e r s Diseas Journal of im e aA lz r f k o i l a n r u ......range in some pathological situations...
2
Volume 2 • Issue 2 • 1000e111 J Alzheimers Dis ISSN:2161-0460 JADP an open access journal Open Access Editorial Ghribi, Alzheimers Dis Res 2012, 2:2 DOI: 10.4172/2161-0460.1000e111 Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders. Both diseases are characterized by the deposition in the brain of insoluble protein aggregates: β-amyloid (Aβ) in AD and α-synuclein in PD. e differences in protein aggregate types that accumulate either in AD or PD suggest that these diseases are two distinct entities. However, a significant proportion of dementia brains showing features of AD also exhibit α-synuclein inclusions. As well, a subset of PD patients has Aβ aggregates in addition to α-synuclein load. e concomitant presence of the two proteins indicates that AD and PD overlap, and that this overlap may be caused by factors that can converge to trigger the overlapping features (i.e. Aβ and α-synuclein). However, currently no genetic or environmental factor that can generate both Aβ and α-synuclein in vivo or in vitro has been identified. us, while the pathogeneses of AD, PD, and mixed AD/PD are still to be determined, identification of signaling mechanisms that can be modulated to trigger the overproduction of Aβ and α-synuclein may help design strategies that prevent or slow the accumulation of these aggregates. e identification of genetic mutations linked to familial forms of AD and PD has led to the development of cellular and animal models that have helped in understanding aspects of the pathophysiology of the inherited, early onset AD and PD forms. However, the majority of AD and PD cases are sporadic. While genetic mutations are responsible for the accumulation of Aβ in familial AD and α-synuclein in familial PD, the causative factors for the accumulation of Aβ and α-synuclein in sporadic AD are not known. is raises the possibility that the accumulation of Aβ and α-synuclein in the absence of genetic mutations might result from abnormalities in specific signaling pathways that lead to an increase in Aβ and α-synuclein production and/or a decrease in their clearance. Factors such as the environment and diet may be implicated in the pathogenesis of sporadic forms of AD and PD. e first identified risk of AD is apolipoprotein E (ApoE) [1]. Some but not all people who have one or two copies of the ApoE ε4 allele are at increased risk of AD. ApoE is a specific type of lipoprotein that plays an important role in the distribution of cholesterol in blood and brain. Carrying ApoE ε4 is associated with high plasma cholesterol [2,3]. e association between ApoE and cholesterol has put cholesterol up front as a potential risk factor for sporadic forms of AD. Both the pioneer studies by Sparks et al. [4] showing that rabbits fed a diet rich in cholesterol exhibit increased Aβ accumulation and the epidemiological studies by Solomon et al. [5] demonstrating that high cholesterol at mid-age increases the risk for AD by 66% later in life link cholesterol to the pathophysiology of AD. For the last few years, high dietary fat intake has also been under scrutiny as a risk factor for PD. A standardized food frequency questionnaire has shown an association of PD with high intake of total fat, saturated fats, and cholesterol [6]. A recent large prospective study has suggested that total serum cholesterol at baseline is associated with an increased risk of PD [7]. In other studies however, elevated serum levels of cholesterol were either not associated with PD risk [8] or were related to a decreased PD risk [9,10]. us, to date, the extent to which disturbances in cholesterol metabolism play a role in the pathogenesis of AD or PD is still unclear. *Corresponding author: Othman Ghribi, Department of Pharmacology, Physiol- ogy and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, North Dakota, 58202, USA, Tel: 1-701-777-2522; Fax: 1-701-777-4490; E-mail: [email protected] Received March 26, 2012; Accepted March 27, 2012; Published March 29, 2012 Citation: Ghribi O (2012) Do Increased Levels of Oxysterols Underlie Alzheimer’s Disease/Parkinson’s Disease Overlap?. J Alzheimers Dis 2:e111. doi:10.4172/2161- 0460.1000e111 Copyright: © 2012 Ghribi O. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Do Increased Levels of Oxysterols Underlie Alzheimer’s Disease/ Parkinson’s Disease Overlap? Othman Ghribi* Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, 58202, USA e absence of a consensus on a role of cholesterol in AD or PD may be explained by the following: First, it may be possible that abnormalities in cholesterol metabolism take part in AD and PD pathogenesis early at mid-age when the disease is initiated; at late-age when symptoms manifest and PD progresses, the correlation between AD/PD and cholesterol status is no longer consistent. Indeed, AD or PD patients may have normal, low or high cholesterol levels. Second, fluctuations in cholesterol oxidation products (oxysterols), rather than cholesterol per se, may correlate better with the onset of AD and PD. Some oxysterols may place the brain at risk of injury following disturbances in their levels. Of these oxysterols, 27-hydroxycholesterol (27-OHC) has the ability to cross lipophilic membranes into and out of the brain [11,12]. As 27-OHC originates almost exclusively from oxidation of cholesterol in the circulation, one can expect that hypercholesterolemia increases turnover of cholesterol to 27-OHC, thus increasing its levels in the circulation and potentially in the brain. Circulating 27-OHC levels are 0.15-0.73 μM, and these concentrations can be in the millimolar range in some pathological situations such as atherosclerosis [13,14]. A marked accumulation of 27-OHC in the brains of Alzheimer’s patients with the Swedish APP 670/671 mutation has been recently demonstrated [15]. Oxysterols were also shown to be elevated in the cerebral cortex of individuals with Lewy body dementia where they are suggested to accelerate α-synuclein aggregation [16]. A recent study also showed increased levels of several oxysterols including 27-OHC in cortex of PD brains [17]. ese studies, together with the known toxic effects of high levels of oxysterols suggest a possible role of these cholesterol metabolites in AD and PD. e question as to what are the potential cellular pathways and mechanisms that mediate the deleterious effects of oxysterols is however still to be answered. Binding to and activating liver X receptors (LXRs) is one of the major mechanisms by which 27-OHC and other oxysterols exert their major functions [18]. LXRs bind to promoters of specific genes to recruit co-activators or co-repressors, thus impacting expression of target genes. We have recently found that treatment with the oxysterol 27-OHC increases Aβ production [19] and reduces tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, and increases α-synuclein levels [20,21]. In support of our data, another independent study also showed that 27-OHC regulates α-synuclein expression levels, and provided further evidence that 27- OHC modulates α-synuclein through activation of LXRs [22]. We also Journal of Alzheimer’s Disease & Parkinsonism J o u r n a l o f A l z h e i m e r s D i s e a s e & P a r k i n s o n i s m ISSN: 2161-0460
Transcript of e r s Diseas Journal of im e aA lz r f k o i l a n r u ......range in some pathological situations...
![Page 1: e r s Diseas Journal of im e aA lz r f k o i l a n r u ......range in some pathological situations such as atherosclerosis [13,14]. A marked accumulation of 27-OHC in the brains of](https://reader033.fdocument.org/reader033/viewer/2022041818/5e5c436ffd56ac71f31d7026/html5/thumbnails/1.jpg)
Volume 2 • Issue 2 • 1000e111J Alzheimers DisISSN:2161-0460 JADP an open access journal
Open AccessEditorial
Ghribi, Alzheimers Dis Res 2012, 2:2 DOI: 10.4172/2161-0460.1000e111
Alzheimer’s disease (AD) and Parkinson’s disease (PD) are the most common neurodegenerative disorders. Both diseases are characterized by the deposition in the brain of insoluble protein aggregates: β-amyloid (Aβ) in AD and α-synuclein in PD. The differences in protein aggregate types that accumulate either in AD or PD suggest that these diseases are two distinct entities. However, a significant proportion of dementia brains showing features of AD also exhibit α-synuclein inclusions. As well, a subset of PD patients has Aβ aggregates in addition to α-synuclein load. The concomitant presence of the two proteins indicates that AD and PD overlap, and that this overlap may be caused by factors that can converge to trigger the overlapping features (i.e. Aβ and α-synuclein). However, currently no genetic or environmental factor that can generate both Aβ and α-synuclein in vivo or in vitro has been identified. Thus, while the pathogeneses of AD, PD, and mixed AD/PD are still to be determined, identification of signaling mechanisms that can be modulated to trigger the overproduction of Aβ and α-synuclein may help design strategies that prevent or slow the accumulation of these aggregates.
