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ABSTRACT: Soluble oligomeric Aβ has been suggested to impair synaptic and neuronal function, leading to neurodegeneration that is clinically observed as the memory and cognitive dysfunction characteristic of Alzheimer disease, while the precise mechanism(s) whereby oligomeric Aβ causes neurotoxicity remains unknown. Recently, the cellular prion protein (PrP (C) ) was reported to be an essential co-factor in mediating the neurotoxic effect of oligomeric Aβ. Our recent study showed that Prnp (-/-) mice are resistant to the neurotoxic effect of oligomeric Aβ in vivo and in vitro. Furthermore, application of an anti-PrP (C) antibody or PrP (C) peptide was able to block oligomeric Aβ-induced neurotoxicity. These findings demonstrate that PrP (C) may be involved in neuropathologic conditions other than conventional prion diseases, i.e., Creutzfeldt-Jakob disease.
Prion 11/2012; 7(2). · 2.85 Impact Factor
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Neurotoxicity Research 07/2012; · 3.51 Impact Factor
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ABSTRACT: This issue of Neurotoxicity Research honors Mark A. Smith. While we will never know the plan that suddenly took him from us almost 2 years ago, his pioneering work and original ideas will live on and influence contemporary thought in Alzheimer disease (AD) research. Mark defined the first oxidative modifications found in AD and pioneered the foundation for cell cycle alteration and metabolic changes. He was also known for questioning the amyloid cascade hypothesis, providing evidence that amyloid-β (Aβ) and tau are protective responses to brain injury. Consequently, his efforts were concentrated on connecting AD to biology, leading to the two-hit hypothesis and other theories which focused on the pleiotropic threshold between pathology and physiology. In his early work, Mark demonstrated oxidative modification of every category of biological macromolecule: protein, carbohydrate, lipids, and nucleic acids. But it was Mark’s rapid comprehension that oxidative damage is countered by an antioxidant response that bound his ideas. Coincident with pathology he reported protective physiological responses and cell cycle re-entry. These findings defined a new concept in oxidative stress, one of homeostasis where radicals do not breach defenses, but a new balance is reached, designed to protect cells from death. Mark’s work on neuronal death changed the view of neuronal apoptosis; rather than dying, neurons in AD resist death through induction of many of the pathways linked to apoptosis, but without completion of the death response these changes played a role in neuronal survival.
In this special issue, we have been fortunate to gather foremost experts in the field to discuss the current state of these exciting areas. We thank the contributors that remind us of Mark’s great vision and contributions to understanding the pathogenesis of AD. We also owe a great debt of gratitude to Dr. Richard Kostrzewa for the opportunity to compile this issue. Lastly, we hope that the contributions from Mark’s legacy will continue to contribute to further research on finding the cure for AD.
edited by Hyoung-gon Lee, George Perry, Xiongwei Zhu, 07/2012; Springer., ISBN: 1029-8428
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ABSTRACT: An age-associated increase in oxidative damage to nucleic acids, predominantly to RNA, has been recently demonstrated in neurons of human and rodent brains, which may play a fundamental role in the development of age-associated neurodegeneration. Indeed, more prominent levels of neuronal RNA oxidation compared to normal aging have been described in neurodegenerative disorders including Alzheimer disease, Parkinson disease, dementia with Lewy bodies, and amyotrophic lateral sclerosis. Moreover, oxidative damage to RNA has been found also in cellular and animal model of neurodegeneration. Oxidative RNA modification can occur not only in protein-coding RNAs but also in non-coding RNAs that are recently revealed to contribute towards the complexity of the mammalian brain. It has been hypothesized that RNA oxidation causes aberrant expression of microRNAs and proteins and subsequently initiates inappropriate cell fate pathways. While less lethal than mutations in the genome and not inheritable, such sublethal damage to cells might be associated with underlying mechanisms of degeneration, especially age-associated neurodegeneration. Of particular interest, the accumulating evidence obtained from studies on either human samples or experimental models coincidentally suggests that RNA oxidation is a feature in neurons of aging brain and more prominently observed in vulnerable neurons at early-stage of age-associated neurodegenerative disorders, indicating that RNA oxidation actively contributes to the background, the onset, and the development of the disorders. Further investigations aimed at understanding of the processing mechanisms related to oxidative RNA damage and its consequences may provide significant insights into the pathogenesis of neurodegenerative disorders and lead to better therapeutic strategies.
