regulate brain and hepatic Sirt1 associated with insulin resistance, α-synuclein aggregation and Aβ dyshomeostasis in AD and PD. Nutritional diets that are low in calories activate the brain and liver Sirt1 activity and increase α-synuclein and Aβ metabolism. Specific dietary lipids requirements such as increased PI contents may act to stabilize membranes and favour lipid-protein interactions that promote the metabolism of α-synuclein and Aβ in various cells. The current global epidemic with the risk of accelerated brain disease such as stroke may involve peripheral organ diseases where abnormal cholesterol and ceramide interactions may determine toxic α-synuclein and Aβ assemblies that lead to early apoptosis and cell death in chronic diseases.
This work was supported by grants from the Edith Cowan University, McCusker Alzheimer's Research Foundation and the National Health and Medical Research Council.
- Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K. Amyloid plaque core protein in Alzheimer disease and Down syndrome. Proc Natl Acad Sci U S A. 1985; 82: 4245-4249.
- Glenner GG, Wong CW. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun. 1984; 120: 885-890.
- Glenner GG, Wong CW. Alzheimer's disease and Down's syndrome: sharing of a unique cerebrovascular amyloid fibril protein. Biochem Biophys Res Commun. 1984; 122: 1131-1135.
- Martins IJ, Creegan R. Links between Insulin Resistance, Lipoprotein Metabolism and Amyloidosis in Alzheimer's Disease. Health. 2014; 6: 1549-1579.
- Bodovitz S, Klein WL. Cholesterol modulates alpha-secretase cleavage of amyloid precursor protein. J Biol Chem. 1996; 271: 4436-4440.
- Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, et al. Beta-secretase cleavage of Alzheimer's amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999; 286: 735-741.
- Esch FS, Keim PS, Beattie EC, Blacher RW, Culwell AR, Oltersdorf T, et al. Cleavage of amyloid beta peptide during constitutive processing of its precursor. Science. 1990; 248: 1122-1124.
- Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci U S A. 1998; 95: 6460-6464.
- Kojro E, Gimpl G, Lammich S, Marz W, Fahrenholz F. Low cholesterol stimulates the nonamyloidogenic pathway by its effect on the alpha -secretase ADAM 10. Proc Natl Acad Sci U S A. 2001; 98: 5815-5820.
- Wahrle S, Das P, Nyborg AC, McLendon C, Shoji M, Kawarabayashi T, et al. Cholesterol-dependent gamma-secretase activity in buoyant cholesterol-rich membrane microdomains. Neurobiol Dis. 2002; 9: 11-23.
- Racchi M, Baetta R, Salvietti N, Ianna P, Franceschini G, Paoletti R, et al. Secretory processing of amyloid precursor protein is inhibited by increase in cellular cholesterol content. Biochem J. 1997; 322: 893-898.
- Galbete JL, Martin TR, Peressini E, Modena P, Bianchi R, Forloni G. Cholesterol decreases secretion of the secreted form of amyloid precursor protein by interfering with glycosylation in the protein secretory pathway. Biochem J. 2000; 348 Pt 2: 307-313.
- Abad-Rodriguez J, Ledesma MD, Craessaerts K, Perga S, Medina M, Delacourte A, et al. Neuronal membrane cholesterol loss enhances amyloid peptide generation. J Cell Biol. 2004; 167: 953-960.
- Martins IJ, Berger T, Sharman MJ, Verdile G, Fuller SJ, Martins RN. Cholesterol metabolism and transport in the pathogenesis of Alzheimer's disease. J Neurochem. 2009; 111: 1275-1308.
- Martins IJ, Gupta V, Wilson AC, Fuller SJ, Martins RN. Interactions between Apo E and Amyloid Beta and their Relationship to Nutriproteomics and Neurodegeneration. Curr. Prot. 2014; 11: 171-183.
- Martins IJ. Nutrition and genotoxic stress contributes to diabetes and neurodegenerative diseases such as Parkinson's and Alzheimer's disease. Book series Frontiers in Clinical Drug Research - CNS and Neurological Disorder. 2015; 3: 1-44.
- Martins IJ. Nutritional and genotoxic stress contributes to diabetes and neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease. 5th World Congress on Diabetes and Metabolism, LAS VEGAS. J Diabet Met. 2014: 5.
- Vernier P, Moret F, Callier S, Snapyan M, Wersinger C, Sidhu A. The degeneration of dopamine neurons in Parkinson's disease: insights from embryology and evolution of the mesostriatocortical system. Ann N Y Acad Sci. 2004; 1035: 231-249.
- Ruipérez V, Darios F, Davletov B. Alpha-synuclein, lipids and Parkinson's disease. Prog Lipid Res. 2010; 49: 420-428.
