MXPA99007622A - Method of preventing and delaying the onset of alzheimer's disease and composition therefor - Google Patents
Method of preventing and delaying the onset of alzheimer's disease and composition thereforInfo
- Publication number
- MXPA99007622A MXPA99007622A MXPA/A/1999/007622A MX9907622A MXPA99007622A MX PA99007622 A MXPA99007622 A MX PA99007622A MX 9907622 A MX9907622 A MX 9907622A MX PA99007622 A MXPA99007622 A MX PA99007622A
- Authority
- MX
- Mexico
- Prior art keywords
- apo
- disease
- beta
- mice
- alzheimer
- Prior art date
Links
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Abstract
A method of preventing and/or delaying the onset of Alzheimer's disease in an animal comprises administering to the animal a phytosterol composition. A composition useful for preventing and/or delaying the onset of Alzheimer's disease in an animal comprises a phytosterol composition.
Description
METHOD TO PREVENT AND DELAY THE I NICIO OF ALZHEIMER'S DISEASE AND COMPOSITION FOR THE SAME
FIELD OF THE I NVENTION This invention refers to the field of Alzheimer's disease and prevention methods for it and delay the onset of it.
BACKGROUND OF THE INVENTION Alzheimer's disease ("AD") is a dementia disorder immutably in progress. It is a major pathological hallmark, it is the development of cytoskeletal changes in a few susceptible neuronal cells. These changes do not inevitably occur with advanced age, but once the disease has begun, no remissions or spontaneous recoveries are observed. The initial cortical changes, described below, develop in the poorly myelinated transenteral region of the medial temporal lobe. The destructive process then follows a predictable pattern as it extends into other cortical areas. The location of the neurons that support the imbroglio and the severity of the changes allow the distinction of six stages in the progression of the disease of the stages I, I, which are clinically silent, to the stages V-VI, which mark AD fully developed A relatively small number of patients exhibit particularly early changes, indicating that advanced age is not a prerequisite for the evolution of the lesions. According to this, AD is in this way, a disease related to age, but not dependent on age. There are a number of current theories regarding the cause and mechanism of AD progression, many associated with genetic defects. A very small percentage of AD patients have a defect in chromosome 21 in relation to the gene for the production of amyloid precursor protein ("APP"). APP is a large protein involved in cell growth and repair, which, when cut into the small nondigestible beta-amyloid protein ("B-A"), can accumulate in plaques within the brain. Additional interesting studies have focused on the relationship between the AD of the last familial start and a polymorphic gene on chromosome 19 coding for apolipoprotein-E ("apo-E"), a protein of molecular weight of 34,000 involved in the movement of cholesterol and other lipids in and out of cells throughout the body. The role of apo-E in the transport and metabolism of lipids is critical and is discussed below. The neurobiological role of apo-E has been supported from a number of observations over the years. First, apo-E mRNA is abundant in the brain, where it is synthesized and secreted mainly by astrocytes (EIshourbagy et al., 1988). Second, lipoproteins containing apo-E are found in the cerebrospinal fluid and appear to play a major role in the transport of lipids in the central nervous system (Pitas et al., 1987). Third, apo-E plus a source of cholesterol promotes a marked extension of neurites in dorsal root ganglia cells in culture (Handelmann et al., 1992). Fourth, apo-E levels increase dramatically after peripheral nerve injury (Muller et al., 1985). According to this, it seems that apo-E participates both in the cleansing of lipids generated after the degeneration of axons and in the redistribution of these lipids to burgeoning neurites of the regeneration of axons and later to Schwann cells for remyelination of the new axons (Boyles et al., 1989). The implication of a role for apo-E, which exists in three different isoforms encoded by three separate alleles (E-2, E-3, E-4) that are inherited in a co-dominant manner at a simple genetic site, in the pathogenesis of AD is based specifically on the association of apo-E with the two neuropathological lesions characteristic of AD-extracellular neuritic plaques (representing deposits of BA) and intracellular neurofibrillary embrittlements (representing filaments of a microtubule-associated protein called tau). For a review, please refer to Weisgraber et al. 1 994). In particular, a genetic association has been found between the apo-E4 isoform and Ad. The homozygous E4 individuals exhibit a higher risk of developing AD than the E4 heterozygotes, who in turn exhibit a higher risk than individuals without any E4 allele. Although the precise mechanism by which this correlation exists remains elusive, researchers have provided some possible answers. It may involve a biological effect of the protein produced by this allele, analogous to the way in which the decrease in the avidity of apo-E2 binding to the LDL receptor results in an increase in plasma cholesterol levels in E2 homozygotes. Strittmatter et al (1993) showed that apo-E4 binds more effectively to the BA peptide leading to the intensified formation of senile plaques as compared to the other two isoforms and therefore it has been proposed that it is not the presence of apoptosis. E4, but the lack of the other isoforms of apo-E resulting in increased predisposition for AD (Strittmatter et al.1994a). Similarly, with respect to the specific interaction of apo-E isoforms with tau protein, whose phosphorylated forms are the main constituents of neurofibrillary entanglements, apo-E3 and non-E4 have been shown to bind tau with high avidity (Strittmatter et al., 1994a). This differential effect has led to the hypothesis that apo-E3 normally allows the tau protein to stabilize microtubules and that its decrease or absence in patients with one or two alleles of apo-E4 leads to a dissociation of microtubule tau and its enhanced phosphorylation and polymerization in helical filaments in pathological pairs (Strittmatter et al., 1994b). Despite the enormous research in the area of AD progression, the treatments are scarce and the methods of prevention and / or delay of the onset of this debilitating disease are virtually non-existent. It is an object of the present invention to counteract or mitigate the above disadvantages.