Neurotoxicity Research 06/2012; 22(3):231-48. · 3.51 Impact Factor
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ABSTRACT: Alzheimer's disease (AD) exhibits a complex etiology that simultaneously manifests as a complex cellular, neurobiological, molecular, anatomic-physiological and clinical entity. Other significant psychiatric conditions, such as depression and schizophrenia, may also present with complex and concurrent clinical and/or molecular phenotypes. These neuropsychiatric pathologies also originate from both environmental and genetic factors. We analyzed the molecular phenotypes of AD and discuss them with respect to the classical theories, which we integrated into mechanisms that share molecular and/or anatomical connections. Based on these mechanisms, we propose an interaction model and discuss the model in light of studies that refute or support it. Given the spectrum of AD phenotypes, we limit the scope of our discussion to a few, which facilitates concrete analysis. In addition, the study of specific, individual pathogenic phenotypes may be critical to defining the complex mechanisms leading to AD, thereby improving strategies for developing novel therapies.
Future Neurology 05/2012; 7(3):287-305.
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Bo Su,
Haihua Liu,
Xinglong Wang,
Shu G Chen,
Sandra L Siedlak,
Eisaku Kondo,
Raymond Choi,
Atsushi Takeda,
Rudy J Castellani,
George Perry,
Mark A Smith,
Xiongwei Zhu, Hyoung-gon Lee
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ABSTRACT: Lewy bodies and Lewy neurites constitute the cardinal neuropathological features of both Parkinson's disease (PD) and Lewy
body dementia (LBD). Whereas α-synuclein has been found to be the major component of the Lewy body, the mechanisms by which
neurons degenerate, as well as basic mechanisms involved in the formation of α-synuclein-related inclusions, remain obscure.
We have suggested previously that potential mechanisms are likely to leave a "molecular signature" or protein adduct within
the Lewy body, and have found examples of such signatures in previous studies. In this study, we demonstrate increased FOXO3
in association with Lewy bodies and Lewy neurites in LBD and PD brain tissue. Since FOXO proteins are involved in several
pathways responsible for the regulation of cell death, cell proliferation, and cell metabolism, the ectopic localization of
FOXO3 to Lewy bodies provides evidence that aberrations in basic cellular biochemistry may contribute to inclusion formation,
which is likely more complex than a simple "gain of function" toxicity as is commonly opined. In light of the known interaction
of FOXO3 and 14-3-3, basic protein-protein interaction between these proteins and α-synuclein may be key.
Molecular Neurodegeneration 04/2012; 4(1):1-5. · 4.28 Impact Factor
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ABSTRACT: Oxidative stress is a striking feature of susceptible neurons in the Alzheimer’s disease brain. Importantly, because oxidative
stress is an early event in Alzheimer’s disease, proximal to the development of hallmark pathologies, it likely plays an important
role in the pathogenesis of the disease. Investigations into the cause of such oxidative stress show that interactions between
abnormal mitochondria and disturbed metal metabolism are, at least in part, responsible for cytoplasmic oxidative damage observed
in these susceptible neurons, which could ultimately lead to their demise. Oxidative stress not only temporally precedes the
pathological lesions of the disease but could also contribute to their formation, which, in turn, could provide some protective
mechanism to reduce oxidative stress and ensure that neurons do not rapidly succumb to oxidative insults. In this review,
we present the evidence for oxidative stress in Alzheimer’s disease and its likely sources and consequence in relation to
other pathological changes.
Molecular Neurobiology 04/2012; 31(1):205-217. · 5.74 Impact Factor
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ABSTRACT: Senescence-accelerated mice 8 (SAMP8), a model of aging, display many established pathological features of Alzheimer's disease (AD); however, whether cell cycle alterations exist in these animals remains unknown. Given that these animals present changes such as tau phosphorylation and redox imbalance, both associated with cell cycle alterations, we determined whether changes in cell cycle markers were present in SAMP8 and SAMR1 (control strain) at 3, 6, and 9 months-old brains. As expected, an increase in tau hyperphosphorylation and its associated machinery, i.e., cdk5 and GSK3β, was observed both between strains and also with aging. Particularly, significant differences in cyclin A, cyclin D1, cyclin E, Cdk2, cyclin B, pR, and E2F1 were found when comparing SAMP8 to SAMR1. More interestingly, a partial correlation with several cell cycle markers described in AD brain is found in SAMP8, indicating that some specific hallmarks of AD are also present in this strain, which has been postulated as an early switch model of the disease.