- Aviles-Olmos I, Limousin P, Lees A, Foltynie T. Parkinson's disease, insulin resistance and novel agents of neuroprotection. Brain. 2013; 136: 374-384.
- Santiago JA, Potashkin JA. Shared dysregulated pathways lead to Parkinson's disease and diabetes. Trends Mol Med. 2013; 19: 176-186.
- Fantini J, Yahi N. The driving force of alpha-synuclein insertion and amyloid channel formation in the plasma membrane of neural cells: key role of ganglioside- and cholesterol-binding domains. Adv Exp Med Biol. 2013; 991: 15-26.
- Fantini J, Barrantes FJ. How cholesterol interacts with membrane proteins: an exploration of cholesterol-binding sites including CRAC, CARC, and tilted domains. Front Physiol. 2013; 4: 31.
- Kurose T, Hyo T, Yabe D, Seino Y. The role of chronobiology and circadian rhythms in type 2 diabetes mellitus: implications for management of diabetes. 2014; 4: 41-49.
- Breen DP, Vuono R, Nawarathna U, Fisher K, Shneerson JM, Reddy AB, et al. Sleep and circadian rhythm regulation in early Parkinson disease. JAMA Neurol. 2014; 71: 589-595.
- Coogan AN, Schutová B, Husung S, Furczyk K, Baune BT, Kropp P, et al. The circadian system in Alzheimer's disease: disturbances, mechanisms, and opportunities. Biol Psychiatry. 2013; 74: 333-339.
- Weldemichael DA, Grossberg GT. Circadian rhythm disturbances in patients with Alzheimer's disease: a review. Int J Alzheimers Dis. 2010; 2010.
- Videnovic A, Golombek D. Circadian and sleep disorders in Parkinson's disease. Exp Neurol. 2013; 243: 45-56.
- Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, et al. Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. Science. 2009; 326: 1005-1007.
- Costandi M. Neurodegeneration: amyloid awakenings. Nature. 2013; 497: S19-20.
- Kudo T, Loh DH, Truong D, Wu Y, Colwell CS. Circadian dysfunction in a mouse model of Parkinson's disease. Exp Neurol. 2011; 232: 66-75.
- Lee SS, Kim YM, Junn E, Lee G, Park KH, Tanaka M, et al. Cell cycle aberrations by alpha-synuclein over-expression and cyclin B immunoreactivity in Lewy bodies. Neurobiol Aging. 2003; 24: 687-696.
- Guarente L. Sirtuins in aging and disease. Cold Spring Harb Symp Quant Biol. 2007; 72: 483-488.
- Hansen MK, Connolly TM. Nuclear receptors as drug targets in obesity, dyslipidemia and atherosclerosis. Curr Opin Investig Drugs. 2008; 9: 247-255.
- Harrison, C. Neurodegenerative Disorders: A Neuroprotective Role for Sirtuin 1. Nature Reviews Drug Discovery. 2012; 11: 108.
- Kawada T, Goto T, Hirai S, Kang MS, Uemura T, Yu R, et al. Dietary regulation of nuclear receptors in obesity-related metabolic syndrome. Asia Pac J Clin Nutr. 2008; 17 Suppl 1: 126-130.
- Swanson HI, Wada T, Xie W, Renga B, Zampella A, Distrutti E, et al. Role of nuclear receptors in lipid dysfunction and obesity-related diseases. Drug Metab Dispos. 2013; 41: 1-11.
- Cakir I, Perello M, Lansari O, Messier NJ, Vaslet CA, Nillni EA. Hypothalamic Sirt1 regulates food intake in a rodent model system. PLoS One. 2009; 4: e8322.
- Kitamura T, Sasaki T. Hypothalamic Sirt1 and Regulation of Food Intake. Diabetology International. 2012; 3: 109-112.
- Dietrich MO, Antunes C, Geliang G, Liu ZW, Borok E, Nie Y, et al. Agrp neurons mediate Sirt1's action on the melanocortin system and energy balance: roles for Sirt1 in neuronal firing and synaptic plasticity. J Neurosci. 2010; 30: 11815-11825.
- Schaffhauser AO, Madiehe AM, Braymer HD, Bray GA, York DA. Effects of a high-fat diet and strain on hypothalamic gene expression in rats. Obes Res. 2002; 10: 1188-1196.
- Lee AK, Mojtahed-Jaberi M, Kyriakou T, Astarloa EA, Arno M, Marshall NJ, et al. Effect of high-fat feeding on expression of genes controlling availability of dopamine in mouse hypothalamus. Nutrition. 2010; 26: 411-422.
