Alzheimer Disease: Wolozin B

Wolozin B. · No affiliation provided · Arch Neurol. · Pubmed #12533083 links to  free full text

This publication has no abstract.

Tezapsidis N, Johnston JM, Smith MA, Ashford JW, Casadesus G, Robakis NK, Wolozin B, Perry G, Zhu X, Greco SJ, Sarkar S. · Neurotez, Inc., Bridgewater, New Jersey 08807, USA. · J Alzheimers Dis. · Pubmed #19387109 No free full text.

Abstract: Adipocyte-derived leptin appears to regulate a number of features defining Alzheimer's disease (AD) at the molecular and physiological level. Leptin has been shown to reduce the amount of extracellular amyloid beta, both in cell culture and animal models, as well as to reduce tau phosphorylation in neuronal cells. Importantly, chronic administration of leptin resulted in a significant improvement in the cognitive performance of transgenic animal models. In AD, weight loss often precedes the onset of dementia and the level of circulating leptin is inversely proportional to the severity of cognitive decline. It is speculated that a deficiency in leptin levels or function may contribute to systemic and CNS abnormalities leading to disease progression. Furthermore, a leptin deficiency may aggravate insulin-controlled pathways, known to be aberrant in AD. These observations suggest that a leptin replacement therapy may be beneficial for these patients.

Wolozin B, Bednar MM. · Department of Pharmacology, Boston University School of Medicine, Boston, MA 02118-2526, USA. · Neurol Res. · Pubmed #16945215 No free full text.

Abstract: OBJECTIVES: To review the contributions of cardiovascular disease to Alzheimer's disease and vascular dementia. METHODS: Review of the literature. RESULTS: Alzheimer's disease and vascular dementia both share significant risk attributable to cardiovascular risk factors. Hypertension and hypercholesterolemia at midlife are significant risk factors for both subsequent dementia. Diabetes and obesity are also risk factors for dementia. Stressful medical procedures, such as coronary artery bypass and graft operations also appear to contribute to the risk of Alzheimer's disease. Apolipoprotein E is the major risk factor for Alzheimer's disease. Apolipoprotein E does not appear to contribute to Alzheimer's disease by increasing serum cholesterol, but it might contribute to the disease through a mechanism involving both Abeta and an increase in neuronal vulnerability to stress. DISCUSSION: The strong association of cardiovascular risk factors with Alzheimer's disease and vascular dementia suggest that these diseases share some biologic pathways in common. The contribution of cardiovascular disease to Alzheimer's disease and vascular dementia suggest that cardiovascular therapies might prove useful in treating or preventing dementia. Antihypertensive medications appear to be beneficial in preventing vascular dementia. Statins might be beneficial in preventing the progression of dementia in subjects with Alzheimer's disease.

Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A. · Department of Pharmacology, Boston University School of Medicine, MA 02118, USA. · Acta Neurol Scand Suppl. · Pubmed #16866913 No free full text.

Abstract: This communication integrates the purported role of cholesterol and statins in Alzheimer's disease (AD) with recent data. Meta-analysis of association studies relevant to AD indicates that apolipoprotein (apo)E4 is the only cholesterol-related polymorphism that shows clear association with AD. This suggests that the effect of apoE4 on the pathophysiology of AD occurs via a mechanism that is not directly related to cholesterol, such as fibrillization of Abeta. Despite the lack of genetic association, cholesterol and statins clearly modulate amyloid precursor protein (APP) processing in cell culture and animal models. Statins appear to act by a pleiotropic mechanism, involving both cholesterol (via lipid rafts) and isoprenylation. The pleiotropic mechanism of statin action clarifies conflicting data from clinical studies, where statins exert an action on Abeta and AD that might be dose dependent because of actions on both cholesterol and isoprenylation. Reduced isoprenylation can also inhibit inflammation. Our own studies of brains from Alzheimer subjects +/- statins indicate that statins inhibit inflammation in humans but might not reduce cerebral Abeta load. These results suggest that the primary action of statins in humans with AD might be to reduce inflammation rather than decrease Abeta load.

Wolozin B. · Department of Pharmacology, Boston University School of Medicine, L-603, Boston, MA 02118-2526, USA. · Curr Opin Lipidol. · Pubmed #15529026 No free full text.