Journal of Alzheimer's disease: JAD 03/2012; 30(3):573-83. · 3.74 Impact Factor
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ABSTRACT: The nervous system interacts directly with the endocrine system to control a plethora of central nervous system (CNS) functions. Metabolic and reproductive hormones are known to be important in the maintenance of neuronal health and their fluctuations are important for CNS aspects ranging from sleep and appetite regulation to cognitive function. This review will summarize and critically evaluate how age-related changes in sex and metabolic hormones modulate affect cognitive function and the implications of targeting the neuroendocrinological system as a therapeutic strategy in Alzheimer's disease.
BioFactors 03/2012; 38(2):123-32. · 4.93 Impact Factor
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Darwin Jeyaraj,
Frank A J L Scheer,
Jürgen A Ripperger,
Saptarsi M Haldar,
Yuan Lu,
Domenick A Prosdocimo,
Sam J Eapen,
Betty L Eapen,
Yingjie Cui,
Ganapathi H Mahabeleshwar, [......],
Mark A Smith,
Gemma Casadesus,
Eric M Mintz,
Haipeng Sun,
Yibin Wang,
Kathryn M Ramsey,
Joseph Bass,
Steven A Shea,
Urs Albrecht,
Mukesh K Jain
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ABSTRACT: Diurnal variation in nitrogen homeostasis is observed across phylogeny. But whether these are endogenous rhythms, and if so, molecular mechanisms that link nitrogen homeostasis to the circadian clock remain unknown. Here, we provide evidence that a clock-dependent peripheral oscillator, Krüppel-like factor 15 transcriptionally coordinates rhythmic expression of multiple enzymes involved in mammalian nitrogen homeostasis. In particular, Krüppel-like factor 15-deficient mice exhibit no discernable amino acid rhythm, and the rhythmicity of ammonia to urea detoxification is impaired. Of the external cues, feeding plays a dominant role in modulating Krüppel-like factor 15 rhythm and nitrogen homeostasis. Further, when all behavioral, environmental and dietary cues were controlled in humans, nitrogen homeostasis exhibited an endogenous circadian rhythmicity. Thus, in mammals, nitrogen homeostasis exhibits circadian rhythmicity, and is orchestrated by Krüppel-like factor 15.
Cell metabolism 03/2012; 15(3):311-23. · 17.35 Impact Factor
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Journal of Neurochemistry 03/2012; 120(6):1139-40. · 4.06 Impact Factor
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ABSTRACT: Although neuronal RNA oxidation is a prominent and established feature in age-associated neurodegenerative disorders such as Alzheimer disease (AD), oxidative damage to neuronal RNA in aging and in the transitional stages from normal elderly to the onset of AD has not been fully examined. In this study, we used an in situ approachto identify an oxidized RNA nucleoside 8-hydroxyguanosine (8OHG) in the cerebral cortex of 65 individuals without dementia ranging in age from 0.3 to 86 years. We also examined brain samples from 20 elderly who were evaluated for their premortem clinicaldementia rating score and postmortem brain pathologic diagnoses to investigate preclinical AD and mild cognitive impairment. Relative density measurements of 8OHG-immunoreactivity revealed a statistically significant increase in neuronal RNA oxidation during aging in the hippocampus and the temporal neocortex. In subjects with mild cognitive impairment but not preclinical AD, neurons of the temporal cortex showed a higher burden of oxidized RNA compared to age-matched controls. These results indicate that, although neuronal RNA oxidation fundamentally occurs as an age-associated phenomenon, more prominent RNA damage than in normal aging correlates with the onset of cognitive impairment in the prodromal stage of AD.
Journal of Neuropathology and Experimental Neurology 03/2012; 71(3):233-41. · 4.26 Impact Factor
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ABSTRACT: A recently developed bivalent ligand BMAOI 14 (7) has been evaluated for its capability to label and detect aggregated β-amyloid (Aβ) peptide as a fluorescent probe. This probe contains curcumin as the Aβ recognition moiety and cholesterol as an anchorage to the neuronal cell membrane/lipid rafts. The results demonstrate that 7 binds to the monomers, oligomers as well as fibrils of Aβ42 with low micromolar to submicromolar binding affinities. This chemical probe also has many of the required optical properties for use in imaging and can rapidly cross the blood-brain barrier (BBB) in vivo. Furthermore, 7 specifically binds to Aβ plaques in both AD human patients and APP transgenic mouse brain tissues. Collectively, these results suggest that 7 is a strong candidate as an Aβ-imaging agent and encourage further optimization of 7 as a new lead to develop the next generation of Aβ-imaging probes.