BRIEF DESCRIPTION OF THE INVENTION The present invention proposes a method for preventing and / or delaying the onset of Alzheimer's disease ("AD") in animals, which comprises administering to the animal a phytosterol composition. In addition, the present invention provides compositions, which are effective in preventing or delaying the onset of AD, which comprise beta-sitosterol, campesterol and stigmastanol.
BRIEF REFERENCE TO THE DIAMETERS The present invention is illustrated by the following non-limiting drawings, in which: Figure 1 represents a graph showing the Morris water maze results expressed as time (%) in each quadrant and where the platform was in Quadrant 1; Figure 2 represents a graph showing the Morris water maze results expressed as time (%) in each quadrant and where the platform was removed from Quadrant 1; Figure 3 represents a graph showing the Morris water maze results expressed as time (%) in each quadrant and where the platform was in Quadrant 3; and Figure 4 represents a graph showing the Morris water maze results expressed as time (%) in each quadrant and where the platform was removed from Quadrant 3.
MODALI DADES PREFERITIES OF THE I NVENTION Phytosterols are compounds similar to sterols synthesized in plants without any direct nutritional value for humans. In plants, they are required for cellular function in a manner similar to the way in which cholesterol is required in humans. The average Western diet contains up to 360 mg of phytosterols per day. Recently, these sterols of dietary plants have received a great deal of attention because of their potential anti-cancer properties and their ability to reduce cholesterol levels when they are provided as food to a number of mammalian species, including humans. Until now, plant sterols had never been suggested or investigated in the prevention and delayed onset (treatment) of AD. Chemically, phytosterols closely resemble cholesterol in structure. The main phytosterols are beta-sitosterol, campesterol and stigmasterol. Others include stigmastanol (beta-sitstanol), desmosterol, calinasterol, poriferasterol, clionasterol and brasicasterol. The composition of the present invention includes all natural and synthetic forms of phytosterols, all hydrogenated counterparts, ie, stanols and all derivatives of the same, including isomers. Although phytosterols are available in vegetable and vegetable oils, the amounts are not necessarily in sufficient significant concentrations or in the correct form to confer the advantages of the present invention. What is provided within the scope of the present invention is a method for preventing and / or delaying the onset of AD by administering to animals, specifically humans, a phytosterol composition. This composition can be incorporated directly into food supplements, oils, vitamins and therapeutic formulations as required and described below. It is contemplated that the phytosterol compositions of the present invention can be mixed with food articles generally available for widely distributed distribution to the population, regardless of the genetic predisposition for AD. Alternatively, these compositions can be selectively administered in a more vigorous program targeting those individuals, who are at risk to develop particular forms of AD, i.e., familial AD. In a preferred form, the compositions are mixed with a vegetable oil selected from the group comprising safflower oil, sesame seed oil, corn oil, rice bran oil, olive oil and rapeseed oil. The olive oil with complement is the most preferred since it is widely used and is low in phytosterols and polyunsaturated fatty acids. Alternatively, the compositions can be incorporated in products based on saturated fat (lard) or confectionery fats, such as butter or margarine. In another embodiment, the compositions can be incorporated into formulations with other conventional or herbal products for the prevention or therapy of AD. These products include, but are not limited to, coiinesterase inhibitors, such as, Aricept ™, risperidone (the schizophrenia medicine now found useful to control AD-related aggression), and possible herbal memory-enhancing remedies.
