Historically, Parkinson’s disease (PD) was thought to be primarily a movement disorder excluding secondary effects. Today, PD is considered to be a disease that can sire a number of issues including, depression, apathy, psychosis, impulse control disorders (ICD’s), anxiety, and sleep disorders (Weintraub & Burn, 2011). With the incidence of dementia proliferating to 80% of individuals who have lived with PD for 20 years or more, cognitive impairments within the PD population is also a point of major complications (Hely et. al., 2008). While cognitive impairment is a concern for many patients and scientists alike, it has been difficult to predict individuals within the PD population who may transition to PD mild cognitive impairment (PDMCI) and PD dementia (PDD). Individuals who do make the transition from normal cognition often are subject to further decline and increased hospitalizations due to falls (Yarnall, Rochester, Burn, 2011). PD’s side effects make it increasingly difficult to administer proper care to patients as their disease progresses.
Recent research has been devoted to the investigation of the role cholesterol (Meilke et al., 2005; Notkola et. al., 1998; Kivipelto et. al., 2001; Romas et. al., 1999; Reitz et. al., 2004) and statins play in cognition in those with Alzheimer’s disease and amongst the general population (Jick et al., 2000; Wolozin et al., 2000, 2004, 2007,; Soloman et al., 2007; Sparks et al., 2005; Rockwood et al., 2002; Yaffe et al., 2002; Simons et al., 2002; Rea et al., 2005). However, the study of statins and their impact upon cognition within the PD population is largely understudied. Recent in vitro studies of statins (Fortin et al., 2004; Bar-On et al., 2008) have shown promising results in their ability to reduce alpha-synuclein within neuronal cell lines.
The objective of this review is to examine research related to cholesterol, statins, cognition and PD and to make a cogent a pathway toward the pursuit of further research into the combination of the outlined fields. Research that examines the underlying effects of cholesterol lowering agents (statins) and cognition in the PD population are essential to understanding cognition and my identify those within the PD population who may be at a greater risk for cognitive decline.
Background: Cholesterol and Statins
Cholesterol is synthesized in two places within the human body, the brain and the liver. Cholesterol is synthesized through a similar process in both, via a multi step process in which the condensation of acetoacetyl-CoA with acetyl-CoA in turn produces mevalonate via a set of reactions, which are catalyzed by 3-hydroxy-3-methylglutaryl (HMG) synthase and HMG-CoA reductase (Figure 1a). It is within this last step that statins work to inhibit the production of mevalonic acid via inhibiting HMG-CoA. Once cholesterol is made it can be secreted, via transport molecules, and can bind to apolipoproteins forming lipid protein complexes. A high density lipoprotein (HDL) can accept cholesterol to form low-density lipoprotein (LDL) complexes which can be further transported throughout the body. While many aspects between liver synthesis and brain synthesis of cholesterol are similar, there are a few major discrepancies between the two processes.
In the brain cholesterol is synthesized, from smaller, simple molecules (de novo synthesis). This discrepancy, while small, is important because unlike the rest of the body, the minute amount of cholesterol that is absorbed into neurons, glia, oligodendrocytes, and astrocytes via plasma, is not enough for the brain to function normally. Astrocytes seem to be the most efficacious at cholesterol synthesis. Once cholesterol is synthesized it is secreted via the same transporter molecule as liver cells, ABCA1. Once engendered, brain HDL, is taken up via lipoprotein receptors on neurons. While there are many different types of lipoprotein receptors, it seems the most abundant within neurons are low-density lipoprotein-related receptors (Herz & Strickland, 2001).
De novo synthesis within the neuron starts in the endoplasmic reticulum (ER) where the ER is continuously enriched with cholesterol and then leads to the formation of lipid rafts. Lipid rafts are cholesterol rich and are frequently found, and most active in, the plasma membrane. Within lipid rafts is where the protein alpha-synuclein and cholesterol interact, which will be discussed in the next section of this review.