- Garaulet M, Esteban Tardido A, Lee YC, Smith CE, Parnell LD, Ordovás JM, et al. SIRT1 and CLOCK 3111T>C Combined Genotype Is Associated with Evening Preference and Weight Loss Resistance in a Behavioral Therapy Treatment for Obesity. Int J Obes. 2012; 36: 1436-1441.
- Shimoyama Y, Suzuki K, Hamajima N, Niwa T. Sirtuin 1 gene polymorphisms are associated with body fat and blood pressure in Japanese. Transl Res. 2011; 157: 339-347.
- Shimoyama Y, Mitsuda Y, Tsuruta Y, Suzuki K, Hamajima N, Niwa T. SIRTUIN 1 gene polymorphisms are associated with cholesterol metabolism and coronary artery calcification in Japanese hemodialysis patients. J Ren Nutr. 2012; 22: 114-119.
- Clark SJ, Falchi M, Olsson B, Jacobson P, Cauchi S, Balkau B, et al. Association of sirtuin 1 (SIRT1) gene SNPs and transcript expression levels with severe obesity. Obesity (Silver Spring). 2012; 20: 178-185.
- Flachsbart F, Croucher PJ, Nikolaus S, Hampe J, Cordes C, Schreiber S, et al. Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Exp Gerontol. 2006; 41: 98-102.
- Jiang M, Wang J, Fu J, Du L, Jeong H, West T, et al. Neuroprotective role of Sirt1 in mammalian models of Huntington's disease through activation of multiple Sirt1 targets. Nat Med. 2011; 18: 153-158.
- Li X, Zhang S, Blander G, Tse JG, Krieger M, Guarente L. SIRT1 deacetylates and positively regulates the nuclear receptor LXR. Mol Cell. 2007; 28: 91-106.
- Nakamuta M, Fujino T, Yada R, Yada M, Yasutake K, Yoshimoto T, et al. Impact of cholesterol metabolism and the LXRalpha-SREBP-1c pathway on nonalcoholic fatty liver disease. Int J Mol Med. 2009; 23: 603-608.
- Defour A, Dessalle K, Castro Perez A, Poyot T, Castells J, Gallot YS, et al. Sirtuin 1 regulates SREBP-1c expression in a LXR-dependent manner in skeletal muscle. PLoS One. 2012; 7: e43490.
- Yang J, Craddock L, Hong S, Liu ZM. AMP-activated protein kinase suppresses LXR-dependent sterol regulatory element-binding protein-1c transcription in rat hepatoma McA-RH7777 cells. J Cell Biochem. 2009; 106: 414-426.
- Yap F, Craddock L, Yang J. Mechanism of AMPK suppression of LXR-dependent Srebp-1c transcription. Int J Biol Sci. 2011; 7: 645-650.
- Camargo N, Smit AB, Verheijen MH. SREBPs: SREBP function in glia-neuron interactions. FEBS J. 2009; 276: 628-636.
- Jordan SD, Lamia KA. AMPK at the crossroads of circadian clocks and metabolism. Mol Cell Endocrinol. 2013; 366: 163-169.
- Price NL, Gomes AP, Ling AJ, Duarte FV, Martin-Montalvo A, North BJ, et al. SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function. Cell Metab. 2012; 15: 675-690.
- Ranhotra HS. Long-term caloric restriction up-regulates PPAR gamma co-activator 1 alpha (PGC-1alpha) expression in mice. Indian J Biochem Biophys. 2010; 47: 272-277.
- Wenz T, Diaz F, Spiegelman BM, Moraes CT. Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype. Cell Metab. 2008; 8: 249-256.
- Li AC, Glass CK. PPAR- and LXR-dependent pathways controlling lipid metabolism and the development of atherosclerosis. J Lipid Res. 2004; 45: 2161-2173.
- Oberkofler H, Schraml E, Krempler F, Patsch W. Potentiation of liver X receptor transcriptional activity by peroxisome-proliferator-activated receptor gamma co-activator 1 alpha. Biochem J. 2003; 371: 89-96.
- Aquilano K, Vigilanza P, Baldelli S, Pagliei B, Rotilio G, Ciriolo MR. Peroxisome proliferator-activated receptor gamma co-activator 1alpha (PGC-1alpha) and sirtuin 1 (SIRT1) reside in mitochondria: possible direct function in mitochondrial biogenesis. J Biol Chem. 2010; 285: 21590-21599.
- Cheng D, Kim WS, Garner B. Regulation of alpha-synuclein expression by liver X receptor ligands in vitro. Neuroreport. 2008; 19: 1685-1689.
- Sun Y, Yao J, Kim TW, Tall AR. Expression of liver X receptor target genes decreases cellular amyloid beta peptide secretion. J Biol Chem. 2003; 278: 27688-27694.