The basis of the present invention is the use of phytosterols in general to prevent and / or delay the onset of AD. Although the preferred compositions for achieving this purpose are listed below, they should not be construed, in any way, as limiting the broad scope of the present invention since many phytosterols, alone or in various combinations can achieve the same beneficial results. Preferred phytosterol compositions of the present application comprise beta-sitosterol, campesterol, stigmastanol (sitostanol) and optionally, campestanol, and analogues / derivatives thereof. In one embodiment, the composition of the present invention comprises at least 10% campesterol and no more than 75% beta-sitosterol. In another preferred form, the composition comprises from 10-25% campesterol, 10-40% stigmastanol and from 45-75% beta-sitosterol. Optionally, 1 -10%, more preferably 3% campestanol may be present. In another preferred form, the compositions of the present invention comprise the following proportion of phytosterols; beta-sitosterol (1); campesterol (0.2-0.4) and stigmastanol (0.2-9.5). More preferably, campesterol and stigmastanol together represent at least 50% of the total concentration of beta-sitosterol. The compositions of the present invention include the following proportions of the three sterols of key plants:
Beta-sitosterol Campesterol Stigmastanol 1 0.354 0.414 1 0.330 0.203 1 0.268 0.299
It has been found that other preferred compositions have sterols (%) distributions as follows: Beta-sitosterol Campesterol Stigmastanol 62.6 16.6 23.2 64.7 16.4 1 7.2 60.0 1 3.6 16.3 32.0 14 29 25.5 7 42.5 51 14 1 9 61 1 7 23
However, it should be understood that in none of these preferred compositions, other plant sterols may be present. Similarly, helpers or carriers can be part of the composition as required. Depending on the mode of delivery of the compositions of the present invention, the dosage may be varied in some way. What is most preferred is that they are administered daily around 1.0 g to 3.0 g. In the method of the present invention, AD is prevented and / or the onset is delayed by administration to the individual of the phytosterol compositions described in detail above. The exact mechanism by which the capacity to learn and memory are intensified, the age-dependent loss of synapses is reduced, and the neurodegenerative processes are diminished by the administration of phytosterols in the diet, it is not clear, although the applicants have several theories which are pointed out in more detail later. These theories are not intended to limit the scope of the present invention, but inversely, they serve to show the complexity of phytosterols in animal lipid homeostasis. As discussed earlier in the background of the invention, it has been shown that the apo-E4 phenotype represents an important risk factor in AD. There is also some evidence that shows the relationship between AD and cardiovascular disease (Kalaria, 1 997). The following is a review of the apo-E function, together with information connecting apo-E to the present invention, with a view to understanding the proposed mechanisms of action of phytosterols.
APO-E Apo-E is only one of the lipid-binding molecules referred to as apolipoproteins. These proteins have three main functions. First, they help to stabilize triglycerides and highly hydrophobic cholesterol by interacting with phospholipids (the core of the complex is the lipid, the outer shell is the apolipoprotein a) to allow these lipids to be transported. Secondly, apolipoproteins regulate the reaction of lipids with enzymes, such as lipoprotein lipase and lecithin acyltransferase: cholesterol. In third place, apolipoproteins bind to cell surface receptors and thus determine the sites of uptake and degradation rates of other constituents of lipoproteins, notably cholesterol. Apo-E is unique among lipoproteins since it has a special importance for nervous tissue. During development or after injury to the peripheral nervous system, apo-E coordinates the mobilization and redistribution of cholesterol in the repair, growth and maintenance of myelin and neuronal membranes (Boyles et al., 1989, supra). In the central nervous system, much less is known about the function of apo-E, which makes the apo-E4 of the invention a possible marker for AD (discussed in the previous section of the background) even more intriguing.
MICE WITH APO-E Several studies with humans and animals have shown the effects of lowering cholesterol in plant sterols, including the anti-atherogenic effects of phytosterol compositions in mice deficient in Apo-E (PCT patent application PCT / CA95 / 00555 published April 4, 1996, and incorporated herein by reference and Moghadasian et al., 1996). More recently, it has been shown that mice deficient in Apo-E are an adequate animal model to study the pathogenesis of AD. Since phytosterols in apo-E-deficient mice prevent the distribution of atypical cholesterol (skin, tendons, aorta, and major arteries), phytosterols could play an important role in determining the distribution of cholesterol in tissue, even in cells cerebral, independent of apo-E phenotypes (study in progress by the applicant).
