Alzheimer Disease: Praticò D

Praticò D. · Department of Pharmacology, Temple University, School of Medicine, Philadelphia, PA 19140, USA. · Ann N Y Acad Sci. · Pubmed #19076432 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disease associated with dementia in the elderly. Although the initiating events are still unknown, it is clear that AD, at least in its sporadic form, results from the combination of genetic risk factors with different epigenetic events. Among them, a growing body of evidence suggests that an imbalance between free radical formation and destruction is involved in AD pathogenesis. This concept originally derived from the free radical hypothesis of aging, which states that the age-related accumulation of free radicals results in damaged cell components. The fact that age is a key risk factor in AD provides support for this hypothesis. There is a long list of surrogate markers, which includes lipid, DNA, and protein oxidation, of oxidant stress-mediated injury that have been reported as elevated in the AD brain. Moreover, epidemiologic studies show that dietary intake of natural or synthetic products with a putative antioxidant effect, such as (but not only) vitamin E, reduces the risk of AD. On the other hand, antioxidative intervention studies in animal models of AD-like amyloidosis show a significant reduction in amyloid beta deposition and behavioral improvements. However, a randomized clinical trial of vitamin E supplementation in AD patients shows only a marginal positive effect. Another study reports no effect of vitamin E on the rate of progression of AD in subjects with mild cognitive impairment. This article will review both promises and caveats of the available data and propose future directions to be taken for addressing them.

Praticò D. · Department of Pharmacology, Temple University, School of Medicine, Philadelphia, PA 19140, USA. · Trends Pharmacol Sci. · Pubmed #18838179 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia. In its sporadic form, AD results from the combination of genetic factors with different epigenetic events. Among them, oxidative metabolic reactions and their by-products have been consistently implicated in AD pathogenesis and represent the biological basis for the 'oxidative stress hypothesis' of AD. Numerous studies demonstrate that different biomarkers of oxidative-stress-mediated events are elevated in the AD brain. Studies in animal models of the disease with antioxidants report significant improvements of their AD-like phenotype. Although epidemiologic studies show that dietary intake of antioxidants reduces the risk of AD, clinical trials with antioxidants show only a marginal positive or no effect. These conflicting results have created a wave of criticism towards the oxidative stress hypothesis of AD. Here, I review the available data and discuss the necessary paths for a fair reappraisal of the hypothesis.

Thal LJ, Kantarci K, Reiman EM, Klunk WE, Weiner MW, Zetterberg H, Galasko D, Praticò D, Griffin S, Schenk D, Siemers E. · University of California San Diego, Department of Neurosciences, La Jolla, California, USA. · Alzheimer Dis Assoc Disord. · Pubmed #16493230 links to  free full text

Abstract: Biomarkers are likely to be important in the study of Alzheimer disease (AD) for a variety of reasons. A clinical diagnosis of Alzheimer disease is inaccurate even among experienced investigators in about 10% to 15% of cases, and biomarkers might improve the accuracy of diagnosis. Importantly for the development of putative disease-modifying drugs for Alzheimer disease, biomarkers might also serve as indirect measures of disease severity. When used in this way, sample sizes of clinical trials might be reduced, and a change in biomarker could be considered supporting evidence of disease modification. This review summarizes a meeting of the Alzheimer's Association's Research Roundtable, during which existing and emerging biomarkers for AD were evaluated. Imaging biomarkers including volumetric magnetic resonance imaging and positron emission tomography assessing either glucose utilization or ligands binding to amyloid plaque are discussed. Additionally, biochemical biomarkers in blood or cerebrospinal fluid are assessed. Currently appropriate uses of biomarkers in the study of Alzheimer disease, and areas where additional work is needed, are discussed.

Firuzi O, Praticò D. · Department of Pharmacology, University of Pennsylvania, School of Medicine. Philadelphia, PA 19014, USA. · Ann Neurol. · Pubmed #16402383 No free full text.

Abstract: The neuropathology of Alzheimer's disease (AD) is characterized by deposits of amyloid beta (Abeta) peptides and neurofibrillary tangles, but also, among other aspects, by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal antiinflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. The classic target of NSAIDs is the prevention of cyclooxygenase (COX) activation. The main mechanism of action of COXs is the synthesis of prostaglandins, some of which have potent inflammatory activity. The discovery of two isoforms of this enzyme, COX-1 and COX-2, and that the latter is inducible by inflammatory cytokines supported the hypothesis that its inhibition would result in a potent antiinflammatory effect and led to the rapid development of selective COX-2 inhibitors, collectively called coxibs. Based on this rationale, some coxibs have been used in clinical trials for AD patients, but all the results obtained so far have been negative. Here, we review our knowledge in terms of COX-2 in the central nervous system, COX-2 and Abeta formation, and finally COX-2 and AD pathogenesis to understand the reasons why these drugs have failed and whether there is any scientific support to keep them as therapeutic tools for this chronic disease.