The identification of genetic mutations linked to familial forms of AD and PD has led to the development of cellular and animal models that have helped in understanding aspects of the pathophysiology of the inherited, early onset AD and PD forms. However, the majority of AD and PD cases are sporadic. While genetic mutations are responsible for the accumulation of Aβ in familial AD and α-synuclein in familial PD, the causative factors for the accumulation of Aβ and α-synuclein in sporadic AD are not known. This raises the possibility that the accumulation of Aβ and α-synuclein in the absence of genetic mutations might result from abnormalities in specific signaling pathways that lead to an increase in Aβ and α-synuclein production and/or a decrease in their clearance. Factors such as the environment and diet may be implicated in the pathogenesis of sporadic forms of AD and PD. The first identified risk of AD is apolipoprotein E (ApoE) [1]. Some but not all people who have one or two copies of the ApoE ε4 allele are at increased risk of AD. ApoE is a specific type of lipoprotein that plays an important role in the distribution of cholesterol in blood and brain. Carrying ApoE ε4 is associated with high plasma cholesterol [2,3]. The association between ApoE and cholesterol has put cholesterol up front as a potential risk factor for sporadic forms of AD. Both the pioneer studies by Sparks et al. [4] showing that rabbits fed a diet rich in cholesterol exhibit increasedAβ accumulation and the epidemiological studies by Solomon et al.[5] demonstrating that high cholesterol at mid-age increases the riskfor AD by 66% later in life link cholesterol to the pathophysiologyof AD. For the last few years, high dietary fat intake has also beenunder scrutiny as a risk factor for PD. A standardized food frequencyquestionnaire has shown an association of PD with high intake of totalfat, saturated fats, and cholesterol [6]. A recent large prospective studyhas suggested that total serum cholesterol at baseline is associated withan increased risk of PD [7]. In other studies however, elevated serumlevels of cholesterol were either not associated with PD risk [8] or wererelated to a decreased PD risk [9,10].
Thus, to date, the extent to which disturbances in cholesterol metabolism play a role in the pathogenesis of AD or PD is still unclear.
*Corresponding author: Othman Ghribi, Department of Pharmacology, Physiol-ogy and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, North Dakota, 58202, USA, Tel: 1-701-777-2522; Fax: 1-701-777-4490; E-mail: [email protected]
Received March 26, 2012; Accepted March 27, 2012; Published March 29, 2012
Citation: Ghribi O (2012) Do Increased Levels of Oxysterols Underlie Alzheimer’s Disease/Parkinson’s Disease Overlap?. J Alzheimers Dis 2:e111. doi:10.4172/2161-0460.1000e111
Copyright: © 2012 Ghribi O. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Do Increased Levels of Oxysterols Underlie Alzheimer’s Disease/Parkinson’s Disease Overlap?Othman Ghribi*Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota, 58202, USA
The absence of a consensus on a role of cholesterol in AD or PD may be explained by the following: First, it may be possible that abnormalities in cholesterol metabolism take part in AD and PD pathogenesis early at mid-age when the disease is initiated; at late-age when symptoms manifest and PD progresses, the correlation between AD/PD and cholesterol status is no longer consistent. Indeed, AD or PD patients may have normal, low or high cholesterol levels. Second, fluctuations in cholesterol oxidation products (oxysterols), rather than cholesterol per se, may correlate better with the onset of AD and PD. Some oxysterols may place the brain at risk of injury following disturbances in their levels. Of these oxysterols, 27-hydroxycholesterol (27-OHC) has the ability to cross lipophilic membranes into and out of the brain [11,12]. As 27-OHC originates almost exclusively from oxidation of cholesterol in the circulation, one can expect that hypercholesterolemia increases turnover of cholesterol to 27-OHC, thus increasing its levels in the circulation and potentially in the brain. Circulating 27-OHC levels are 0.15-0.73 μM, and these concentrations can be in the millimolar range in some pathological situations such as atherosclerosis [13,14]. A marked accumulation of 27-OHC in the brains of Alzheimer’s patients with the Swedish APP 670/671 mutation has been recently demonstrated [15]. Oxysterols were also shown to be elevated in the cerebral cortex of individuals with Lewy body dementia where they are suggested to accelerate α-synuclein aggregation [16]. A recent study also showed increased levels of several oxysterols including 27-OHC in cortex of PD brains [17]. These studies, together with the known toxic effects of high levels of oxysterols suggest a possible role of these cholesterol metabolites in AD and PD.