REMEMBERS OF QUI LOMICRON Chylomicrons are the largest lipoprotein particles consisting mainly of triglycerides with smaller amounts of phospholipids, free cholesterol and esters. They are synthesized in the intestine or enterocytes in response to fat and cholesterol in the diet, enter the lymph of the thoracic and mesenteric duct, where they acquire apo-E. The enzyme lipoprotein lipase ("LL") catalyzes the triglyceride hydrolysis of the chylomicrons, where the free fatty acids generated are taken mainly by adipocytes and the remaining minor portions of the lipoprotein (which are enriched in cholesterol) are referred to as remnants of chylomicrons ("CR"), CR are clarified from the plasma by a seive receptor mechanism dependent on apo-E of the liver (receptor related to low density lipoprotein, the "LRP receptor"), where cholesterol is used either in Lipoprotein or membrane biosynthesis or is excreted as free cholesterol or metabolized to bile acids. For particles to be internalized, the presence of apo-E is considered critical. The liver and brain cells are particularly rich in this LRP receptor.
LI POPROTEIN NAS DE M UY LOW DENSITY Very low density lipoprotein ("VLDL") is similar in structure to chylomicrons, but is smaller and contains less triglyceride, but relatively more cholesterol, phospholipid, and protein (mixture of E, apo-C and apo-B 100). VLDL is synthesized mainly in the liver and its main function is the transport of triglycerides. VLDL particles vary in size but subsequent lipolysis, either by LL or hepatic lipase ("HL") produces even smaller particles: remnants of VLDL (also known as intermediate density lipoprotein) and low density lipoprotein ("LDL ").
LIPASAS DE LI POPROTEI NAS There are at least two different triglyceride lipases. Extrahepatic or lipoprotein lipase ("LL") is found mainly in adipose tissue and skeletal muscle. Hepatic lipase ("HL") is located in the endothelium of liver cells. Both LL and HL are involved in the catabolism of CR and VLDL.
APO-E RECEPTORS There are four known receptors that are involved in the transport of apo-E / lipoprotein (chylomicron, VLDL or LDL) to plasma cells: the low density lipoprotein receptor ("LDL receptor"), the LRP receptor (defined above), the newly described very low density lipoprotein receptor ("VLDL receptor") and the epithelial glycoprotein receptor 330 ("GP330 receptor"). The four receptors are found in the brain. The discovery that the receptor for the activated form of alpha2-macroglobulin ("alpha2 / M") is identical to the LRP receptor is evidence that the LRP receptor is a multi-factorial receptor protein called alpha2M / LRP receptor. This receptor is expressed almost in every cell in the body, particularly the liver and brain, focusing on enzymes, proteins, CR and LDL cholesterol and seems to play a complex role in proteolysis, immunity, cell proliferation and cell death. With respect to the transport of apo-E in neuronal cells, it has been found that not only neurons are very rich in surface LRP receptors and that the immunoreactivity of the LRP receptor increased in plaques in AD (Rebeck et al., 1993) , but apo-E / LRP complexes are also located in plaques in the human brain (Ikeda et al, unpublished data). LRP not only binds remnants containing apo-E but also interacts with important enzymes of chylomicron metabolism, such as LL. This last ligature is independent of apoE (Beisiegel et al., 1991). The ability of phytosterols to prevent apo-E-deficient mice, the development of atherosclerotic plaque formation inside the liver, is catabolized by LL or an apo-E dependent receptor mechanism, namely, the LRP or alpha2M / LRP receiver.
MECHANISMS PROPU THESE ACTIONS OF PHYTOSTEROLES IN AD There are three primary interrelated mechanisms through which phytosterols exert a beneficial effect in the prevention and initiation of AD: 1) phytosterols increase the clarification of CR independent of apo-E in the Liver pathway via LRP by a complex mechanism (and still not fully understood) involving activation of allosteric LL and complex formation of LL with CR; and / or 2) the phytosterols decrease the circulation of and / or the apo-E dependent receptor-mediated uptake of apo-E / lipoprotein complexes in cells in a general but in particular brain cells; I
3) Phytosterols decrease endothelial cell change and preserve endothelial blood-brain barrier function. 10 Phytosterols are linked to circulating chylomicrons and lipoproteins and have a modifying effect on these particles within plasma and on the physicochemical properties of enzymes, such as LL and HL. In other words, the applicants suggest that phytosterols
function as apoproteins, thereby changing the structure, composition and function of chylomicrons and lipoproteins in circulation and also influencing many other cellular functions that are indirectly critical through the LRP receptor. Simply put, with respect to the first mechanism, the
Phytosterols bind to lipoproteins, ie chylomicrons, and prevent ligation of these particles to the alpha2M / LPR receptors and subsequent passage of these particles through the cellular barrier to the brain. According to this, the amount of apo-E in the neuronal cells would be reduced, which is particularly important for those individuals
"> -. who are homozygous for apo-E4.