- Loane DJ, Washington PM, Vardanian L, Pocivavsek A, Hoe HS, Duff KE, et al. Modulation of ABCA1 by an LXR agonist reduces β-amyloid levels and improves outcome after traumatic brain injury. J Neurotrauma. 2011; 28: 225-236.
- Marwarha G, Rhen T, Schommer T, Ghribi O. The oxysterol 27-hydroxycholesterol regulates a-synuclein and tyrosine hydroxylase expression levels in human neuroblastoma cells through modulation of liver X receptors and estrogen receptors-Relevance to Parkinson's disease J Neurochem. 2011; 119: 1119-1136.
- Kudo T, Loh DH, Truong D, Wu Y, Colwell CS. Circadian dysfunction in a mouse model of Parkinson's disease. Exp Neurol. 2011; 232: 66-75.
- Hastings MH, Goedert M. Circadian clocks and neurodegenerative diseases: time to aggregate? Curr Opin Neurobiol. 2013; 23: 880-887.
- Oosterhof N, Dekens DW, Lawerman TF, van Dijk M. Yet another role for SIRT1: reduction of α-synuclein aggregation in stressed neurons. J Neurosci. 2012; 32: 6413-6414.
- Rieker C, Dev KK, Lehnhoff K, Barbieri S, Ksiazek I, Kauffmann S. Neuropathology in mice expressing mouse alpha-synuclein. PLoS One. 2011; 6: e24834.
- Donmez G, Arun A, Chung CY, McLean PJ, Lindquist S, Guarente L, et al. SIRT1 protects against α-synuclein aggregation by activating molecular chaperones. J Neurosci. 2012; 32: 124-132.
- Zhang A, Wang H, Qin X, Pang S, Yan B. Genetic analysis of SIRT1 gene promoter in sporadic Parkinson's disease. Biochem Biophys Res Commun. 2012; 422: 693-696.
- Oosterhof N, Dekens DW, Lawerman TF, van Dijk M. Yet another role for SIRT1: reduction of α-synuclein aggregation in stressed neurons. J Neurosci. 2012; 32: 6413-6414.
- Martins IJ. Induction of NAFLD with increased risk of obesity and chronic disease in developed countries. Open Journal of Endocrine and Metabolic Diseases. 2014; 4: 90-120.
- Martins IJ. The cholesterol-ceramide connection as a possible link between diabetes and Alzheimer's disease. Papers and Posters. World Congress on Diabetes 2014 - Bit's 3rd Annual World Congress of Diabetes 2014.
- Marsh SE, Blurton-Jones M. Examining the mechanisms that link β-amyloid and α-synuclein pathologies. Alzheimers Res Ther. 2012; 4: 11.
- Jiang P, Gan M, Ebrahim AS, Lin WL, Melrose HL, Yen SH. ER stress response plays an important role in aggregation of α-synuclein. Mol Neurodegener. 2010; 5: 56.
- Nath S, Goodwin J, Engelborghs Y, Pountney DL. Raised calcium promotes α-synuclein aggregate formation. Mol Cell Neurosci. 2011; 46: 516-526.
- Calí T, Ottolini D, Negro A, Brini M. a-Synuclein controls mitochondrial calcium homeostasis by enhancing endoplasmic reticulum-mitochondria interactions. J Biol Chem. 2012; 287: 17914-17929.
- Chen Q, Thorpe J, Keller JN. Alpha-synuclein alters proteasome function, protein synthesis, and stationary phase viability. J Biol Chem. 2005; 280: 30009-30017.
- Martins IJ, Vilchèze C, Mortimer BC, Bittman R, Redgrave TG. Sterol side chain length and structure affect the clearance of chylomicron-like lipid emulsions in rats and mice. J Lipid Res. 1998; 39: 302-312.
- McMullen TPW, Lewis R, McElhaney RN. Cholesterol-phospholipid interactions, the liquid-ordered phase and lipid rafts in model and biological membranes Curr. Opin. Colloid Interface Sci. 2004; 8: 459-468.
- Di Scala C, Yahi N, Lelièvre C, Garmy N, Chahinian H, Fantini J. Biochemical identification of a linear cholesterol-binding domain within Alzheimer's β amyloid peptide. ACS Chem Neurosci. 2013; 4: 509-517.
- Masliah E, Rockenstein E, Veinbergs I, Sagara Y, Mallory M, Hashimoto M, et al. Beta-amyloid peptides enhance alpha-synuclein accumulation and neuronal deficits in a transgenic mouse model linking Alzheimer's disease and Parkinson's disease. Proc Natl Acad Sci U S A. 2001; 98: 12245-12250.