Cholesterol and Alpha-Synuclein interaction
Alpha-synuclein is a presynaptic protein that for the past two decades has been implicated in the pathology underlying PD (Serpell et al., 2000; Biere et al., 2000; Giasson et al., 2001). Alpha-synuclein is one of three total synucleins in their own respective family, which include beta and gamma as well. However, beta and gamma synuclein failed to assemble and aggregate, unlike alpha synuclein in various experiments and thus provides further evidence supporting that alpha-synuclein accumulation is an important piece of the neurodegeneration puzzle in Lewy body diseases (Serpell et al., 2000; Biere et al., 2000; Giasson et al., 2001). The functions of these proteins remain poorly understood, but the finding that beta and alpha are proximal to synaptic nerve terminals and an earlier finding within the in vitro rat brain showed that the A30P monomer (monomer that helps assemble alpha-synuclein) when mutated has produced a reduction of alpha synuclein binding to vesicles, leads one to believe that alpha-synuclein is essential for normal synaptic transmission (Goedert, 2001; Jensen et al., 1998; Clayton & George, 1999; Murphy et al., 2000; Fortin et al., 2004).
A series of studies have shown that oxidation products of cholesterol can impact the amount of alpha synuclein in vitro. Until recently, researchers held the belief that peripheral cholesterol, via dietary factors, did not have an effect upon brain cholesterol levels, however this idea has been put into contention with the finding by Rantham-Prabhakara et al., (2008). Their findings demonstrated that an oxidized metabolite, 27-hydroxycholesterol, can cross the blood brain barrier and increase levels of alpha-synuclein to the point of apoptosis in vitro. Beischke et al., (2006) showed that lewy body dementia brains had significantly higher levels of cholesterol oxidation products vs. controls. The group further suggests that synucleinophathies, which have been linked to elevated levels of alpha-synuclein, could in turn be linked to the formation of reactive oxygen species then leading to a cycle in which oxidative metabolites accelerate alpha-synuclein aggregation, and finally, inducing the generation of more reactive oxygen species. Bieschke et al., 2006 was also able to observe that while cholesterol was not a direct risk factor for alpha-synuclein, areas within a cell membrane, which are high in cholesterol, also have a propensity for alpha-synuclein to be proximally located. Substantiating Beishke et al., (2006) study, Bosco et al., (2006) showed that alpha-synuclein fibrilization can be accelerated via elevated levels of oxidized cholesterol metabolites in lewy body diseased brains. In a study by Bieschke et al., (2005) they showed that cholesterol oxidation can be induced by inflammation which in turn can produce cholesterol aldehydes that are able to modify proteins and make them amyloidogenic. Again in 2006, Bosco et. al, showed that oxidative cholesterol metabolites and cholesterol metabolite, bearing a carboxylic acid, can accelerate alpha synuclein fibrilization which affords itself to aggregate morphologies analogous to those observed in lewy-bodies and lewy-body diseases.
Many studies have shown that alpha synuclein may be a lipid binding protein (Davidson et al., 1998; Jensen et al., 1998; McLean et al., 2000; Jo et al., 2000; Perrin et al., 2000; Eliezer et al., 2001). Once bound to a lipid membrane, alpha-synuclein undergoes a structural conformation change into an alpha helix (Davidson et al., 1998; Jo et al., 2000; Perrin et al., 2000; Eliezer et al., 2001). Lipid rafts were further shown to mediate the localization of alpha-synuclein in a study performed by Fortin et al., (2004) in which chronic treatment of drugs that block the synthesis of sphingolipids and cholesterol, disrupting lipid rafts and reducing the synaptic enrichment of alpha synuclein. In turn, when the mutated monomer, A30P, assembles alpha-synuclein it contributes to the disruption of the raft association with alpha-synuclein, part of the pathogenesis of PD (Fortin et al., 2004). Lipid membranes and rafts show a point of direct interaction with alpha-synuclein, if cholesterol can be manipulated with statins then alpha-synuclein may be mediated/modulated such as cases examined below.
Alpha-Synuclein and statins: how they interact
The interaction between statins and cholesterol has been understood for a number of years. What is less understood is how statins affect alpha-synuclein through the inhibition of cholesterol production. The point of interaction between statins and alpha-synuclein is not a direct one. Reviewed earlier, cholesterol maintains lipid rafts and lipid membranes. Alpha-synuclein has been shown to interact with cholesterol at lipid rafts (Fortin et al., 2004) and cholesterol metabolites have been shown to be elevated in PD brains and may in fact accelerate alpha-synuclein aggregation (Bieschke et al., 2006). A study by Davidson et al., (1998) also showed that alpha-synuclein’s conformational structure may be changed by binding to lipid membranes. All evidence points to an indirect interaction between alpha-synuclein and statins, due to their ability to decrease cholesterol production. One can then reasonably extrapolate that statins have an affect upon alpha-synuclein.