ACS Chemical Neuroscience 02/2012; 3(2):141-146. · 3.68 Impact Factor
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ABSTRACT: While oxidative stress has been linked to Alzheimer's disease, the underlying pathophysiological relationship is unclear. To examine this relationship, we induced oxidative stress through the genetic ablation of one copy of mitochondrial antioxidant superoxide dismutase 2 (Sod2) allele in mutant human amyloid precursor protein (hAPP) transgenic mice. The brains of young (5-7 months of age) and old (25-30 months of age) mice with the four genotypes, wild-type (Sod2(+/+)), hemizygous Sod2 (Sod2(+/-)), hAPP/wild-type (Sod2(+/+)), and hAPP/hemizygous (Sod2(+/-)) were examined to assess levels of oxidative stress markers 4-hydroxy-2-nonenal and heme oxygenase-1. Sod2 reduction in young hAPP mice resulted in significantly increased oxidative stress in the pyramidal neurons of the hippocampus. Interestingly, while differences resulting from hAPP expression or Sod2 reduction were not apparent in the neurons in old mice, oxidative stress was increased in astrocytes in old, but not young hAPP mice with either Sod2(+/+) or Sod2(+/-). Our study shows the specific changes in oxidative stress and the causal relationship with the pathological progression of these mice. These results suggest that the early neuronal susceptibility to oxidative stress in the hAPP/Sod2(+/-) mice may contribute to the pathological and behavioral changes seen in this animal model.
PLoS ONE 01/2012; 7(1):e28033. · 4.09 Impact Factor
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ABSTRACT: Down syndrome (DS) individuals are at high risk for developing Alzheimer's disease (AD) and consequently provide a unique opportunity to examine the factors leading to the onset of AD. This paper focuses on the neglected vascular parallels between AD and DS that can readily be examined in DS. Several recent AD studies provide evidence that internal jugular vein (IJV) reflux may result in white matter lesions and a 30% decrease in cerebrospinal fluid (CSF) clearance of amyloid-β. At the same time, studies analyzing the synthesis of amyloid-β in DS showed greater than expected amounts of Aβ than would be predicted by the increase in gene dosage, perhaps due to slower clearance. These studies are discussed along with the possibility that the venous and CSF dysfunction found in AD patients may be present early in life in persons with DS, leaving them particularly vulnerable to early onset AD. Studying IJV function in DS provides an opportunity to understand the role of vascular function in the initiation of AD.
Current Gerontology and Geriatrics Research 01/2012; 2012:929734.
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ABSTRACT: Over a year has passed since Mark A. Smith’s death, and a
void remains. His baritone voice, endless enthusiasm, support
of colleagues (often transformed to friends) and family, and for
the readers here, his ability to integrate and effectively communicate
novel views of pathophysiology are irreplaceable.
Mark was often labeled a personal and professional rebel,
by those who saw his fearlessly alternative views, concurrent
work with numerous biotechnology firms, and real estate ventures.
In contrast, those close to him know that Mark held
fundamental values of truth, community, family, and consistency.
In arguing the role of amyloid-� (A�), Mark came to the view
after meticulous consideration of data, that it might be a protective
response that contrasted with a purely toxic role, a
view that may have lost grants and gained scoffs. Yet Mark
was undeterred. He let his knowledge and observations guide
him—what could be more fundamental? Fear was not part of
the equation, knowing as he did that fundamentals will endure.
After over a decade of Mark’s questioning of the A� cascade,
his views continue to be supported by additional evidence and
failure of benefit from A� removal.
Family and community values guided his devotion to his wife,
children, friends, colleagues, and community development, as
it also did his interest where he could make a difference for
patients suffering from Alzheimer’s disease.