- Kim WS, Halliday GM. Changes in sphingomyelin level affect alpha-synuclein and ABCA5 expression. J Parkinsons Dis. 2012; 2: 41-46.
- Kamp F, Beyer K. Binding of alpha-synuclein affects the lipid packing in bilayers of small vesicles. J Biol Chem. 2006; 281: 9251-9259.
- Martinez Z, Zhu M, Han S, Fink AL. GM1 specifically interacts with alpha-synuclein and inhibits fibrillation. Biochemistry. 2007; 46: 1868-1877.
- Lücke C, Gantz DL, Klimtchuk E, Hamilton JA. Interactions between fatty acids and alpha-synuclein. J Lipid Res. 2006; 47: 1714-1724.
- Narayanan V, Guo Y, Scarlata S. Fluorescence studies suggest a role for alpha-synuclein in the phosphatidylinositol lipid signaling pathway. Biochemistry. 2005; 44: 462-470.
- Hellstrand E, Grey M, Ainalem ML, Ankner J, Forsyth VT, Fragneto G, et al. Adsorption of α-synuclein to supported lipid bilayers: positioning and role of electrostatics. ACS Chem Neurosci. 2013; 4: 1339-1351.
- Michikawa M. Role of cholesterol in amyloid cascade: cholesterol-dependent modulation of tau phosphorylation and mitochondrial function. Acta Neurol Scand Suppl. 2006; 185: 21-26.
- Di Scala C, Chahinian H, Yahi N, Garmy N, Fantini J. Interaction of Alzheimer's β-amyloid peptides with cholesterol: mechanistic insights into amyloid pore formation. Biochemistry. 2014; 53: 4489-4502.
- Michikawa M. The role of cholesterol in pathogenesis of Alzheimer's disease: dual metabolic interaction between amyloid beta-protein and cholesterol. Mol Neurobiol. 2003; 27: 1-12.
- Morshedi D, Aliakbari F, Reza H, Lotfinia NM, Fallahi J. Using small molecules as a new challenge to redirect metabolic pathway. Biotech. 2014; 4: 513-522.
- Ono K, Ikemoto M, Kawarabayashi T, Ikeda M, Nishinakagawa T, Hosokawa M, et al. A chemical chaperone, sodium 4-phenylbutyric acid, attenuates the pathogenic potency in human alpha-synuclein A30P + A53T transgenic mice. Parkinsonism Relat Disord. 2009; 15: 649-654.
- Wiley JC, Pettan-Brewer C, Ladiges WC. Phenylbutyric acid reduces amyloid plaques and rescues cognitive behavior in AD transgenic mice. Aging Cell. 2011; 10: 418-428.
- de Chaves EP, Narayanaswami V. Apolipoprotein E and cholesterol in aging and disease in the brain. Future Lipidol. 2008; 3: 505-530.
- Zhao Y, Chen X, Yang H, Zhou L, Okoro EU, Guo Z, et al. A novel function of apolipoprotein E: upregulation of ATP-binding cassette transporter A1 expression. PLoS One. 2011; 6: e21453.
- Gallardo G, Schlüter OM, Südhof TC. A molecular pathway of neurodegeneration linking alpha-synuclein to ApoE and Abeta peptides. Nat Neurosci. 2008; 11: 301-308.
- Wilhelmus MM, Bol JG, Van Haastert ES, Rozemuller AJ, Bu G, Drukarch B, et al. Apolipoprotein E and LRP1 Increase Early in Parkinson's Disease Pathogenesis. Am J Pathol. 2011; 179: 2152-2156.
- Khan N, Graham E, Dixon P, Morris C, Mander A, Clayton D, et al. Parkinson's disease is not associated with the combined alpha-synuclein/apolipoprotein E susceptibility genotype. Ann Neurol. 2001; 49: 665-668.
- Nybond S, Björkqvist J, Slotte JP, Ramstedt B. Sulfatide Exhibits Calcium Dependent Stabilization of Sphingomyelin/Cholesterol Domains in Bilayer Membranes. Chem Phys Lipids. 2007; 149: S36.
- Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab. 2012; 15: 585-594.
- Costantini C, Kolasani RM, Puglielli L. Ceramide and cholesterol: possible connections between normal aging of the brain and Alzheimer's disease. Just hypotheses or molecular pathways to be identified? Alzheimers Dement. 2005; 1: 43-50.
- Galadari S, Rahman A, Pallichankandy S, Galadari A, Thayyullathil F. Role of ceramide in diabetes mellitus: evidence and mechanisms. Lipids Health Dis. 2013; 12: 98.
- de la Monte SM, Wands JR. Alzheimer's disease is type 3 diabetes-evidence reviewed. J Diabetes Sci Technol. 2008; 2: 1101-1113.