In 2008, Bar-On et al., showed that statins indeed had an effect upon alpha synuclein via the reduction of alpha synuclein in in vitro models of PD. After 24 hours of treatment with lovastatin, followed by pravastatin and simvastatin respectively showed each less than 5% of cell death in B103 neuronal cell lines, with lovastatin showing the greatest effect of maintaining cell life. These results were significant and also showed a significant reduction of alpha-synuclein immunoreactivity. Bar-On and colleagues (2008) were also able to show that statins reduce levels of oxidized alpha synuclein in alpha-synuclein expressing neuronal cells. To further substantiate their results they increased the levels of cholesterol within the cells and the results showed increased alpha-synuclein immunoreactivity, specifically in neuritic processes and a small increase within the cell bodies.
In a recent study by Koob et al., (2009) lovastatin was used successfully to ameliorate alpha-synuclein accumulation and oxidation in transgenic mouse models of alpha-synucleinopathies. The study team used two transgenic mouse lines that overexpressed alpha-synuclein under different neural promoters. Their findings showed that lovastatin was successful at not only lowering plasma cholesterol levels but also oxidized cholesterol metabolites. They also showed that with treatment of lovastatin, accumulations of alpha-synuclein within neurons were significantly reduced. The study conducted by Koob et al., (2009) also showed that with lovastatin treatment total oxidized alpha-synuclein accumulation levels were reduced in the brains of transgenic mice. Alpha-synuclein is able to be mediate/modulated through the used of statins, the question as to whether or not cognition can be modulated as a direct impact of pathological changes via reduction of alpha-synuclein is still a point that should be further researched and one that finds evidence for the argument in the following sections.
Statins and the effect upon the NMDA glutamatergic receptors and dopaminergic systems
The depletion of dopamine in the PD brain is the major cause of many PD symptoms. The typical pathology that is observed in PD is the loss of dopaminergic neurons in the ventrolateral and caudal portions of the substantia nigra pars compacta vs. the dorsomedial portion of the substantia nigra pars compact that is typically seen in normal aging (Fernley & Lees, 1991). The dorsolateral putamen sees a pronounced depletion of dopamine (Bernheimer et al., 1973). However, the neuropathological findings are not limited to just dopaminergic cells; cell loss has been reported in the following areas: locus coeruleous (noradrenergic), raphe nucleus (serotonergic), nucleus basalis of Meynert (cholinergic), dorsal motor nucleus of vagus (cholingergic), the cerebral cortex [specifically the cingulate and entorhinal cortices], olfactory bulb, and the autonomic nervous system. All of these systems are able to experiences neurodegeneration and development of the hallmark of PD, Lewy body inclusions (Dauer & Przedborski, 2003; Hornykeiwicz & Kish, 1987). A pharmacologic agent that brings about the cessation of this depletion of cells is needed, both for the vitality of cells and the safeguarding of dopamine within the synaptic cleft, and subsequently upon the post-synaptic membrane.