Townsend KP, Praticò D. · Center for Experimental Therapeutics and Department of Pharmacology; University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania, USA. · FASEB J. · Pubmed #16195368 links to  free full text

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disorder with dementia in the elderly. The AD brain pathology is characterized by deposits of amyloid-beta (Abeta) peptides and neurofibrillary tangles but also (among other aspects) by signs of a chronic inflammatory process. Epidemiological studies have shown that long-term use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of developing AD and delays its onset. Classical targets of NSAIDs include cycloxygenase, nuclear factor kappaB, and peroxisome proliferator-activated receptors. Modulation of these pathways, all of which have been implicated in AD pathogenesis, could explain the NSAID effect on AD progression. However, recent studies indicate that a subset of NSAIDs such as ibuprofen, indomethacin, and flurbiprofen may have direct Abeta-lowering properties in cell cultures as well as transgenic models of AD-like amyloidosis. A renewed interest in the old and a discovery of new pharmacological properties of these drugs are providing vital insight for future clinical trials. In this review we will summarize how the combination of traditional (anti-inflammatory) and new (anti-amyloidogenic) properties of some NSAIDs is providing unprecedented opportunities for drug discovery and could potentially result in novel therapeutic approaches for the treatment of AD.

Praticò D, Rokach J, Lawson J, FitzGerald GA. · Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia, PA 19104, USA. · Chem Phys Lipids. · Pubmed #15037161 No free full text.

Abstract: Isoprostanes are a new class of lipids, isomers of conventional enzymatically derived prostaglandins, which are produced in vivo primarily by a free radical-catalyzed peroxidation of polyunsaturated fatty acids. F2-isoprostanes, isomers of the enzyme-derived prostaglandin F2alpha, are the most studied species. Because of their mechanisms of formation, specific structural features that distinguish them from other free radical-generated products and chemical stability, they provide a reliable index of the oxidative component of several diseases in vivo. Consistent data suggest that formation of F2-isoprostanes is indeed altered in a variety of clinical settings associated with inflammation and oxidant stress. Moreover, measurement of F2-isoprostanes might provide a sensitive biochemical basis of dose-selection in studies of natural and synthetic antioxidants.

Praticò D. · Department of Pharmacology, Center for Experimental Therapeutics School of Medicine, University of Pennsylvania, 421 Curie Blvd., BRB 2/3, Room 812, Philadelphia, PA 19104, USA. · Biochem Pharmacol. · Pubmed #11992623 No free full text.

Abstract: Alzheimer's disease (AD) is the most common form of neurodegenerative disease, with dementia, in the elderly. In addition to the presence of senile plaques and neurofibrillary tangles, the AD brain exhibits evidence for oxygen radical-mediated damage, a situation commonly known as oxidative stress. However, the ability to directly implicate this mechanism in AD has been a difficult task for several reasons. First, most of the analytical approaches used to investigate oxidative stress turned out to be unreliable. Second, the majority of the published studies have been performed in post-mortem tissues with advanced disease, leaving open the question as to whether oxidative stress is an early event or a common final step secondary to the degenerative process. The discovery of the isoprostanes, recent studies performed in living patients, and the development of transgenic animal models of AD-amyloidosis are three important factors that are helping us to better understand and define the role that oxygen radicals might play in AD pathogenesis. Here we review some of the most recent works that have supported the importance of oxygen radical-mediated damage in AD. The accumulated information points toward an earlier involvement than previously thought of oxidative stress in the pathogenesis of the disease, making this a potential target for therapeutic intervention, especially in subjects at high risk for developing AD.

Praticò D, Delanty N. · Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA. · Am J Med. · Pubmed #11063960 No free full text.

Abstract: Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease.