- Krishnan R, Goodman JL, Mukhopadhyay S, Pacheco CD, Lemke EA, Deniz AA, et al. Conserved features of intermediates in amyloid assembly determine their benign or toxic states. Proc Natl Acad Sci U S A. 2012; 109: 11172-11177.
- Martins IJ, Fernando WMADB. High fibre diets and Alzheimer's disease. Food and Nutrition Sciences. 2014; 5: 410-424.
- Malek N, Swallow D, Grosset KA, Anichtchik O, Spillantini M, Grosset DG, et al. Alpha-synuclein in peripheral tissues and body fluids as a biomarker for Parkinson's disease - a systematic review. Acta Neurol Scand. 2014; 130: 59-72.
- Phillips RJ, Billingsley CN, Powley TL. Macrophages are unsuccessful in clearing aggregated alpha-synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats. Anat Rec (Hoboken). 2013; 296: 654-669.
- Mina G, Perera TJ, Chen Z, Chou J, Lin JC. Novel Roles of alpha-Synuclein in Energy and Glucose Homeostasis. American Diabetes Association. 2009.
- Gardai SJ, Mao W, Schüle B, Babcock M, Schoebel S, Lorenzana C, et al. Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease. PLoS One. 2013; 8: e71634.
- Shavali S, Combs CK, Ebadi M. Reactive macrophages increase oxidative stress and alpha-synuclein nitration during death of dopaminergic neuronal cells in co-culture: relevance to Parkinson's disease. Neurochem Res. 2006; 31: 85-94.
- Rodrìguez-Leyva I, Calderón-Garcidueñas AL, Jiménez-Capdeville ME, Renterìa-Palomo AA, Hernandez-Rodriguez HG, Valdés-Rodrìguez R, et al. α-Synuclein inclusions in the skin of Parkinson's disease and parkinsonism. Ann Clin Transl Neurol. 2014; 1: 471-478.
- Steneberg P, Bernardo L, Edfalk S, Lundberg L, Backlund F, Ostenson CG, et al. The type 2 diabetes-associated gene ide is required for insulin secretion and suppression of α-synuclein levels in β-cells. Diabetes. 2013; 62: 2004-2014.
- Millership S, Ninkina N, Rochford JJ, Buchman VL. γ-synuclein is a novel player in the control of body lipid metabolism. Adipocyte. 2013; 2: 276-280.
- Martins IJ. Unhealthy Nutrigenomic diets accelerate NAFLD and Adiposity in Western Communities. Track 1-2: Molecular and Cell Biology at BIT's 5th Annual World Gene Convention. 2014.
- Tanji K, Mori F, Imaizumi T, Yoshida H, Matsumiya T, Tamo W, et al. Upregulation of alpha-synuclein by lipopolysaccharide and interleukin-1 in human macrophages. Pathol Int. 2002; 52: 572-577.
- Pfeiffer A, Böttcher A, Orsó E, Kapinsky M, Nagy P, Bodnár A, et al. Lipopolysaccharide and ceramide docking to CD14 provokes ligand-specific receptor clustering in rafts. Eur J Immunol. 2001; 31: 3153-3164.
- Kelly LP, Carvey PM, Keshavarzian A, Shannon KM, Shaikh M, Bakay RA, et al. Progression of intestinal permeability changes and alpha-synuclein expression in a mouse model of Parkinson's disease. Mov Disord. 2014; 29: 999-1009.
- Kaplan R, Gan X, Menke JG, Wright SD, Cai TQ. Bacterial lipopolysaccharide induces expression of ABCA1 but not ABCG1 via an LXR-independent pathway. J Lipid Res. 2002; 43: 952-959.
- Majdalawieh A1, Ro HS. LPS-induced suppression of macrophage cholesterol efflux is mediated by adipocyte enhancer-binding protein 1. Int J Biochem Cell Biol. 2009; 41: 1518-1525.
- Hoban DB, Connaughton E, Connaughton C, Hogan G, Thornton C, Mulcahy P, et al. Further characterisation of the LPS model of Parkinson's disease: a comparison of intra-nigral and intra-striatal lipopolysaccharide administration on motor function, microgliosis and nigrostriatal neurodegeneration in the rat. Brain Behav Immun. 2013; 27: 91-100.
- Liu M, Bing G. Lipopolysaccharide animal models for Parkinson's disease. Parkinsons Dis. 2011; 2011: 327089.
- Im SS, Yousef L, Blaschitz C, Liu JZ, Edwards RA, Young SG, et al. Linking lipid metabolism to the innate immune response in macrophages through sterol regulatory element binding protein-1a. Cell Metab. 2011; 13: 540-549.