Abstract: PURPOSE OF REVIEW: Advances in cholesterol biology suggest that cholesterol metabolism modulates beta-amyloid production, and that pharmaceuticals that inhibit cholesterol metabolism might be valuable in therapy of Alzheimer's disease. Although the genetics and cell biology continue to support the link between cholesterol and Alzheimer's disease, recent clinical studies suggest that the animal studies might not directly translate to clinical studies in humans. RECENT FINDINGS: This review will highlight advances in genetics, cell biology and clinical sciences investigating the relationship between cholesterol and Alzheimer's disease. SUMMARY: Cholesterol, its catabolites and proteins that regulate cholesterol levels all modulate processing of amyloid precursor protein. Statins hold promise in therapy of Alzheimer's disease, but the current data are more consistent with a model of statins that act as neuroprotective agents rather than inhibitors of beta-amyloid production.

Wolozin B, Brown J, Theisler C, Silberman S. · Department of Pharmacology, Loyola University Medical Center, Bldg. 102, Rm. 3634, 2160 South First Ave., Maywood, IL 60153, USA. · CNS Drug Rev. · Pubmed #15179443 No free full text.

Abstract: The causes of late onset Alzheimer disease (AD) are poorly understood. Although beta-amyloid (Abeta) is thought to play a critical role in the pathophysiology of AD, no genetic evidence directly ties Abeta to late onset AD. This suggests that the accumulation of Abeta and neurodegeneration associated with AD might result from an abnormality that indirectly affects Abeta production or accumulation. Increasing evidence suggests that abnormalities in the metabolism of cholesterol and related molecules, such as cholseterol esters and 24(S) hydroxycholesterol might contribute to the pathophysiology of late onset AD by increasing production of Abeta. 24(S) Hydroxycholesterol is a member of a family of oxidized cholesterol catabolites, termed oxysterols, which function to regulate export of cholesterol from the cell and transcription of genes related to cholesterol metabolism. Cholesterol esters are cholesterol derivatives used for cholesterol storage. Levels of 24(S) hydroxycholesterol increase with AD. Polymorphisms in several different genes important for cholesterol physiology are associated with an increased load or level of Abeta in AD. These genes include apolipoprotein E, cholesterol 24 hydroxylase (Cyp46), acyl-CoA:cholesterol acetyltransferase (ACAT), and the cholesterol transporter ABCA1. Other studies show that levels of cholesterol, or its precursors, are elevated in subjects early in the course of AD. Finally, studies of the processing of amyloid precursor protein show that cholesterol and its catabolites modulate amyloid precursor protein processing and Abeta production. These lines of evidence raise the possibility that genetic abnormalities in cholesterol metabolism might contribute to the pathophysiology of AD.

Wolozin B. · Department of Pharmacology, Loyola University Medical Center, Maywood, IL 60153, USA. · Neuron. · Pubmed #14715130 No free full text.

Abstract: Recent results implicating cholesterol metabolism in the pathophysiology of Alzheimer's disease (AD) bring cholesterol to the forefront of AD research. Research from genetics, epidemiology, and cell biology all converge, suggesting that cholesterol plays a central role in the biology of amyloid precursor protein and the toxic peptide generated by its cleavage, beta-amyloid (Abeta). The ability of cholesterol to modulate Abeta production suggests opportunities for therapeutic intervention, although the functional significance underlying the connection between cholesterol and Abeta remains to be investigated.

Wolozin B. · Department of Pharmacology, Loyola University Medical Center, Bldg. 102, Rm. 3634, 2160 South First Avenue, Maywood, IL 60153, USA. · Biochem Soc Trans. · Pubmed #12196129 No free full text.

Abstract: Accumulation of a 40-42-amino acid peptide, termed amyloid-beta peptide (A beta), is associated with Alzheimer's disease (AD), and identifying medicines that inhibit A beta could help patients with AD. Recent evidence suggests that a class of medicines that lower cholesterol by blocking the enzyme 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase), termed statins, can inhibit A beta production. Increasing evidence suggests that the enzymes that generate A beta function best in a high-cholesterol environment, which might explain why reducing cholesterol would inhibit A beta production. Studies using both neurons and peripheral cells show that reducing cellular cholesterol levels, by stripping off the cholesterol with methyl-beta-cyclodextrin or by treating the cells with HMG-CoA reductase inhibitors, decreases A beta production. Studies performed on animal models and on humans concur with these results. In humans, lovastatin, an HMG-CoA reductase inhibitor, has been shown to reduce A beta levels in blood of patients by up to 40%. The putative role of A beta in AD raises the possibility that treating patients with statins might lower A beta, and thereby either delay the occurrence of AD or retard the progression of AD. Two large retrospective studies support this hypothesis. Both studies suggest that patients taking statins had an approx. 70% lower risk of developing AD. Since statins are widely used by doctors, their ability to reduce A beta offers a putative therapeutic strategy for treating AD by using medicines that have already been proved safe to use in humans.