Firuzi O, Zhuo J, Chinnici CM, Wisniewski T, Praticò D. · Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA 19140, USA. · FASEB J. · Pubmed #17998412 links to  free full text

Abstract: 5-Lipoxygenase (5LO), by producing leukotrienes, is a proinflammatory enzyme, and there is evidence suggesting that it is up-regulated with aging and may be involved in Alzheimer's disease (AD). In this paper, we studied the effect of 5LO-targeted gene disruption on the amyloid phenotype of a transgenic mouse model of AD, the Tg2576. Amyloid-beta (Abeta) deposition in the brains of Tg2576 mice lacking 5LO was reduced by 64-80% compared with Tg2576 controls. This reduction was associated with a similar significant decrease in Abeta levels measured by sandwich ELISA. Absence of 5LO did not induce any significant change in amyloid-beta precursor protein (APP) levels and processing, or Abeta catabolic pathways. Furthermore, in vitro studies showed that 5LO activation or 5LO metabolites increase, whereas 5LO inhibition decreases, Abeta formation, secondary to correspondent changes in gamma-secretase activity. These data establish for the first time a novel functional role for 5LO in the pathogenesis of AD-like amyloidosis, thereby modulating gamma-secretase activity. Our work suggests that pharmacological inhibition of 5LO could provide a novel therapeutic tool for AD.

Irizarry MC, Yao Y, Hyman BT, Growdon JH, Praticò D. · Massachusetts Alzheimer's Disease Research Center, Massachusetts General Hospital, Boston, MA, USA. · Neurodegener Dis. · Pubmed #17934322 No free full text.

Abstract: BACKGROUND: Oxidative damage is implicated in the pathophysiology of Alzheimer's disease (AD). F2-isoprostane is a marker of lipid peroxidation which is elevated in AD CSF. Plasma F2-isoprostane has been proposed as a diagnostic marker for AD and mild cognitive impairment (MCI). OBJECTIVE: To determine whether plasma F2-isoprostane levels differ between nondemented control individuals and patients with AD, MCI, or Parkinson's disease (PD). Methods: We collected plasma from191 outpatients with a diagnosis of AD (49), MCI (47), nondemented PD (47), and no dementia (48). Plasma levels of the isoprostane iP2alpha-IV (F2A) were determined by gas chromatography/mass spectroscopy. RESULTS: Mean plasma levels of F2A isoprostane did not differ significantly between the four diagnostic groups. Within the MCI and AD groups, F2A levels did not correlate with duration of memory impairment or with cognitive test scores. F2A levels were marginally lower in users of cholinesterase inhibitors and individuals with an APOE epsilon4 allele. CONCLUSIONS: While CSF isoprostane levels are elevated in AD, plasma isoprostane measures were neither sensitive nor specific for the clinical diagnosis of MCI or AD.

Yao Y, Clark CM, Trojanowski JQ, Lee VM, Praticò D. · Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. · Ann Neurol. · Pubmed #16037976 No free full text.

Abstract: The 12/15 lipoxygenase (12/15LOX) enzyme is increased in pathologically affected frontal and temporal regions of Alzheimer's disease (AD) brains compared with controls. Herein, we measured 12(S)-HETE and 15(S)-HETE levels, products of 12/15LOX, in cerebrospinal fluid (CSF) of normal individuals, subjects with mild cognitive impairment (MCI) and AD. Compared with controls, there was a significant increase of both metabolites in CSF from AD and MCI, which correlated with lipid peroxidation and tau protein levels. These results suggest that the activation of this enzyme occurs early in the course of AD, before the onset of overt dementia, thereby implicating 12/15LOX-mediated lipid peroxidation in the pathogenesis of AD.

Praticò D. · University of Pennsylvania, School of Medicine, Department of Pharmacology, 3620 Hamilton Walk, John Morgan Building, Room 124, Philadelphia, PA 19104, USA. · Neurobiol Aging. · Pubmed #15708431 No free full text.

This publication has no abstract.

Sung S, Yang H, Uryu K, Lee EB, Zhao L, Shineman D, Trojanowski JQ, Lee VM, Praticò D. · Department of Pharmacology, University of Pennsylvania, Philadelphia, PA 19104, USA. · Am J Pathol. · Pubmed #15579461 links to  free full text

Abstract: Epidemiological studies show that some nonsteroidal anti-inflammatory drugs, nonspecific inhibitors of the cyclooxygenase enzyme, reduce the incidence of Alzheimer's disease (AD). We determined the impact of two nonsteroidal anti-inflammatory drugs on A beta levels, deposition, and metabolism in a mouse model (the Tg2576) of AD-like amyloidosis. To this end, mice were treated with indomethacin and nimesulide continuously from 8 months of age until they were 15 months old. At the end of the study, indomethacin significantly reduced A beta(1-40) and A beta(1-42) levels in both cortex and hippocampus. This decrease was coincidental with a significant reduction of the nuclear factor (NF)-kappa B activity. By contrast, nimesulide had no effect on both A beta peptides and NF-kappa B. Consistently, mice receiving indomethacin, but no nimesulide, showed a significant reduction in the amyloid burden compared with placebo. Neither drug had an effect on plasma levels of A beta peptides or the A beta precursor protein metabolism. In vitro studies confirmed that genetic absence of this factor reduces the anti-amyloidogenic effect of indomethacin. These findings indicate that chronic administration of indomethacin by blocking the activation of the NF-kappa B significantly reduces the amyloid pathology in Tg2576 mice, and provide insights into the mechanisms by which this drug could slow progression of AD.