In addition, phytosterols increase LL activity through allosteric modification, so that chylomicrons enriched with phytosterols are rapidly metabolized by this enzyme. The CRs are then rapidly cleared from the circulation by CR receptors of apo-E independent hepatocytes, which are identical to the LRP receptors. As discussed above, LL is a major enzyme involved in triglyceride metabolism (chylomicrons and VLDL) having a carboxyl ("C") and a nitrogen ("N") terminal. Its regulation, structural and functional relationship and domination of C-terminal lipoprotein lipase (in the induction of CR catabolism via the LRP receptor) are well understood by researchers and focus on applicants on the possibility of an independent lipoprotein catabolism from apo-E It is believed that the phytosterol compositions of the present invention alter the physicochemical properties by allosteric modification. Consequently, LL activity, influenced by phytosterols, could more efficiently utilize mass of enzymes for triglyceride catabolism by the terminal "N" catalytic site, while the terminal "C" domain could serve as a ligand for CR . The LL "C" -CR domain complexes with low fatty acid liver flux are then internalized by an identical receptor with the cleansing receptors (alpha2M / LRP) and then catabolized by hepatic lipase with marked further degradation of the acid esters fatty acids.
In other words, it is possible for phytosterols to intensify the binding of terminal "C" ligand from LL to CR, thereby increasing the catabolism of CR. Since these processes are independent of apo-E, they should not result in over-regulation of the LDL receptor. With respect to the third but complementary mechanism, phytosterols have been found to decrease cell turnover (the endothelial effect) by the applicants than in normal and hypercholesterolemic rats, the dietary administration of a phytosterols composition decreases endothelial cell turnover by 50-70 %, respectively. This is a critical finding considering the role of the endothelium in the blood-brain barrier and in the passage of unwanted damaged particles to the brain, which can lead to AD. Additionally, integrins, a diverse class of glycoprotein receptors, are involved in the interaction of extracellular matrix cells ("ECM"). The breakdown of integrin expression in the brain may be associated with an increase in sub-endothelial penetration of apo-E. NDE directs the growth, differentiation and function of the recumbent epithelium (Getlenburg et al., 1990). Additionally, applicants believe that plant sterols modify membranes, including the blood-brain barrier. According to this, the transportation of potently toxic substances, such as beta-amyloid precursor through this membrane can deteriorate resulting in delayed onset of AD. In addition, mice deficient in apo-E suffer from oxidative stress in their brains (Mathews et al., 1996). This could be associated with AD.
Applicants have shown in research that it is currently being carried out, that plant sterols may have antioxidant activity. According to this, these sterols can protect the brain from oxidative stress, leading to a delay in the initiation or even prevention of AD. A summary of the possible modes of action of phytosterols is as follows: 1) Enzymatic effect, allosteric modification of LL and changes in molecular configuration in lipoprotein complexes.
2) Chylomicrons and CR • Stimulation of LL? CR enriched with LL • Inhibition of HL • Dependent uptake not of apo-E of LRP receptor or
CR? -VLDL, using C-terminus of LL monomer as ligand for receptor binding and / or internalization, inhibition of CR uptake monomer HL through the LDL receptor • Enter the endoplasmic reticulum of soft hepatocyte • Stimulation of 7- alpha-hydrolase? increase in bile acid synthesis? Increase the biliary yield of cholesterol, decrease the cholesterol content of the liver, increase the HMG-CoA activity in an independent way of LDL metabolism, that is, it could inhi receptor VLD L or LDL by CR • Decreased changing endothelial cells • Formation of more hydrophilic membranes
The following non-limiting examples are provided to show various aspects of the present invention. In particular, the study shows that the acceleration of the development of atherosclerosis in mice deficient in apo-E is delayed by the administration of a phytosterol composition, and there is an improvement in the development of the AS lesion. "FCP-3PI" refers to a preferred composition within the scope of the present invention.