The question as to what are the potential cellular pathways and mechanisms that mediate the deleterious effects of oxysterols is however still to be answered. Binding to and activating liver X receptors (LXRs) is one of the major mechanisms by which 27-OHC and other oxysterols exert their major functions [18]. LXRs bind to promoters of specific genes to recruit co-activators or co-repressors, thus impacting expression of target genes. We have recently found that treatment with the oxysterol 27-OHC increases Aβ production [19] and reduces tyrosine hydroxylase (TH), the rate limiting enzyme in dopamine synthesis, and increases α-synuclein levels [20,21]. In support of our data, another independent study also showed that 27-OHC regulates α-synuclein expression levels, and provided further evidence that 27-OHC modulates α-synuclein through activation of LXRs [22]. We also
Journal ofAlzheimer’s Disease & ParkinsonismJo
urna
l of A
lzheim
ers Disease &Parkinsonism
ISSN: 2161-0460
![Page 2: e r s Diseas Journal of im e aA lz r f k o i l a n r u ......range in some pathological situations such as atherosclerosis [13,14]. A marked accumulation of 27-OHC in the brains of](https://reader033.fdocument.org/reader033/viewer/2022041818/5e5c436ffd56ac71f31d7026/html5/thumbnails/2.jpg)
Citation: Ghribi O (2012) Do Increased Levels of Oxysterols Underlie Alzheimer’s Disease/Parkinson’s Disease Overlap?. J Alzheimers Dis 2:e111. doi:10.4172/2161-0460.1000e111
Page 2 of 2
Volume 2 • Issue 2 • 1000e111J Alzheimers DisISSN:2161-0460 JADP an open access journal
investigated the potential of estrogen receptors (ERs) as the target for 27-OHC as it has been recently discovered that 27-OHC, in addition tobeing an LXR agonist, is also a selective estrogen receptor modulator(SERM) [23] and ERs were also shown to regulate the expression levelsof TH [24]. We speculated that 27-OHC acts as an inverse agonistof ERs, competitively antagonizes ERs and reduces TH levels. Weincubated SH-SY5Y cells for 24 h with 27-OHC and/or estradiol (E2),the most abundant and potent endogenous estrogen that activates ER,and found that while 27-OHC reduces TH expression, E2 increasesbasal levels and opposes 27-OHC effects on TH [20].
Overall, the involvement of cholesterol metabolism in AD and PD needs to be re-examined. Oxysterols, normal lipid components in the brain, can regulate Aβ, TH and α-synuclein through LXRs and ERs in vitro. Modulation of LXRs and ERs in vivo models remain to be carried out to determine their potential in causing or protecting againstAD and PD. More importantly, further studies demonstrating the accumulation of 27-OHC in brains exhibiting overlapping AD and PD pathologies are needed. Confirmation of involvement of LXRs and ERs pathways in the regulation of Aβ, TH and α-synuclein levels may lead to novel therapeutic avenues that consist in the use of an LXR antagonist to reduce Aβ and α-synuclein accumulation and an ER agonist to prevent TH reduction. These agents, used as mono or combined therapies, may be a promising therapeutic strategy to protect against AD/PD overlap. References
1. Corder EH, Saunders AM, Strittmatter WJ, Schmechel DE, Gaskell PC, et al. (1993) Gene dose of apolipoprotein E type 4 allele and the risk of Alzheimer’s disease in late onset families. Science 261: 921-923.
2. Eto M, Watanabe K, Chonan N, Ishii K (1988) Familial hypercholesterolemia and apolipoprotein E4. Atherosclerosis 72: 123-128.
3. Murakami K, Shimizu M, Yamada N, Ishibashi S, Shimano H, et al. (1993) Apolipoprotein E polymorphism is associated with plasma cholesterol response in a 7-day hospitalization study for metabolic and dietary control in NIDDM. Diabetes Care 16: 564-569.
4. Sparks DL, Scheff SW, Hunsaker JC, Liu H, Landers T, et al. (1994) Induction of Alzheimer-like beta-amyloid immunoreactivity in the brains of rabbits with dietary cholesterol. Exp Neurol 126: 88-94.