Lee TA, Wolozin B, Weiss KB, Bednar MM. · Midwest Center for Health Services and Policy Research, Hines VA Hospital, Hines, IL, USA. · J Alzheimers Dis. · Pubmed #16131734 No free full text.

Abstract: Post-Operative Cognitive Decline (POCD) is a complication of Coronary Artery Bypass Graft (CABG) surgery and is consistent with reduced neuronal reserve. We performed a retrospective cohort analysis of Veterans Affairs (VA) patients undergoing CABG or PTCA between October 1, 1996 and September 30, 1997 to examine if CABG surgery is associated with the earlier emergence of cognitive impairment such as Alzheimer's Disease (AD). The emergence of dementia following CABG surgery was compared to dementia in a cardiac population undergoing percutaneous transluminal coronary angioplasty (PTCA). Patients were followed from the date of their procedure until September 30, 2002, the diagnosis of Alzheimer's disease or death. Cox proportional hazards models were used to compare the risk of AD development. Patients analyzed were > or = 55 yrs old without baseline dementia. The results show that a total of 119 patients (CABG = 78; PTCA = 41) developed AD during the follow-up period. The adjusted risk of AD associated with CABG versus PTCA was 1.71 (95% CI, 1.02 to 2.87; p = 0.04). These results suggest that patients undergoing CABG surgery were at increased risk for the emergence of AD than those undergoing PTCA. These data support the hypothesis that CABG surgery is associated with a reduced neuronal reserve in an aging population.

Brown J, Theisler C, Silberman S, Magnuson D, Gottardi-Littell N, Lee JM, Yager D, Crowley J, Sambamurti K, Rahman MM, Reiss AB, Eckman CB, Wolozin B. · Departments of Pharmacology and Pathology, Loyola University Medical Center, Maywood, IL 60153, USA. · J Biol Chem. · Pubmed #15148325 links to  free full text

Abstract: Cholesterol is eliminated from neurons by oxidization, which generates oxysterols. Cholesterol oxidation is mediated by the enzymes cholesterol 24-hydroxylase (CYP46A1) and cholesterol 27-hydroxylase (CYP27A1). Immunocytochemical studies show that CYP46A1 and CYP27A1 are expressed in neurons and some astrocytes in the normal brain, and CYP27A1 is present in oligodendrocytes. In Alzheimer's disease (AD), CYP46A1 shows prominent expression in astrocytes and around amyloid plaques, whereas CYP27A1 expression decreases in neurons and is not apparent around amyloid plaques but increases in oligodendrocytes. Although previous studies have examined the effects of synthetic oxysterols on the processing of amyloid precursor protein (APP), the actions of the naturally occurring oxysterols have yet to be examined. To understand the role of cholesterol oxidation in AD, we compared the effects of 24(S)- and 27-hydroxycholesterol on the processing of APP and analyzed the cell-specific expression patterns of the two cholesterol hydroxylases in the human brain. Both oxysterols inhibited production of Abeta in neurons, but 24(S)-hydroxycholesterol was approximately 1000-fold more potent than 27-hydroxycholesterol. The IC(50) of 24(S)-hydroxycholesterol for inhibiting Abeta secretion was approximately 1 nm. Both oxysterols induced ABCA1 expression with IC(50) values similar to that for inhibition of A beta secretion, suggesting the involvement of liver X receptor. Oxysterols also inhibited protein kinase C activity and APP secretion following stimulation of protein kinase C. The selective expression of CYP46A1 around neuritic plaques and the potent inhibition of APP processing in neurons by 24(S)-hydroxycholesterol suggests that CYP46A1 affects the pathophysiology of AD and provides insight into how polymorphisms in the CYP46A1 gene might influence the pathophysiology of this prevalent disease.

Perry G, Castellani RJ, Smith MA, Harris PL, Kubat Z, Ghanbari K, Jones PK, Cordone G, Tabaton M, Wolozin B, Ghanbari H. · Institute of Pathology, Case Western Reserve University, 2085 Adelbert Road, Cleveland, OH 44106, USA. · Acta Neuropathol. · Pubmed #12955399 No free full text.