EXAM PLO 1 Improvement of the capacity and memory of mice deficient in apo-E by FCP-3PI
Introduction: Mice deficient in apo-E (apo E-KO) are known as the model of atherosclerosis, xanthomatosis, and Alzheimer's disease (16-18). Apo-E-deficient mice have been used as a useful system to learn the importance of apolipoprotein e in brain function. Among these studies, several have focused on the ability to learn and work and reference memory in mice deficient in apo-E (1,20). Hippocampal synapse density and regenerative capacity after hippocampal injury are reduced in these mice (21 .22). We effectively delay / prevent the first two disorders mentioned above by dietary supplementation with a mixture of phytosterols FCP-3PI (11, 23). The purpose of the present study is to evaluate the effects of dietary supplementation with FCP-3PI at a rate of 2% (w / w) for 33 weeks in the learning and memory capacity of apo-E-deficient mice.
Hypothesis Dietary supplementation with FCP-3PI improves learning and memory capacity in mice deficient in apo-E.
Materials and methods Twenty-four male mice deficient in apo-E of 2 weeks of age and 24 similar wild-type counterparts were purchased with their adoptive mothers at Jackson Laboratory. At week 4 of age, the mice were weaned and divided into 4 groups marked with body weight and total plasma cholesterol levels. The groups were fed the following diets for 33 weeks. Group 1 (n = 10): Apo-E-deficient mice were fed normal mouse food containing 4.5% (w / w) fat (NC) supplemented with 2% (w / w) of FCP-3PI. Group 2 (n = 10): wild-type mice were fed with NC supplemented with 2% (w / w) FCP-3PI. Group 3 (n = 10): Apo-E-deficient mice were fed with NC Group 4 (n = 10): wild-type mice were fed NC The animals were housed individually (each mouse was given an empty bottle with a large hole to play with), were observed daily for their physical activity and behavior and their body weights were recorded weekly. At week 0.4, 1, 7 and 29 of the study, blood was taken from the tail veins and plasma cholesterol levels were determined enzymatically. 33 weeks after the initiation of the experimental diet, the mice were tested using the Morris water maze technique for their behavior as previously described. The procedure was recorded by a video camera and the results were analyzed by computerized systems. At the end of the study, the mice were sacrificed and their brain fixed at 10% formalin and used for histochemical assessment. Sections embedded in paraffin of brains were stained with a) hematoxylin and eosin (H & amp; amp;; E), as a standard staining method for histological examination, b) Congo red for evaluation of amyloid plaque formation, c) Bielchowsky for axon evaluations, and d) Luxol fast blue for myelin examination. Furthermore, in collaboration with the University of Miami, brains were stained (immunohistochemistry) for potential markers of neurodegenerative diseases, including Glial Fibrillary Acid Protein (GFA), Amyloid Precursor Protein (APP), Neurofilament (NF) and U-biotin. A mouse from group 1 and a mouse from group 3 were euthanized early in the experiment due to weight loss and reduced feed intake. A mouse from group 2 and a mouse from group 4 were removed from the study to match other experimental groups.
During the experiment, a g rupo 1 mouse was sacrificed at week 17 due to skin lesions and a group 3 mouse died suddenly of possibly heart disease at week 14. During the Morris water maze process, a mouse apo E-KO of contro (# 1 5) of gruo 3) showed seizure attacks twice during the first day of training.
Results: A: Body weight The mouse body weight was recorded weekly. The results are summarized in Table 1. As is evident, all the animals gained weight during the experimental course. This indicates that the growth and development were similar among the 4 groups of mice. The addition of FCP-3PI to the mouse feed had no effect on body weight.
B: Plasma cholesterol levels Total plasma cholesteroi levels were determined at the beginning and during the experimental course. The results are summarized in Table 2. The addition of FCP-3PI to the mouse feed was associated with a significant decrease in total plasma cholesterol concentrations in apo E-KO mice, which is in agreement with our previous findings. On the other hand, complementation of mouse feed with FCP-3PI had little effect on plasma total cholesterol concentrations in wild-type mice.
C: Morris water maze test analysis The four groups of mice underwent a behavioral test using the established Morris water maze technique. The computerized analyzes of the data showed no significant differences with respect to the learning ability and memory among the groups of mice. Figures 1-4 summarize the results obtained from each group of mice. Figure 1 indicates the percentage of time that each group of mice spent in each quadrant of the deposit to locate the platform. Figure 2 indicates the percentage of time each group of mice spent in each quadrant to search the platform after being trained. This indicates the spatial memory of the mouse. In this regard, wild-type mice that were fed with FCP-3PI showed a tendency to have better memory than other groups of animals. As evident in Figure 2, the wild-type mice fed with FCP-3PI spent more time in quadrant 1 for the platform (the platform site was placed in training periods). This is also evident in Figure 3, indicative of a slightly better learning to locate the position of the platform (the place where the platform was located during the training periods). This is also evident in Figure 3, indicative of slightly better learning to locate the position of the platform (quadrant 3) by wild-type mice fed with FCP-3PI. Figure 4 shows no difference between groups of mice when tested by preference of quadrant 3 (reverse probe trace) indicative of poor retention among the four groups of mice.