Praticò D, Yao Y, Rokach J, Mayo M, Silverberg GG, McGuire D. · Department of Pharmacology, The Center for Experimental Therapeutics, University of Pennsylvania, School of Medicine, Philadelphia 19104, USA. · J Alzheimers Dis. · Pubmed #15345808 No free full text.

Abstract: Alzheimer's disease (AD) is associated with an increase in cerebrospinal fluid (CSF) levels of the isoprostane 8,12-iso-iPF2alpha-VI, a specific marker of in vivo lipid peroxidation. Poor cerebral clearance of end products of oxidative reactions via CSF circulation may contribute to and sustain ongoing stress. CSF drainage via a low-flow ventriculoperitoneal (VP) shunt may improve removal of these products, reducing oxidative stress. We quantified this biomarker in patients with AD undergoing to VP shunt placement at baseline and after one-year period. CSF sampling occurred at baseline and quarterly visits for one year. Levels of this isoprostane were determined simultaneously at the end of the study by gas chromatography negative ion chemical ionization mass spectrometry. Over one-year, CSF 8,12-iso-iPF2alpha-VI levels consistently decreased versus baseline (51% of initial level), while CSF protein, glucose, cell count and IgG concentrations remained within normal limits. This finding supports the hypothesis that improving CSF drainage enhances extra-cellular clearance of end products of oxidative reactions and lowers brain lipid peroxidation.

Praticò D, Zhukareva V, Yao Y, Uryu K, Funk CD, Lawson JA, Trojanowski JQ, Lee VM. · Center for Experimental Therapeutics, Institute on Aging, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · Am J Pathol. · Pubmed #15111312 links to  free full text

Abstract: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that impairs cognition and behavior. Although the initiating molecular events are not known, increasing evidence suggests that oxidative stress could play a functional role in its pathogenesis. Lipoxygenase (LOX) enzymes by oxidizing polyunsaturated fatty acids synthesize hydroperoxyacids, which are potent pro-oxidant mediators. Because circumstantial evidence suggests that 12/15-LOX is a major source of oxidative stress, we investigated the protein levels and activity of this enzyme in different brain regions of histopathologically confirmed AD and control cases. Using quantitative Western blot analysis we demonstrated that in affected frontal and temporal regions of AD brains the amount of 12/15-LOX was higher compared with controls, whereas no difference between the two groups was detected in the cerebellum. This observation was confirmed by immunohistochemical studies. Levels of 12/15-hydroxyeicosatetraenoic acids, metabolic products of 12/15-LOX, were also markedly elevated in AD brains compared to controls. This increase directly correlated with brain lipid peroxidation, and inversely with vitamin E levels. Finally, genetic deletion of this enzyme in vitro resulted in a reduction of the cellular oxidative stress response after incubation with H2O2 or amyloid beta. These data show that the 12/15-LOX metabolic pathway is increased and correlates with an oxidative imbalance in the AD brain, implying that this enzyme might contribute to the pathogenesis of this neurodegenerative disorder.

Praticò D, Sung S. · Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. · J Alzheimers Dis. · Pubmed #15096701 No free full text.

Abstract: Alzheimer's disease (AD) is a growing public health problem worldwide. Clinically, AD is a progressive neurodegenerative disorder characterized by a global cognitive decline. Accumulating evidence indicates that reactive oxygen species-mediated reactions, particularly of neuronal lipids, are extensive in those AD brain areas directly involved in the disease processes. Traditional views claim that oxidative-mediated tissue injury in the AD brain is the result of neurodegeneration. In recent years, numerous investigations have pointed to the functional importance of oxidative imbalance as a crucial event in mediating AD pathogenesis. The availability of specific and sensitive markers to monitor in vivo oxidative stress, in combination with studies performed in living patients with clinical diagnosis of AD are helping us to elucidate these issues. The evidence we have accumulated so far clearly indicates that oxidative imbalance and subsequent oxidative stress are early events during the evolution of the disease, and secondary to specific mechanism(s) present in AD but not in other neurodegenerative diseases. These new concepts implicate that this phenomenon may play a more important role in AD pathogenesis than previously anticipated, and that any therapeutic intervention targeting oxidative stress should be initiated at the earliest possible stage of the disease.