Abstract: Increased oxidative damage is a prominent and early feature of vulnerable neurons in Alzheimer's disease (AD). However, while damage to proteins, sugars, lipids, nucleic acids and organelles such as lysosomes, mitochondria, and endoplasmic reticulum are evident, the source of increased reactive oxygen species has not been determined. Furthermore, a major limitation in further determining the source, as well as finding a means to arrest damage, is the paucity of cellular models directly homologous to AD since the vulnerable neurons of the brain in AD cannot be studied in vitro. Here, we examined the olfactory epithelium in situ to see if neurons there exhibit a similar pathological oxidative balance to vulnerable neurons in AD. In biopsy specimens, (eight AD and three controls) we found that neurons, and also the surrounding epithelial cells, show an increase in oxidative damage for a subset of the markers increased in the brain of cases of AD. Lipid peroxidation and heme oxygenase-1, a stress response protein, were increased, while nucleic acid or protein oxidation, demonstrated in vulnerable neurons in AD, were not increased. These findings highlight the systemic nature of oxidative abnormalities in AD, but that different cell types may express this abnormality by a different array of oxidative stress markers, supporting the potential for using olfactory neurons or other cells derived from AD patients in culture to understand the mechanistic basis for increased oxidative damage in AD and as a model to screen compounds for therapeutic intervention.

Pappolla MA, Bryant-Thomas TK, Herbert D, Pacheco J, Fabra Garcia M, Manjon M, Girones X, Henry TL, Matsubara E, Zambon D, Wolozin B, Sano M, Cruz-Sanchez FF, Thal LJ, Petanceska SS, Refolo LM. · University of South Alabama, Mobile, USA. · Neurology. · Pubmed #12874399 No free full text.

Abstract: BACKGROUND: Epidemiologic and experimental data suggest that cholesterol may play a role in the pathogenesis of AD. Modulation of cholesterolemia in transgenic animal models of AD strongly alters amyloid pathology. OBJECTIVE: To determine whether a relationship exists between amyloid deposition and total cholesterolemia (TC) in the human brain. METHODS: The authors reviewed autopsy cases of patients older than 40 years and correlated cholesterolemia and presence or absence of amyloid deposition (amyloid positive vs amyloid negative subjects) and cholesterolemia and amyloid load. Amyloid load in human brains was measured by immunohistochemistry and image analysis. To remove the effect of apoE isoforms on cholesterol levels, cases were genotyped and duplicate analyses were performed on apoE3/3 subjects. RESULTS: Cholesterolemia correlates with presence of amyloid deposition in the youngest subjects (40 to 55 years) with early amyloid deposition (diffuse type of senile plaques) (p = 0.000 for all apoE isoforms; p = 0.009 for apoE3/3 subjects). In this group, increases in cholesterolemia from 181 to 200 almost tripled the odds for developing amyloid, independent of apoE isoform. A logistic regression model showed consistent results (McFadden rho2 = 0.445). The difference in mean TC between subjects with and without amyloid disappeared as the age of the sample increased (>55 years: p = 0.491), possibly reflecting the effect of cardiovascular deaths among other possibilities. TC and amyloid load were not linearly correlated, indicating that there are additional factors involved in amyloid accumulation. CONCLUSIONS: Serum hypercholesterolemia may be an early risk factor for the development of AD amyloid pathology.

Palacino JJ, Murphy MP, Murayama O, Iwasaki K, Fujiwara M, Takashima A, Golde TE, Wolozin B. · Department of Pharmacology and Neuroscience Program, Loyola University Medical Center, Maywood, Illinois 60153, USA. · J Biol Chem. · Pubmed #11504726 links to  free full text

Abstract: Presenilin 1 (PS1) is linked with Alzheimer's disease but exhibits functional roles regulating growth and development. For instance, PS1 binds to beta-catenin and modulates beta-catenin signaling. In the current study, we observed that knockout of PS1 inhibited beta-catenin-mediated transcription by 35%, as shown by a luciferase reporter driven by the hTcf-4 promoter. Overexpressing wild-type PS1 increased beta-catenin-mediated transcription by 37.5%, and overexpressing PS1 with mutations associated with Alzheimer's disease decreased beta-catenin-mediated transcription by 66%. To examine whether regulation of beta-catenin by PS1 requires phosphorylation by glycogen synthase kinase 3beta (GSK 3beta), we examined whether inhibiting GSK 3beta activity overcomes the inhibition of beta-catenin transcription induced by mutant PS1 constructs. Cells expressing wild-type or mutant PS1 were treated with LiCl, which inhibits GSK 3beta, or transfected with beta-catenin constructs that lack the GSK 3beta phosphorylation sites. Neither treatment overcame PS1-mediated inhibition of beta-catenin signaling, suggesting that regulation of beta-catenin by PS1 was not affected by the activity of GSK 3beta. To investigate how PS1 might regulate beta-catenin signaling, we determined whether PS1 interacts with other elements of the beta-catenin signaling cascade, such as the Tcf-4 transcription factor. Coimmunoprecipitation studies showed binding of PS1 and hTcf-4, and examining nuclear isolates indicated that nuclear hTcf-4 was decreased in cells expressing mutant PS1. These data show that PS1 interacts with multiple components of the beta-catenin signaling cascade and suggest that PS1 regulates beta-catenin in a manner independent of GSK 3beta activity.