D: Histogymics The brains of all groups were examined histologically. The staining with hematoxylin and eosin showed slight degenerative changes in the brains of the four groups of animals. The spotted Congo red did not show any evidence of amyloid plaque formation in any brain of all 4 groups of animals. Similarly, Bielchowsky's fast blue Luxol did not reveal any significant difference between the 4 groups of mice with respect to the characteristics of myelin and brain axon. Immunohistochemical titers will be performed by an independent neuropathologist at the St. Paul Hospital. The results will be presented as soon as the assessment is finished.
Comments This study showed that the addition of FCP-3PI (2% w / w) significantly reduces total plasma cholesterol levels in apo E-KO mice. This dose of FCP-3PI has no apparent side effect and is well tolerated by all groups of animals. The addition of FCP-3PI to the diet of wild type mice was associated with the improvement in their learning capacity and their memory, compared with other groups.
Table 1: mouse body weight at the beginning and during the experimental course (mean + SD, g) Groups Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 33
Apo E-KO 182 ± 19 218 ± 11 236 ± 10 25 + 08 253 ± 18 27 + 09 27 ± 11 288 + 18 treated with FCP Apo E-KO 182 ± 2 223 ± 22 2 2 ± 22 25 ± 21 252 ± 33 271 ± 14 28 ± 13 295 ± 14 control Natural type 179 + 14 23 ± 13 247 + 13 26 + 13 272 ± 15 274 ± 13 279 ± 15 294 ± 18 treated with FCP Natural type 182 ± 14 235 ± 12 245 ± 09 26 ± 09 277 ± 09 278 ± 09 284 ± 11 305111 control
Table 2: Levels of total cholesterol in plasma at the beginning and during the experimental course (mean ± SD, mmol / l) Groups Week 0 Week 4 Week 17 Week 29
Apo E-KO treated 126 + 2.2 11.5 + 2.6 * 14.6 ± 2.2 * 15.1 + 28 * with FCP Apo E-KO of 13.2 + 2.5 16.4 + 24 19.7 + 3.5 20.3 ± 2.2 control Natural type 2 + 0.2 1 6 ± 0.2 1.5 ± 0.2 1.6 + 0.2 treated with FCP Natural type of 2 + 01 1.6x01 1 6 + 0.2 1 5 + 0.2 control * p < 0002 compared to controls REFERENCES
1 . ELSHOURBAGY et al. 1 985 Apolipoprotein E m RNA is abundant in the brain and adrenals, as well as in the liver, and present in other tissues and rats and marmosets. (Apolipoprotein E mRNA is abundant in the brain and adrenals, as well as in the liver, and is present in other peripheral tissues in rats and marmosets) Proc Nati. Acad. Sci USA 82: 203-207 2. PITAS et al. 1987 Lipoproteins and their receptors in the CNS: Characterization of lipoproteins in CSF and identification of apolipoproteins B, E (LDL) n brain. (Lipoproteins and their receptors in the CNS: Characterization of lipoproteins in CSF and identification of apolipoproteins B, E (LDL) in the brain) J. Biol. Chem. 262: 14352-14360
3. HANDELMANN et al. 1992. Effects of apolipoprotein E, Beta-very low density lipoproteins and cholesterol on the extension of neurites by rabbit dorsal root ganglion neurons n vivo. (Effects of apolipoprotein e, very low density lipoprotein beta and cholesterol in the extension of neurites by rabbit dorzai root ganglia neurons in vivo). J. Lipid Res. 33: 1677-1688 4. MULLER et al. 1 985 A specific 37,000-dalton protein that accumulates in regenerating but not in non-regenerating mammalian nerves. (A specific protein of 37,000 daltnes that accumulates to regenerate but not in nerves of non-regenerating mammals) Science 228: 499-501 5. BOYLES et al. 1 989 A role for apolipoprotein-E, apolipoprotein A-l and low density lipoprotein receptors in transporter transport during regeneration and remyelination of the rat sciatic nerve. (A role for apolipoprotein E, apolipoprotein A-1 and low density lipoprotein receptors in cholesterol transport during regeneration and remyelination of the rat sciatic nerve) J. Clin. Invest. 83: 1015-1031 6. WESGRABER et al. 1994 Lipoproteins, neurobiology and Alzheimer's disease: Structure and function of apolipoprotein-E. (Lipoproetins, neurobiology and Alzheimer's disease: Structure and function of apolipoprotein E) Curr. Opin. Struct. Biol. 4: 507-515. 