The void Mark left remains a fountain of strength as others
attempt to tackle the intractable issues necessary to impact
Alzheimer’s disease
Coordination Chemistry Reviews 01/2012; 256(19-20):2127-2128. · 12.11 Impact Factor
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The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 01/2012; 39(1):4. · 0.97 Impact Factor
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ABSTRACT: The study of Alzheimer's disease neuropathology has been intimately associated with the field of oxidative stress for nearly 20 years. Indeed, increased markers of oxidative stress have been associated with this neurodegenerative condition, resulting from oxidation of lipids, proteins and nucleic acids. Increased nuclear and mitochondrial DNA oxidation are observed in Alzheimer's disease, stemming from increased reactive oxygen species attack to DNA bases and from the impairment of DNA repair mechanisms. Moreover, mitochondrial DNA is found to be more extensively oxidized than nuclear DNA. This review is intended to summarizes the most important cellular reactive oxygen species producers and how mitochondrial dysfunction, redox-active metals dyshomeostasis and NADPH oxidases contribute to increased oxidative stress in Alzheimer's disease. A summary of the antioxidant system malfunction will also be provided. Moreover, we will highlight the mechanisms of DNA oxidation and repair. Importantly, we will discuss evidence relating the DNA repair machinery and accumulated DNA oxidation with Alzheimer's disease.
Free radical research 12/2011; 46(4):565-76. · 2.22 Impact Factor
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Rudy J Castellani,
Yashi Gupta,
Baiyang Sheng,
Sandra L Siedlak,
Peggy Lr Harris,
Jeff M Coller,
George Perry, Hyoung-Gon Lee,
Massimo Tabaton,
Mark A Smith,
Xinglong Wang,
Xiongwei Zhu
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ABSTRACT: The phosphorylated ribosomal protein S6 (pS6) is associated with the 40S ribosomal subunit in eukaryotes and is thought to have a role in RNA storage, degradation, and re-entry into translation. In this study, we found pS6 localized to granulovacuolar degeneration (GVD) within the pyramidal neurons. Immunohistochemical analysis found that nearly 20-fold more neurons contain pS6-positive granules in Alzheimer's disease (AD) hippocampus compared with age-matched controls. Further, pS6-positive granules were more common in neurons not containing neurofibrillary tangles (NFTs), were never associated with extracellular NFTs or in apoptotic neurons, and contained less RNA than neighboring pyramidal neurons not containing pS6-positive granules. In model systems, pS6 is a specific marker for stress granules, and another stress granule protein, p54/Rck, was also found to be a component of GVD in the current study. Stress granules are transient, intracellular, dense aggregations of proteins and RNAs that accumulate as a stress response, protecting cells from apoptosis and inappropriate transcriptional activity, often described as a form of 'molecular triage.' The RNA oxidation modification 8-hydroxyguanosine (8OHG) is strikingly increased in AD, yet this study reports that those neurons with pS6 granules display reduced RNA oxidation demonstrated by lower levels of 8OHG. Since chronic oxidative stress is central to AD pathogenesis, and RNA is a specific oxidative stress target and is intimately associated with stress granule biogenesis in model systems, we suggest that GVD in human brain parallel stress granules, and may in fact be more representative of early disease pathogenesis than traditionally believed. This proposed origin for GVD as a neuroprotective response, may represent a morphologic checkpoint between cell death and reversible cellular stress that proceeds in the absence of other inclusions.
Laboratory Investigation 12/2011; 91(12):1777-86. · 3.64 Impact Factor
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ABSTRACT: In Alzheimer disease (AD), amyloid-β (Aβ) oligomer is suggested to play a critical role in imitating neurodegeneration, although its pathogenic mechanism remains to be determined. Recently, the cellular prion protein (PrP(C)) has been reported to be an essential co-factor in mediating the neurotoxic effect of Aβ oligomer. However, these previous studies focused on the synaptic plasticity in either the presence or the absence of PrP(C) and no study to date has reported whether PrP(C) is required for the neuronal cell death, the most critical element of neurodegeneration in AD. Here, we show that Prnp(-/-) mice are resistant to the neurotoxic effect of Aβ oligomer in vivo and in vitro. Furthermore, application of an anti-PrP(C) antibody or PrP(C) peptide prevents Aβ oligomer-induced neurotoxicity. These findings are the first to demonstrate that PrP(C) is required for Aβ oligomer-induced neuronal cell death, the pathology essential to cognitive loss.
Human Molecular Genetics 11/2011; 21(5):1138-44. · 7.64 Impact Factor