- Costales P, Castellano J, Revuelta-López E, Cal R, Aledo R, Llampayas O, et al. Lipopolysaccharide downregulates CD91/low-density lipoprotein receptor-related protein 1 expression through SREBP-1 overexpression in human macrophages. Atherosclerosis. 2013; 227: 79-88.
- Chaung WW, Jacob A, Ji Y, Wang P. Suppression of PGC-1alpha by Ethanol: Implications of Its Role in Alcohol Induced Liver Injury. Int J Clin Exp Med. 2008; 1: 161-170.
- Suzuki MM, Matsumoto M, Omi H, Kobayashi T, Nakamura A, Kishi H, et al. Interaction of peptide-bound beads with lipopolysaccharide and lipoproteins. J Microbiol Methods. 2014; 100: 137-141.
- Vreugdenhil AC, Snoek AM, van 't Veer C, Greve JW, Buurman WA. LPS-binding protein circulates in association with apoB-containing lipoproteins and enhances endotoxin-LDL/VLDL interaction. J Clin Invest. 2001; 107: 225-234.
- Wurfel MM, Kunitake ST, Lichenstein H, Kane JP, Wright SD. Lipopolysaccharide (LPS)-binding protein is carried on lipoproteins and acts as a cofactor in the neutralization of LPS. J Exp Med. 1994; 180: 1025-1035.
- Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, et al. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes. 2007; 56: 1761-1772.
- Moreno-Navarrete JM, Ortega F, Serino M, Luche E, Waget A, Pardo G, et al. Circulating lipopolysaccharide-binding protein (LBP) as a marker of obesity-related insulin resistance. Int J Obes (Lond). 2012; 36: 1442-1449.
- Amyot J, Semache M, Ferdaoussi M, Fontés G, Poitout V. Lipopolysaccharides impair insulin gene expression in isolated islets of Langerhans via Toll-Like Receptor-4 and NF-κB signalling. PLoS One. 2012; 7: e36200.
- Moreno-Navarrete JM, Escoté X, Ortega F, Serino M, Campbell M, Michalski MC, et al. A role for adipocyte-derived lipopolysaccharide-binding protein in inflammation- and obesity-associated adipose tissue dysfunction. Diabetologia. 2013; 56: 2524-2537.
- MacKichan ML, DeFranco AL. Role of ceramide in lipopolysaccharide (LPS)-induced signaling. LPS increases ceramide rather than acting as a structural homolog. J Biol Chem. 1999; 274: 1767-1775.
- Schilling JD, Machkovech HM, He L, Sidhu R, Fujiwara H, Weber K, et al. Palmitate and lipopolysaccharide trigger synergistic ceramide production in primary macrophages. J Biol Chem. 2013; 288: 2923-2932.
- Blachnio-Zabielska A, Baranowski M, Zabielski P, Górski J. Effect of exercise duration on the key pathways of ceramide metabolism in rat skeletal muscles. J Cell Biochem. 2008; 105: 776-784.
- Helge JW, Dobrzyn A, Saltin B, Gorski J. Exercise and training effects on ceramide metabolism in human skeletal muscle. Exp Physiol. 2004; 89: 119-127.
- Dobrzyn A, Knapp M, Górski J. Effect of acute exercise and training on metabolism of ceramide in the heart muscle of the rat. Acta Physiol Scand. 2004; 181: 313-319.
- Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med. 2011; 17: 55-63.
- Lancaster GI, Febbraio MA. Adiponectin sphings into action. Nat Med. 2011; 17: 37-38.
- Sekiyama K, Waragai M, Akatsu H, Sugama S, Takenouchi T, Takamatsu Y, et al. Disease-Modifying Effect of Adiponectin in Model of α-Synucleinopathies. Ann Clin Transl Neurol. 2014; 1: 479-489.
- Martins IJ. The Global Obesity Epidemic is related to Stroke, Dementia and Alzheimer's disease. JSM Alzheimer's Dis Related Dementia. 2014; 1: 1010.
- Ali MR, Cheng KH, Huang J. Ceramide drives cholesterol out of the ordered lipid bilayer phase into the crystal phase in 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine/cholesterol/ceramide ternary mixtures. Biochem. 2006; 45: 12629-12638.
- Castro BM, Silva LC, Fedorov A, de Almeida RF, Prieto M. Cholesterol-rich fluid membranes solubilize ceramide domains: implications for the structure and dynamics of mammalian intracellular and plasma membranes. J Biol Chem. 2009; 284: 22978-22987.
- Goers J, Uversky VN, Fink AL. Polycation-induced oligomerization and accelerated fibrillation of human alpha-synuclein in vitro. Protein Sci. 2003; 12: 702-707.
