Marked accumulation of 27-hydroxycholesterol in the brains of Alzheimer's patients with the Swedish APP 670/671 mutation

Abstract

There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor. We show here that there is a 4-fold accumulation of 27OHC in different regions of the cortexes of patients carrying the Swedish amyloid precursor protein (APPswe) 670/671 mutation. The brain levels of sitosterol and campesterol were not significantly different in the AD patients compared with the controls, suggesting that the blood-brain barrier was intact in the AD patients. We conclude that accumulation of 27OHC is likely to be secondary to neurodegeneration, possibly a result of reduced activity of CYP7B1, the neuronal enzyme responsible for metabolism of 27OHC. We discuss the possibility of a vicious circle in the brains of the patients with familial AD whereby neurodegenerative changes cause an accumulation of 27OHC that further accelerates neurodegeneration. There is a significant flux of the neurotoxic oxysterol 27-hydroxycholesterol (27OHC) from the circulation across the blood-brain barrier. Because there is a correlation between 27OHC and cholesterol in the circulation and lipoprotein-bound cholesterol does not pass the blood-brain barrier, we have suggested that 27OHC may mediate the effects of hypercholesterolemia on the brain. We previously demonstrated a modest accumulation of 27OHC in brains of patients with sporadic Alzheimer's disease (AD), consistent with a role of 27OHC as a primary pathogenetic factor. We show here that there is a 4-fold accumulation of 27OHC in different regions of the cortexes of patients carrying the Swedish amyloid precursor protein (APPswe) 670/671 mutation. The brain levels of sitosterol and campesterol were not significantly different in the AD patients compared with the controls, suggesting that the blood-brain barrier was intact in the AD patients. We conclude that accumulation of 27OHC is likely to be secondary to neurodegeneration, possibly a result of reduced activity of CYP7B1, the neuronal enzyme responsible for metabolism of 27OHC. We discuss the possibility of a vicious circle in the brains of the patients with familial AD whereby neurodegenerative changes cause an accumulation of 27OHC that further accelerates neurodegeneration. The large pool of cholesterol in the brain is efficiently isolated from other pools of cholesterol in the body by the efficient blood-brain barrier (for reviews, see 1Dietschy J.M. Turley S.D. Thematic review series: Brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal.J. Lipid Res. 2004; 45: 1375-1397Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar, 2Bjorkhem I. Meaney S. Brain cholesterol: long secret life behind a barrier.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 806-815Crossref PubMed Scopus (726) Google Scholar). In contrast to the lipoprotein-bound cholesterol in the circulation, side-chain oxidized cholesterol metabolites are able to cross the blood-brain barrier and fluxes of oxysterols have been demonstrated in both directions. We (3Lutjohann D. Breuer O. Ahlborg G. Nennesmo I. Siden A. Diczfalusy U. Bjorkhem I. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.Proc. Natl. Acad. Sci. USA. 1996; 93: 9799-9804Crossref PubMed Scopus (569) Google Scholar, 4Bjorkhem I. Lutjohann D. Breuer O. Sakinis A. Wennmalm A. Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro.J. Biol. Chem. 1997; 272: 30178-30184Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar) and others (5Russell D.W. Halford R.W. Ramirez D.M. Shah R. Kotti T. Cholesterol 24-hydroxylase: an enzyme of cholesterol turnover in the brain.Annu. Rev. Biochem. 2009; 78: 1017-1040Crossref PubMed Scopus (212) Google Scholar) have shown that about two-thirds of the synthesis of cholesterol in the brain is compensated for by a flow of 24S-hydroxycholesterol (24OHC) from the brain into the circulation. We also demonstrated a flux of the extracerebral metabolite 27-hydroxycholesterol (27OHC) from the circulation into the brain with a net uptake of this oxysterol (6Heverin M. Meaney S. Lutjohann D. Diczfalusy U. Wahren J. Bjorkhem I. Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain.J. Lipid Res. 2005; 46: 1047-1052Abstract Full Text Full Text PDF PubMed Scopus (190) Google Scholar). Most of the 27OHC present in the cerebrospinal fluid originates from the circulation (7Leoni V. Masterman T. Patel P. Meaney S. Diczfalusy U. Bjorkhem I. Side chain oxidized oxysterols in cerebrospinal fluid and the integrity of blood-brain and blood-cerebrospinal fluid barriers.J. Lipid Res. 2003; 44: 793-799Abstract Full Text Full Text PDF PubMed Scopus (115) Google Scholar). Despite the substantial uptake of 27OHC by the brain, the levels of this oxysterol in the brain are very low, reaching only 5–10% of the levels of 24OHC (3Lutjohann D. Breuer O. Ahlborg G. Nennesmo I. Siden A. Diczfalusy U. Bjorkhem I. Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.Proc. Natl. Acad. Sci. USA. 1996; 93: 9799-9804Crossref PubMed Scopus (569) Google Scholar, 8Heverin M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The reason for this is a highly efficient metabolism. We have shown that the end metabolite of 27OHC in the brain is a steroid acid, 7α-hydroxy-3-oxo-4-cholestenoic acid, and that there is a continuous flux of this acid from the brain into the circulation (9Meaney S. Heverin M. Panzenboeck U. Ekstrom L. Axelsson M. Andersson U. Diczfalusy U. Pikuleva I. Wahren J. Sattler W. Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7alpha-hydroxy-3-oxo-4-cholestenoic acid.J. Lipid Res. 2007; 48: 944-951Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). The nature of this acid as an end metabolite is illustrated by a very substantial accumulation of it in encapsulated brain hematomas (10Nagata K. Takakura K. Asano T. Seyama Y. Hirota H. Shigematsu N. Shima I. Kasama T. Shimizu T. Identification of 7 alpha-hydroxy-3-oxo-4-cholestenoic acid in chronic subdural hematoma.Biochim. Biophys. Acta. 1992; 1126: 229-236Crossref PubMed Scopus (17) Google Scholar). The rate-limiting step in the conversion of 27OHC into the steroid acid appears to be the introduction of a 7α-hydroxyl group catalyzed by the enzyme oxysterol 7α-hydroxylase, CYP7B1 (9Meaney S. Heverin M. Panzenboeck U. Ekstrom L. Axelsson M. Andersson U. Diczfalusy U. Pikuleva I. Wahren J. Sattler W. Novel route for elimination of brain oxysterols across the blood-brain barrier: conversion into 7alpha-hydroxy-3-oxo-4-cholestenoic acid.J. Lipid Res. 2007; 48: 944-951Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). This enzyme is exclusively located in neuronal cells in the brain (11Yau J.L. Rasmuson S. Andrew R. Graham M. Noble J. Olsson T. Fuchs E. Lathe R. Seckl J.R. Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease.Neuroscience. 2003; 121: 307-314Crossref PubMed Scopus (98) Google Scholar). Despite the fact that lipoprotein-bound cholesterol does not pass the blood-brain barrier (1Dietschy J.M. Turley S.D. Thematic review series: Brain lipids. Cholesterol metabolism in the central nervous system during early development and in the mature animal.J. Lipid Res. 2004; 45: 1375-1397Abstract Full Text Full Text PDF PubMed Scopus (775) Google Scholar, 2Bjorkhem I. Meaney S. Brain cholesterol: long secret life behind a barrier.Arterioscler. Thromb. Vasc. Biol. 2004; 24: 806-815Crossref PubMed Scopus (726) Google Scholar), hypercholesterolemia is regarded to be a risk factor for Alzheimer's disease (AD) (12Launer L.J. White L.R. Petrovitch H. Ross G.W. Curb J.D. Cholesterol and neuropathologic markers of AD: a population-based autopsy study.Neurology. 2001; 57: 1447-1452Crossref PubMed Scopus (138) Google Scholar, 13Pappolla M.A. Bryant-Thomas T.K. Herbert D. Pacheco J. Fabra Garcia M. Manjon M. Girones X. Henry T.L. Matsubara E. Zambon D. Mild hypercholesterolemia is an early risk factor for the development of Alzheimer amyloid pathology.Neurology. 2003; 61: 199-205Crossref PubMed Scopus (267) Google Scholar), in particular in midlife (14Kivipelto M. Helkala E.L. Hanninen T. Laakso M.P. Hallikainen M. Alhainen K. Soininen H. Tuomilehto J. Nissinen A. Midlife vascular risk factors and late-life mild cognitive impairment: a population-based study.Neurology. 2001; 56: 1683-1689Crossref PubMed Scopus (606) Google Scholar). Because there is a close correlation between cholesterol and 27OHC in the circulation (15Babiker A. Dzeletovic S. Wiklund B. Pettersson N. Salonen J. Nyyssonen K. Eriksson M. Diczfalusy U. Bjorkhem I. Patients with atherosclerosis may have increased circulating levels of 27-hydroxycholesterol and cholestenoic acid.Scand. J. Clin. Lab. Invest. 2005; 65: 365-375Crossref PubMed Scopus (35) Google Scholar), hypercholesterolemia is likely to result in an increased uptake of this oxysterol. We have discussed the possibility that 27OHC is mediating the effect of hypercholesterolemia and that this oxysterol may be a primary pathogenetic factor in the development of AD (16Bjorkhem I. Heverin M. Leoni V. Meaney S. Diczfalusy U. Oxysterols and Alzheimer's disease.Acta Neurol. Scand. Suppl. 