Sung S, Yao Y, Uryu K, Yang H, Lee VM, Trojanowski JQ, Praticò D. · Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · FASEB J. · Pubmed #14656990 links to  free full text

Abstract: Increased brain oxidative stress is a key feature of Alzheimer's disease (AD) and manifests predominantly as lipid peroxidation. However, clinical evidence that antioxidants can affect the clinical course of the disease is limited. In the present study, we investigated the effect of the antioxidant Vitamin E on the AD-like phenotype when given to a transgenic mouse model (Tg2576) of the disease before or after the amyloid plaques are deposited. One group of Tg2576 received Vitamin E starting at 5 months of age until they were 13 months old, the second group started at 14 months of age until they were 20 months old. Brain levels of 8,12-iso-iPF2alpha-VI, a specific marker of lipid peroxidation, were significantly reduced in both groups of mice receiving Vitamin E compared with placebo. Tg2576 administered with Vitamin E at a younger age showed a significant reduction in Abeta levels and amyloid deposition. By contrast, mice receiving the diet supplemented with Vitamin E at a later age did not show any significant difference in either marker when compared with placebo. These results support the hypothesis that oxidative stress is an important early event in AD pathogenesis, and antioxidant therapy may be beneficial only if given at this stage of the disease process.

Yao Y, Zhukareva V, Sung S, Clark CM, Rokach J, Lee VM, Trojanowski JQ, Praticò D. · Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia 19104, USA. · Neurology. · Pubmed #12939420 No free full text.

Abstract: OBJECTIVE: To quantify the isoprostane 8,12-iso-iPF2alpha-VI in brain tissues obtained from patients with AD, patients with frontotemporal dementia (FTD), and controls. BACKGROUND: Enhanced brain oxidative stress with secondary damage to cellular macromolecules may play a role in the pathogenesis of AD and FTD. The isoprostane 8,12-iso-iPF2alpha-VI is a specific and sensitive marker of in vivo lipid peroxidation and is increased in AD. METHODS: Levels of this isoprostane were determined by gas chromatography/negative ion chemical ionization mass spectrometry. RESULTS: Levels of 8,12-iso-iPF2alpha-VI were markedly elevated in both frontal and temporal cortex of AD brains compared to the corresponding areas of FTD and controls. No significant difference in brain 8,12-iso-iPF2alpha-VI levels for any regions considered was observed between FTD and controls. CONCLUSIONS: Lipid peroxidation is a feature of AD, but not FTD. The generation of 8,12-iso-iPF(2alpha)-VI in the brain is not a general or final common pathway of neurodegeneration, but may be relatively specific for disease processes in AD and not FTD.

Praticò D, Clark CM, Liun F, Rokach J, Lee VY, Trojanowski JQ. · Center for Experimental Therapeutics, University of Pennsylvania, BRB II/III, Room 812, 421 Curie Blvd, Philadelphia, PA 19104. · Arch Neurol. · Pubmed #12056933 links to  free full text

Abstract: BACKGROUND: The isoprostane 8,12-iso-iPF(2alpha)-VI, a specific marker of in vivo lipid peroxidation, is increased in Alzheimer disease (AD). The pathological changes associated with AD have a long silent phase before the appearance of clinical symptoms. Several studies have shown that AD is preceded by a prodromal phase characterized by mild cognitive impairment (MCI). OBJECTIVE: To investigate levels of this biomarker in subjects with MCI. DESIGN AND MAIN OUTCOME MEASURES: Using gas chromatography-mass spectrometry analysis, we measured 8,12-iso-iPF(2alpha)-VI levels in urine, plasma, and cerebrospinal fluid of patients with AD, subjects with MCI, and cognitively normal elderly subjects. SETTING AND PATIENTS: Subjects attending the Memory Disorders Clinic. RESULTS: We found significantly higher 8,12-iso-iPF(2alpha)-VI levels in cerebrospinal fluid, plasma, and urine of subjects with MCI compared with cognitively normal elderly subjects. CONCLUSIONS: These results imply that individuals with MCI have increased brain oxidative damage before the onset of symptomatic dementia. Measurement of this isoprostane may identify a subgroup of patients with MCI with increased lipid peroxidation who are at increased risk to progress to symptomatic AD.