Statins are able to interact with dopaminergic systems and therefore potentially, be prescribed as a remedy for dopaminergic changes that occur throughout the progression of PD. De Bartolomeis and colleagues (2005) showed that glutamatergic NMDA receptors and monoamine dopaminergic systems interact with one another. Hallett and colleages (2004; 2006) have furthered the connection between the glutamatergic NMDA receptor and dopaminergic systems by showing that dopaminergic disturbances can lead to NMDA receptor changes. Simvastatin, at a high dose, was shown was shown to up-regulate NMDA receptors in the insular cortex and the primary somatosensory cortex (densities of high binding efficacy to [3H]MK-801 binding sights), while moderate binding was observed in the prefrontal cortex, primary motor cortex, and limbic regions (including the cingulate cortex and hippocampus) (Wang et al., 2009). The integrity of NMDA receptors is of vital importance if neurons are to remain viable in their role to support the cell-to-cell communication. Two studies have shown that simvastatin can affect D1 and D2 dopaminergic receptors and alter the levels of dopamine within the striatum via prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydro –pyridine induction (Selley et al., 2005) and that within the prefrontal cortex of mice, simvastatin was able to up-regulate D1 and D2 expression (Wang et al., 2005). Complimentary findings in a study by Yan and colleagues (2011) also found that simvastatin was able to prevent and restore dopaminergic neurodegeneration in the substantia nigra pars compacta. Yan and colleagues (2011) showed this result upon injection of 6-OHDA, which produced 78% decrease in neurons on the ipsilateral side of the brain, that simvastatin was able to prevent neuronal loss in the substantia nigra pars compacta. Furthermore, they also showed that after a three week treatment of simvastatin, [3H]MK-801 binding density in the hippocampus, CA1 region, amygdala and the caudate putament were all restored to baseline binding propensity (Yan et al., 2011). Statins should therefore protect dopaminergic systems and glutamatergic NMDA receptors that are disrupted through the pathology of Parkinson’s disease. Furthermore, it would be plausible to assume that statins would have an affect upon motoric and cognitive symptoms via the interaction of the aforementioned system.
Statin use and the risk of Parkinson’s disease
Some research has proposed that statins are able to lower risk of developing PD, these studies come in the form of both observational studies and pathological studies. Large population based studies (on average 487,867 participants) show that taking statins has a negative correlation with PD incidence (Gao et al., 2012; Wahner et al., 2008; Wolozin et al., 2007; Lee et al., 2013; Tan & Tan, 2013). Pathological studies have shown that statins may in fact be helpful and neuroprotective. Previous research has shown that PD pathology includes oxidative stress and neuroinflammation (Hunot &Hirsch, 2003; Henchcliffe & Beal, 2008; Danielson & Andersen, 2008). Statins have been shown to have anti-oxidant properties and were able to attenuate neuroinflammation due to their ability to ameliorate free radical injury via the attenuation of free radicals (Di Napoli et al., 2002; Cucchiara & Kasner, 2001). Both large population studies and pathological studies point to protective factors to both incidence rate and cellular vitality in individuals taking statins with the pathology or risk of pathology for PD.
However, there has been conflicting results within this field of research with other researchers have reported that lowering cholesterol could in fact induce PD (Haung et al., 2006; de Lau et al., 2006; Ritz et al., 2010) or worsen PD (Shults et al., 2002; Mortensen et al., 1997), via the ingestion of statins. But, other studies in the same context, have shown that there is no relationship between statin use and PD incidence (Ritz et al., 2010; Becker et al., 2008). A study by Lamperti (1991) also showed that there was a lower plasma cholesterol concentration in PD patients than in controls. Further research has shown that higher LDL cholesterol may be protective of PD (Huang et al., 2007; 2013; 2014; Scigliano et al., 2006; Miyake et al., 2010; de Lau et al., 2006). The aforementioned increased risk of PD may be due to the concomitant effect of lowering ubiquinone (CoQ-10)(Shults et al., 2002; Mortensen et al., 1997). A further study based upon the hypothesis that lowering of ubiquinone can cause PD to worsen, showed that reduction of ubiquinone via statins did not worsen PD in terms of stage development, prevalence, dyskinesia, or dementia. The field of statin research within the PD population has been antithetical in its results, and should be closely controlled for medications, co-morbidities, and diet.
Cognition and statins
Many previous epidemiological studies have suggested that hypercholesterolemia and hypertension may be risk factors for dementia (Nash & Fillit, 2006; Luchsinger et al., 2005; Newman et al., 2005; Breteler et al., 1994). While it would seem like a simple theory and subsequent application of statins to keep cholesterol levels in check and also at the same time decrease the chances of developing dementia; the connection between the beneficial effects of statins upon the risk of dementia is a bit of a grey area due to conflicting studies (Wolozin et al., 2000; Jick et al., 2000; Rea et al., 2005; Sparks et al., 2005; Yaffe et al., 2002; Simons et al., 2002; Rockwood et al., 2002). A possible reason for the mixed results is due to the ability for statins to pass the blood brain barrier and have an impact upon brain cholesterol levels. Statins do indeed differ in their lipophilicity and ability to cross the blood-brain barrier, their permeability’s are ranked in order: lovastatin>simvastatin> atorvastatin (Vuletic et al., 2006; Saheki et al., 1994; Hawkins & Davis, 2005)(figure 1b).