2006; 185: 43-49Crossref PubMed Scopus (31) Google Scholar, 17Bjorkhem I. Cedazo-Minguez A. Leoni V. Meaney S. Oxysterols and neurodegenerative diseases.Mol. Aspects Med. 2009; 30: 171-179Crossref PubMed Scopus (214) Google Scholar). The findings from a number of in vitro studies are thus consistent with the possibility that 27OHC may accelerate neurodegeneration. In cultured neuroblastoma cells, 27OHC counteracts the inhibiting effect of 24OHC on generation of amyloid (18Famer D. Meaney S. Mousavi M. Nordberg A. Bjorkhem I. Crisby M. Regulation of alpha- and beta-secretase activity by oxysterols: cerebrosterol stimulates processing of APP via the alpha-secretase pathway.Biochem. Biophys. Res. Commun. 2007; 359: 46-50Crossref PubMed Scopus (85) Google Scholar) and in retinal pigment epithelial cells, it increases β-amyloid and oxidative stress (19Dasari B. Prasanthi J.R. Marwarha G. Singh B.B. Ghribi O. The oxysterol 27-hydroxycholesterol increases beta-amyloid and oxidative stress in retinal pigment epithelial cells.BMC Ophthalmol. 2010; 10: 22Crossref PubMed Scopus (62) Google Scholar). It has also been shown to increase β-amyloid formation in hippocampal slices and in neuronal preparations from rabbits (20Ghribi O. Potential mechanisms linking cholesterol to Alzheimer's disease-like pathology in rabbit brain, hippocampal organotypic slices, and skeletal muscle.J. Alzheimers Dis. 2008; 15: 673-684Crossref PubMed Scopus (52) Google Scholar). In addition to this, 27OHC reduces the production of the “memory protein” activity-regulated cytoskeleton-associated protein (arc) in mouse brain (21Mateos L. Akterin S. Gil-Bea F.J. Spulber S. Rahman A. Bjorkhem I. Schultzberg M. Flores-Morales A. Cedazo-Minguez A. Activity-regulated cytoskeleton-associated protein in rodent brain is down-regulated by high fat in vivo and by 27-hydroxycholesterol in 2009; PubMed Scopus Google Scholar). We have demonstrated increased levels of 27OHC both in the brain M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar) and cerebrospinal fluid V. Masterman T. Mousavi B. Diczfalusy U. J. Bjorkhem I. of cerebral and extracerebral Chem. Lab. Med. 2004; PubMed Scopus Google Scholar) of patients with the sporadic of There are different for the increased increased uptake of 27OHC from the circulation to reduced of the blood-brain and reduced metabolism of 27OHC to of CYP7B1 activity as a of neuronal The are consistent with the of 27OHC as a primary pathogenetic factor the possibility that the accumulation of 27OHC is secondary to the neurodegeneration. In to between the different we measured 27OHC in brain autopsy from patients with a familial of AD in the primary pathogenetic factor is a in the the amyloid precursor protein M. K. L. Winblad B. L. pathogenetic for Alzheimer's disease in the APP the of 1992; PubMed Scopus Google Scholar). In the present we a accumulation of 27OHC in the brains of and the levels of 27OHC were the levels we previously in the brains of patients with the sporadic of the disease M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). We conclude that accumulation of 27OHC is likely to be secondary to the neurodegeneration. is that the accumulation is likely to be to reduced CYP7B1 activity to increased of the blood-brain barrier increased synthesis in the brain. brain from the and cortexes was from AD patients carrying the Swedish APP 670/671 from the Brain of AD patients the of to the of and and Alzheimer's and G. D. M. R. D. of Alzheimer's of the of of and on Alzheimer's PubMed Google Scholar) and the of AD was by to a for Alzheimer's A. D. G. L. The to a for AD of the of Alzheimer's PubMed Google Scholar). from with of and changes for were in this The cause of for was and for AD patients and In with the Swedish the were for a of and to a the autopsy was from the different brain regions were from the with a of for AD patients and for The were and to autopsy brain in the was by the in and the Swedish of in the from of was for studies to 24OHC and 27OHC were as previously S. Breuer O. E. Diczfalusy U. of cholesterol in human by Biochem. PubMed Scopus Google Scholar). was from by human and the for of other H. M. Andersson U. Pikuleva I. Bjorkhem I. K. of a novel chain a cholesterol by Biophys. Acta. 2008; PubMed Scopus Google Scholar). The the with and Brain was to J. M. for the and of from Biol. Chem. Full Text PDF PubMed Google Scholar) with of was in of in a of were to the brain The was by for in The were for and the was in a The was and both were The was