5. Solomon A, Kivipelto M, Wolozin B, Zhou J, Whitmer RA (2009) Midlife serum cholesterol and increased risk of Alzheimer’s and vascular dementia three decades later. Dement Geriatr Cogn Disord 28: 75-80.
6. Johnson CC, Gorell JM, Rybicki BA, Sanders K, Peterson EL (1999) Adult nutrient intake as a risk factor for Parkinson’s disease. Int J Epidemiol 28: 1102-1109.
7. Hu G, Antikainen R, Jousilahti P, Kivipelto M, Tuomilehto J (2008) Total cholesterol and the risk of Parkinson disease. Neurology 70: 1972-1979.
8. de Lau LM, Bornebroek M, Witteman JC, Hofman A, Koudstaal PJ, et al. (2005) Dietary fatty acids and the risk of Parkinson disease: the Rotterdam study. Neurology 64: 2040-2045.
9. Powers KM, Smith-Weller T, Franklin GM, Longstreth WT Jr, Swanson PD, et al. (2009) Dietary fats, cholesterol and iron as risk factors for Parkinson’s disease. Parkinsonism Relat Disord 15: 47-52.
10. Scigliano G, Musicco M, Soliveri P, Piccolo I, Ronchetti G, et al. (2006) Reduced risk factors for vascular disorders in Parkinson disease patients: a case-control study. Stroke 37: 1184-1188.
11. Bjorkhem I, Meaney S, Diczfalusy U (2002) Oxysterols in human circulation: which role do they have? Curr Opin Lipidol 13: 247-253.
12. Lutjohann D, Breuer O, Ahlborg G, Nennesmo I, Siden A, et al. (1996) Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation. Proc Natl Acad Sci U S A 93: 9799-9804.
13. Dzeletovic S, Breuer O, Lund E, Diczfalusy U (1995) Determination of
cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem 225: 73-80.
14. Umetani M, Domoto H, Gormley AK, Yuhanna IS, Cummins CL, et al. (2007) 27-Hydroxycholesterol is an endogenous SERM that inhibits the cardiovascular effects of estrogen. Nat Med 13: 1185-1192.
15. Shafaati M, Marutle A, Pettersson H, Lovgren-Sandblom A, Olin M, et al. (2011) Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer’s patients with the Swedish APP 670/671 mutation. J Lipid Res 52: 1004-1010.
16. Bosco DA, Fowler DM, Zhang Q, Nieva J, Powers ET, et al. (2006) Elevated levels of oxidized cholesterol metabolites in Lewy body disease brains accelerate alpha-synuclein fibrilization. Nat Chem Biol 2: 249-253.
17. Cheng D, Jenner AM, Shui G, Cheong WF, Mitchell TW, et al. (2011) Lipid pathway alterations in Parkinson’s disease primary visual cortex. PLoS One 6: e17299.
18. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ (1996) An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383: 728-731.
19. Prasanthi JR, Huls A, Thomasson S, Thompson A, Schommer E, et al. (2009) Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on beta-amyloid precursor protein levels and processing in human neuroblastoma SH-SY5Y cells. Mol Neurodegener 4: 1.
20. Marwarha G, Rhen T, Schommer T, Ghribi O (2011) The oxysterol 27-hydroxycholesterol regulates alpha-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 119: 1119-1136.
21. Rantham Prabhakara JP, Feist G, Thomasson S, Thompson A, Schommer E, et al. (2008) Differential effects of 24-hydroxycholesterol and 27-hydroxycholesterol on tyrosine hydroxylase and alpha-synuclein in human neuroblastoma SH-SY5Y cells. J Neurochem 107: 1722-1729.
22. Cheng D, Kim WS, Garner B (2008) Regulation of alpha-synuclein expression by liver X receptor ligands in vitro. Neuroreport 19: 1685-1689.
23. DuSell CD, Umetani M, Shaul PW, Mangelsdorf DJ, McDonnell DP (2008) 27-hydroxycholesterol is an endogenous selective estrogen receptor modulator. Mol Endocrinol 22: 65-77.
24. Ivanova T, Beyer C (2003) Estrogen regulates tyrosine hydroxylase expression in the neonate mouse midbrain. J Neurobiol 54: 638-647.