Wolozin B. · Department of Pharmacology, Molecular Pharmacology Laboratory, Loyola University Medical Center, 2160 South First Street, Building 102, Room 3634, Maywood, IL 60153, USA. · Proc Natl Acad Sci U S A. · Pubmed #11344276 links to  free full text

This publication has no abstract.

Wolozin B, Kellman W, Ruosseau P, Celesia GG, Siegel G. · Department of Pharmacology, Loyola University Medical Center, Bldg 102, Room 3634, 2160 S First Ave, Maywood, IL 60153. · Arch Neurol. · Pubmed #11030795 links to  free full text

Abstract: CONTEXT: Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer disease (AD). For instance, an elevated serum cholesterol level has been shown to be a risk factor for AD. OBJECTIVE: To determine whether patients taking 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins), which are a group of medicines that inhibit the synthesis of cholesterol, have a lower prevalence of probable AD. DESIGN: The experiment uses a cross-sectional analysis comparing the prevalence of probable AD in 3 groups of patients from hospital records: the entire population, patients receiving 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (hereafter referred to as the statins), and patients receiving medications used to treat hypertension or cardiovascular disease. PATIENTS: The subjects studied were those included in the computer databases of 3 different hospitals for the years October 1, 1996, through August 31, 1998. MAIN OUTCOME MEASURES: Diagnosis of probable AD. RESULTS: We find that the prevalence of probable AD in the cohort taking statins during the study interval is 60% to 73% (P < .001) lower than the total patient population or compared with patients taking other medications typically used in the treatment of hypertension or cardiovascular disease. CONCLUSIONS: There is a lower prevalence of diagnosed probable AD in patients taking 2 different 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors-lovastatin and pravastatin. While one cannot infer causative mechanisms based on these data, this study reveals an interesting association in the data, which warrants further study. Arch Neurol. 2000;57:1439-1443

Sunderland T, Wolozin B, Galasko D, Levy J, Dukoff R, Bahro M, Lasser R, Motter R, Lehtimäki T, Seubert P. · Geriatric Psychiatry Branch, National Institute of Mental Health, NIH, Bethesda, MD 20892-1275, USA. · Biol Psychiatry. · Pubmed #10494442 No free full text.

Abstract: BACKGROUND: Antemortem levels of tau in the cerebrospinal fluid (CSF) of Alzheimer's disease (AD) patients have repeatedly been demonstrated to be elevated when compared to controls. Although CSF tau has been reported to be elevated even in very mild AD, it is unknown how tau levels change during the course of the disease. METHODS: We have followed 29 mild-to-moderately affected AD subjects over 2 years with repeated CSF taps. Clinical measures of dementia severity (Clinical Dementia Rating Scale, Global Deterioration Scale and Mini-Mental Status Examination) were obtained at the start and conclusion of the observation period, and CSF tau was measured with a standard enzyme-linked immunoabsorbent assay (ELISA) using two monoclonal antibodies. RESULTS: Despite significant changes in the clinical measures consistent with progression of the disease, no significant overall change in CSF tau levels (548 +/- 355 vs. 557 +/- 275 pg/mL, NS) was observed. None of the clinical variables was significantly correlated with either baseline measures of CSF tau or delta CSF tau (last-first). Similarly, CSF tau at baseline and changes over time were not significantly related to Apolipoprotein E (APO E) phenotype. CONCLUSIONS: These data suggest that CSF tau levels are stable over extended periods of time in a group of mild-to-moderately demented AD subjects and that CSF tau levels do not predict the severity or rate of progression of AD, at least not during the middle stages of the illness.

Takashima A, Shimojo M, Wolozin B. · No affiliation provided · Nat Med. · Pubmed #16829940 No free full text.

This publication has no abstract.

Bednar MM, Lee TA, Wolozin B, Weiss KB. · No affiliation provided · Neurology. · Pubmed #16769972 No free full text.

This publication has no abstract.