in and of the oxysterol to of the was with to and and as previously S. Breuer O. E. Diczfalusy U. of cholesterol in human by Biochem. PubMed Scopus Google Scholar). to the was with for The was and in and to The and were for of and and the and for of and of by has not been of the a of of cholesterol and sterols were by as J. A. K. D. M. Lutjohann D. I. of cholesterol and sterols in cultured Sci. 2009; PubMed Scopus Google Scholar) the as from the brain were to on a and to The were for in in by in a with an from D. of and an a secondary with was and for The were in from to the The was by from were also from the brain and to and the as with the that the was by an M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). shown in the levels of 27OHC in brain from the cortexes of the AD patients were as compared with in the from the The of 24OHC was in the AD patients as compared with in the The between 27OHC and 24OHC was in the cortexes of the AD patients and in the from the shown in the levels of 27OHC in brain from the cortexes of the AD patients were as compared with in the from the The for 24OHC were in the patients and in the as were in the of brain from the cortexes of AD patients and not the activity of the enzyme CYP7B1 is the factor for elimination of 27OHC from the brain and this activity is reduced in the brains of patients with reduced levels of the be a reduced between this and 27OHC. The levels of were to be in the brain from the cortexes of the AD patients as compared with in the from the The in the of in brain from the cortexes of the AD patients was and The levels of the are thus in the brains of patients with AD in the controls, the between and is in are consistent with not a reduced to 27OHC into in the brains of the AD patients. shown in the levels of sitosterol in the brain from the cortexes of the AD patients were as compared with in the The levels of campesterol in the of the brains of AD patients were as compared with in the The levels of sitosterol in brain from the cortexes of the AD patients were as compared with in the The levels of campesterol in brain from the were in the AD patients as compared with in the there were significant between AD and with to levels of sterols in the brain. Because the sterols are of the are consistent with an intact blood-brain in the AD patients. is a for cholesterol shown in the levels of this steroid in the were as compared with in the In the brain from the the levels were and The a reduced synthesis of cholesterol in the cortexes not in the cortexes of the AD patients. the high levels of 27OHC be to increased shown in with human in the of the of brain from the AD patients as in the of the from the brains of the was also with human and on the of brain from the patients and the significant was between the patients and the The are consistent with levels of and in the brains of the AD patients. The brain levels of 27OHC and 24OHC in the present were to be to of the previously the M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). In that we that the levels of 27OHC were increased by in the and cortexes of sporadic AD patients. In the present we that brain levels of 27OHC are increased by a factor of about in AD patients carrying the Swedish APP 670/671 mutation. The APP 670/671 on in this Swedish is to be the cause of the disease it APP metabolism to an accumulation of and formation M. T. G. L. A. P. I. D. of the amyloid precursor protein in AD increases 1992; Scholar, L. Bogdanovic N. H. K. L. G. D. J. Winblad B. precursor protein Alzheimer's disease in a Swedish PubMed Scopus Google Scholar, E. M. A. of levels in the brain of familial and sporadic Alzheimer's 2009; Scopus Google Scholar, A. U. Bogdanovic N. L. Nordberg A. in Alzheimer's patients with the Swedish amyloid precursor protein 670/671 1992; Scholar). of AD has been of this and the of the disease between and of K. H. Winblad B. L. and of large Swedish Alzheimer with a 670/671 amyloid precursor protein Neurol. 