- Munishkina LA, Henriques J, Uversky VN, Fink AL. Role of protein-water interactions and electrostatics in alpha-synuclein fibril formation. Biochemistry. 2004; 43: 3289-3300.
- Strassmann G, Graber N, Goyert SM, Fong M, McCullers S, Rong GW, et al. Inhibition of lipopolysaccharide and IL-1 but not of TNF-induced activation of human endothelial cells by suramin. J Immunol. 1994; 153: 2239-2247.
- Wecke J, Franz M, Giesbrecht P. Inhibition of the bacteriolytic effect of beta-lactam-antibiotics on Staphylococcus aureus by the polyanionic drugs suramin and Evans Blue. APMIS. 1990; 98: 71-81.
- Trapp J, Meier R, Hongwiset D, Kassack MU, Sippl W, Jung M, et al. Structure-activity studies on suramin analogues as inhibitors of NAD+-dependent histone deacetylases (sirtuins). ChemMedChem. 2007; 2: 1419-1431.
- Vansterkenburg EL, Coppens I, Wilting J, Bos OJ, Fischer MJ, Janssen LH, et al. The uptake of the trypanocidal drug suramin in combination with low-density lipoproteins by Trypanosoma brucei and its possible mode of action. Acta Trop. 1993; 54: 237-250.
- Nikanjam M, Blakely EA, Bjornstad KA, Shu X, Budinger TF, Forte TM, et al. Synthetic nano-low density lipoprotein as targeted drug delivery vehicle for glioblastoma multiforme. Int J Pharm. 2007; 328: 86-94.
- Dao TT1, Tran TL, Kim J, Nguyen PH, Lee EH, Park J. Terpenylated coumarins as SIRT1 activators isolated from Ailanthus altissima. J Nat Prod. 2012; 75: 1332-1338.
- Jang HL, El-Gamal MI, Choi HE, Choi HY, Lee KT, Oh CH, et al. Synthesis of tricyclic fused coumarin sulfonates and their inhibitory effects on LPS-induced nitric oxide and PGE2 productions in RAW 264.7 macrophages. Bioorg Med Chem Lett. 2014; 24: 571-575.
- Rotili D, Carafa V, Tarantino D, Botta G, Nebbioso A, Altucci L, et al. Simplification of the tetracyclic SIRT1-selective inhibitor MC2141: coumarin- and pyrimidine-based SIRT1/2 inhibitors with different selectivity profile. Bioorg Med Chem. 2011; 19: 3659-3668.
- Lira FS, Rosa JC, Pimentel GD, Seelaender M, Damaso AR, Oyama LM, et al. Both adiponectin and interleukin-10 inhibit LPS-induced activation of the NF-κB pathway in 3T3-L1 adipocytes. Cytokine. 2012; 57: 98-106.
- Kraus D, Winter J, Jepsen S, Jäger A, Meyer R, Deschner J, et al. Interactions of adiponectin and lipopolysaccharide from Porphyromonas gingivalis on human oral epithelial cells. PLoS One. 2012; 7: e30716.
- O'Reilly B, Vander AJ, Kluger MJ. Effects of chronic infusion of lipopolysaccharide on food intake and body temperature of the rat. Physiol Behav. 1988; 42: 287-291.
- Aubert A, Kelley KW, Dantzer R. Differential effect of lipopolysaccharide on food hoarding behavior and food consumption in rats. Brain Behav Immun. 1997; 11: 229-238.
- Martins IJ. Appetite dysregulation and obesity in Western Countries. Emma Jones, editor. Acquisition Editor LAP LAMBERT Academic Publishing is a trademark of: AV Akademikerverlag GmbH & Co. KG. 2013.
- Martins IJ, Creegan R, Lim WLF, Martins RN. Molecular insights into appetite control and neuroendocrine disease as risk factors for chronic diseases in Western countries. Open Journal of Endocrine and Metabolic Diseases. 2013; 3: 11-33.
- Kurita-Ochiai T, Amano S, Fukushima K, Ochiai K. Cellular events involved in butyric acid-induced T cell apoptosis. J Immunol. 2003; 171: 3576-3584.
- Takigawa S, Sugano N, Ochiai K, Arai N, Ota N, Ito K. Effects of sodium bicarbonate on butyric acid-induced epithelial cell damage in vitro. J Oral Sci. 2008; 50: 413-417.
Citation: Chaudhry ZL and Ahmed BY. The Role of Caspases in Parkinson’s Disease Pathogenesis: A Brief Look at the Mitochondrial Pathway. Austin Alzheimers J Parkinsons Dis. 2014;1(4): 5. ISSN: 2377-357X