7. STRITTMATTER et al. 1 993 Binding of human apolipoprotein-E to synthetic amyloid beta-peptide: soform specific effects and implications for late onset Alzheimer's disease. (Ligation of human apolipoprotein-E to synthetic beta-amyloid peptide: specific effects of isoforms and implications for late-onset Alzheimer's disease) Proc. Nati Acad. Sci. USA 90: 8098-81 02 8. STRITTMATTER et al. 1 994a Isoform specific interactions of apolipoprotein-E with microtubule associated protein tau, implications for Alzheimer's disease. (Specific interactions of apolipoprotein-E isoforms with microtubule-associated tau protein, implications for Alzheimer's disease) Proc. Nati Acad. Sci. USA 91: 1 1 1 83-1 1 1 86 9. STRITTMATTER et al. 1 994b Hypothesis: microtubule instability and paired helical filament formation in the Alzheimer's disease brain are related to apolipoprotein-E genotype. (Hypothesis: microtubule instability and formation of helic filaments in pairs in the brain with Alzheimer's disease are related to the genotype of apolipoprotein E) Exp. Neurol. 125: 163-171 10. KALARIA et a. 1997 Society Neurosci.23: 2215 11. MOGHADASIAN et al. 1996 Arteriosclero. Throm. Vasc. Biol. 17: 119-126 12. REBECK et al. 1993 Apolipoprotein E in sporadic Alzheimer's disease: allelic variation and receptor interactions. (Apolipoprotein e in sporadic Alzheimer's disease: allelic variation and receptor interactions) Neuron 11 (4): 575-580 13. BEISIEGEL et al. 1991 Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor related protein. (Lipoprotein lipase enhances the binding of chylomicrons to protein-related low density lipoprotein receptor) Proc. Nati Acad. Sci. USA 88: 8342-8346 14. GETLENBURG et al. 1990 The tissue matrix: celi dynamic and hormone action. (The dynamic matrix: tissue cell and hormone action) Endocrine Review 11: 399 15. MATHEWS et al. 1996 Brain Res.718: 181-184 16. Nakashime et al. Arterioscerol Thromb 1994; 14: 133-140 17. van Ree et al. Atherosclerosis 1995; 112: 237-243 18. Oitzl et al. Brain Research 1997; 752: 189-196 19. Gordon et al. Neuroscience Letters 2995; 199: 1-4 20. Gordon et al. Mol. Chem. Neuropathol 1996: 97-103 21. Masliah et al; Neurobiol Aging 1994; 155: 46 22. Poirier J. Trends Neuroscience 1994; 17: 525-530 23. Moghadasian et al. Can J. cardiol 1997; 13: 81B
24. Morris R.J. Neurosci Methods 1984; 11: 47-60
Claims (10)
- REIVI NDICATIONS 1 . A method for preventing or delaying the onset of Alzheimer's disease in an animal, which comprises administering to the animal a phytosterol composition.
- 2. The method of claim 1, wherein the animal is a human.
- 3. The method of claim 1, wherein the composition comprises beta-sitosterol, campesterol and stigmastanol.
- The method of claim 1, wherein the composition comprises beta-sitosterol, campesterol and stigmastanol, and wherein campesterol and stigmastanol together comprise at least 50% of the concentration of beta-sitosterol.
- The method of claim 1, wherein the composition comprises beta-sitoesteroi, campesterol and stigmastanol, and wherein the composition comprises from 1 0-25% campesterol, 1 0-40% stigmastanol and from 45-75% of beta-sitosterol.
- 6. The method of claim 1, wherein the composition comprises beta-sitosterol, campesterol, stigmastanol and campestanol.
- 7. A therapeutically effective product for preventing Alzheimer's disease, comprising beta-sitosterol, campesterol and stigmastanol.
- 8. The product of claim 7, wherein the campesterol and stigmastanol together comprise at least 50% of the concentration of beta-sitosterol '.
- 9. The product of claim 7, comprising from 10-25% campesterol, 1-0-25% > of stigmastanol and 45-75% of beta-sitosterol.
- 10. The product of claim 7, further comprising campestanol.
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US08993901 | 1997-12-18 |
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