57: Scopus Google Scholar). In there was a in the levels of 24OHC in the brains of the patients with the sporadic of AD M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). In the present a of levels was in the cortexes not in the cortexes of the patients. The of as measured by was not significantly different between patients and to the of in the neuronal cells, the of cells in the brains of AD patients be to be with a in the of the other we have shown that the of in the neuronal cells may in be compensated for by an expression of in cells in the brains of patients with AD N. Bretillon L. Diczfalusy U. L. Winblad B. D. I. the turnover of brain cholesterol in patients with Alzheimer's of the enzyme in 2001; PubMed Scopus Google Scholar). It is of to the present findings in patients with the familial of AD with a mouse for AD the Swedish APP mutation. to the of we that have levels of 27OHC to in the M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). the of and there was a modest increase in the levels of 27OHC. The increase was with a increase in the levels of sterols in the brain. Because the increase is likely to be to an increased of the blood-brain barrier, it likely that the accumulation of 27OHC in the brains of the is to a efficient blood-brain barrier to a effect of the neurodegeneration. It is that there are between patients with an APP and the mouse of the for the accumulation of 27OHC in the brains of the may be the 4-fold levels of this oxysterol in the circulation as compared with the levels in It may be that this in circulating levels is to a of metabolism in compared with that of It is that the high accumulation of 27OHC in the brains of the patients with familial AD and a pathogenetic mechanism the disease is a a cause of the neurodegeneration. the of it be that the accumulation of this oxysterol may the disease and that a vicious circle is in the increased may further neurodegeneration. The accumulation of 27OHC in the brains of the patients with an may the early and disease in patients compared with that of sporadic AD A. M. N. in Alzheimer's disease is not to amyloid 2010; PubMed Scopus Google Scholar). The of the the of may be of for the accumulation of 27OHC and the present patients were It may be that in studies on brain autopsy from patients between and of there was correlation between the the of and the accumulation of 27OHC M. Bogdanovic N. Lutjohann D. Bayer T. Pikuleva I. Bretillon L. Diczfalusy U. Winblad B. Bjorkhem I. Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.J. Lipid Res. 2004; 45: 186-193Abstract Full Text Full Text PDF PubMed Scopus (247) Google Scholar). The reason for the increased accumulation of 27OHC in the AD patients the APP Swedish is not likely to be increased of the blood-brain barrier. there was significant accumulation of sterols in the brains of the patients. Because the protein of the enzyme was in the brains of the AD patients and the controls, a production of 27OHC in the brains of the AD patients is also The likely to be a reduced of CYP7B1, the neuronal enzyme responsible for metabolism of 27OHC. It has been previously that the levels of CYP7B1 are reduced in the brains of patients with AD (11Yau J.L. Rasmuson S. Andrew R. Graham M. Noble J. Olsson T. Fuchs E. Lathe R. Seckl J.R. Dehydroepiandrosterone 7-hydroxylase CYP7B: predominant expression in primate hippocampus and reduced expression in Alzheimer's disease.Neuroscience. 2003; 121: 307-314Crossref PubMed Scopus (98) Google Scholar). number of in to CYP7B1 by in human brain different preparations of have thus We a reduced between and 27OHC in the brains of APP 670/671 AD patients. The levels of the in the brains of the AD patients. The are consistent with not that the activity of CYP7B1 is reduced in the AD patients. it was shown that a of patients with have a in the for CYP7B1 K. Y. M.A. Patel H. CYP7B1 cholesterol homeostasis in J. 2008; Full Text Full Text PDF PubMed Scopus Google Scholar). a patients have high levels of 27OHC in and R. T. Y. S. M. N. L. I. accumulation of in patients with and a in the for the oxysterol 7 Lipid Res. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar) and also in the brain. not the accumulation of 27OHC in patients is of the is not this of patients not neurodegeneration, a is The possibility has been discussed that may be to 27OHC other neuronal cells, evidence for this is R. T. Y. S. M. N. L. I. accumulation of in patients with and a in the for the oxysterol 7 Lipid Res. 2010; Full Text Full Text PDF PubMed Scopus Google Scholar). In patients with the present familial of AD have a 4-fold accumulation of 27OHC in the brain, the accumulation in the brains of patients with the sporadic of the disease and in the brains of a mouse for we evidence that the accumulation is a of the neurodegeneration. We discuss the possibility of a vicious circle in the brains of patients with AD whereby neurodegenerative changes cause an accumulation of 27OHC that further accelerates neurodegeneration. Alzheimer's disease Swedish amyloid precursor protein 24S-hydroxycholesterol 27-hydroxycholesterol