A study that stands out from others is one with a large cohort. The study, conducted by Wolozin et al., (2007) observed the incidence of the transition of individuals with normal cognition to dementia or PD. The study had approximately 4.5 million subjects with approximately 110 million prescriptions annually. However a pitfall to this subject database is that 94.4% of the subjects were male. This flaw in the data is due to the database coming from the Department of Veterans Affairs (Sohn et al., 2006). The results of the 2007 Wolozin et. al, study showed a decrease in incidence of dementia and PD with those individuals who took simvastatin, while the results of individuals taking either atorvastatin or lovastatin were not associated with significant effects for either increasing or decrease of incidence for PD or dementia. Other recent research has substantiated this finding, specifically a study by Yaffe et al., (2002) who found in older women with no history of dementia and who had their LDL cholesterol lowered by statins had a greater chance of not being diagnosed with dementia. Yaffe et al., (2002) also concluded that there is a positive association between statin use and cognitive function, which seems to be independent of total cholesterol levels.
Some of the strongest evidence for statins to be used as a neuroprotective factor comes from two studies conducted in 2000. Firstly, Wolozin et al., (2000) conducted a study of 60,349 patients (those who took statins [1-5 years], entire population of random sample, and patients receiving medications to treat hypertension or cardiovascular disease [not statins]) and found that the prevalence of dementia of the Alzheimer’s type was lower by 60% to 73% for those individuals taking either lovastatin or pravastatin compared to those in the entire population random sample group. A second study conducted by Jick et al., (2000), with a sample size of 60,901 patients, showed that people who were prescribed statins have a risk of dementia which is 70% lower than those who do not have hyperlipideamia and those who were not on lipid lowering treatments. Jick et al., (2000) described a possible shortcoming in their research may have in that the reduced risk could be engendered via some other characteristic within statin users that the study did not take into account. The research that has been conducted on the interaction between cognition and statins has shown that statins may have a positive effect upon cognition, however, none of the aforementioned studies have looked specifically at the effects of statins on a PD population such as posed in the conclusion of this review.
In the aforementioned studies it has been shown that statins have an indirect effect upon alpha-synuclein, via a direct effect upon cholesterol and lipid rafts. The complete biological picture behind statins and alph-synuclein in terms of their interaction with one another remains opaque. However, from the previously mentioned studies it would seem that statins are efficacious at the mediation of alpha-synuclein via cholesterol modulation/ mediation (Bieschke et al., 2006; Bosco et al., 2006; Fortin et al., 2004; Bar-On et al., 2008; Prabhakara et al., 2008; Koob et al., 2009; Huang 2015). Statins seem to not only be effective at reducing plasma cholesterol levels but also at reducing the aggregation of alpha-synuclein within neurons (Koob et al., 2009). If the pharmacological research is correct then it is plausible to expect that cognition may be preserved in individuals with alpha-synucleinopathies, specifically PD.
A number of studies have shown that statins protect cognition from dementia and Alzheimer’s disease in individuals compared to those who do not take statins (Solomon et al., 2007; Yaffe et al., 2002; Jick et al., 2000; Wolozin et al., 2000; 2007). However, the literature on Parkinson’s Disease and cognition has yet to be explored. A controlled study of the long-term effects of statins and cognition within the greater PD population should be conducted.
With PD affecting 4.5-19/ 100k individuals worldwide it is a massive global health complication (World Health Organization 2006). Furthermore, the world’s population is living much longer than ever before and the amount of individuals living with PD will only proliferate, and as it does, so too does the issue of 80% of those who have been diagnosed with PD for 20 years or more will experience dementia (Hely et al., 2008). Large sample based cognitive and pharmacological studies are needed to substantiate the initial pharmacological studies as well as explore the use of statins as a neuroprotective agent in Parkinson’s disease.
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