Uryu K, Laurer H, McIntosh T, Praticò D, Martinez D, Leight S, Lee VM, Trojanowski JQ. · Department of Pathology and Laboratory Medicine, Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-4283, USA. · J Neurosci. · Pubmed #11784789 links to  free full text

Abstract: Traumatic brain injury (TBI) increases susceptibility to Alzheimer's disease (AD), but it is not known how TBI contributes to the onset or progression of this common late life dementia. To address this question, we studied neuropathological and behavioral consequences of single versus repetitive mild TBI (mTBI) in transgenic (Tg) mice (Tg2576) that express mutant human Abeta precursor protein, and we demonstrate elevated brain Abeta levels and increased Abeta deposition. Nine-month-old Tg2576 and wild-type mice were subjected to single (n = 15) or repetitive (n = 39) mTBI or sham treatment (n = 37). At 2 d and 9 and 16 weeks after treatment, we assessed brain Abeta deposits and levels in addition to brain and urine isoprostanes generated by lipid peroxidation in these mice. A subset of mice also was studied behaviorally at 16 weeks after injury. Repetitive but not single mTBI increased Abeta deposition as well as levels of Abeta and isoprostanes only in Tg mice, and repetitive mTBI alone induced cognitive impairments but no motor deficits in these mice. This is the first experimental evidence linking TBI to mechanisms of AD by showing that repetitive TBI accelerates brain Abeta accumulation and oxidative stress, which we suggest could work synergistically to promote the onset or drive the progression of AD. Additional insights into the role of TBI in mechanisms of AD pathobiology could lead to strategies for reducing the risk of AD associated with previous episodes of brain trauma and for preventing progressive brain amyloidosis in AD patients.

Praticò D, Uryu K, Leight S, Trojanoswki JQ, Lee VM. · Center for Experimental Therapeutics and Department of Pharmacology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA. · J Neurosci. · Pubmed #11404403 links to  free full text

Abstract: Oxidative stress is a key feature in the Alzheimer's disease (AD) brain and manifests as lipid peroxidation (LPO). Isoprostanes (iPs) are specific and sensitive markers of in vivo LPO. To determine whether amyloid beta (Abeta) deposition in vivo is associated with increased LPO, we examined iP levels in a transgenic mouse model (Tg2576) of AD amyloidosis. Urine, plasma, and brain tissues were collected from Tg2576 and littermate wild-type (WT) animals at different time points starting at 4 months of age and continuing until 18 months of age. Levels of urinary 8,12-iso-iPF(2alpha)-VI were higher in Tg2576 than in WT animals as early as 8 months of age and remained this high for the rest of the study. A similar pattern was observed for plasma levels of 8,12-iso-iPF(2alpha)-VI. Homogenates from the cerebral cortex and hippocampus of Tg2576 mice had higher levels of 8,12-iso-iPF(2alpha)-VI than those from WT mice starting at 8 months of age. In contrast, a surge of Abeta 1-40 and 1-42 levels as well as Abeta deposits in Tg2576 mouse brains occurred later, at 12 months of age. A direct correlation was observed between brain 8,12-iso-iPF(2alpha)-VI and Abeta 1-40 and 1-42. Because LPO precedes amyloid plaque formation in Tg2576 mice, this suggests that brain oxidative damage contributes to AD pathogenesis before Abeta accumulation in the AD brain.

Praticò D, Clark CM, Lee VM, Trojanowski JQ, Rokach J, FitzGerald GA. · Center for Experimental Therapeutics, University of Pennsylvania, Philadelphia 19104, USA. · Ann Neurol. · Pubmed #11079549 No free full text.

Abstract: The isoprostane 8,12-iso-iPF2alpha-VI is a sensitive and specific marker of in vivo lipid peroxidation. We found elevated levels in the urine, blood, and cerebrospinal fluid of patients with Alzheimer's disease (AD) that correlated with measures of cognitive and functional impairment, established biomarkers of AD pathology (cerebrospinal fluid tau and amyloid) and the number of apolipoprotein E epsilon4 alleles. These results suggest that 8,12-iso-iPF2alpha-VI is a useful biomarker of oxidative damage in AD.

Praticò D, Trojanowski JQ. · The Center for Experimental Therapeutics, Department of Pharmacology, University of Pennsylvania, School of Medicine, Philadelphia, PA 19104, USA. · Neurobiol Aging. · Pubmed #10858591 No free full text.

This publication has no abstract.