Search PubMed⌕ Search

Biomedical subjects

George Perry

Publications and source records attributed to George Perry.

At least 145 records · Page 8Linked to original sources
PubMed2002

Is oxidative damage the fundamental pathogenic mechanism of Alzheimer's and other neurodegenerative diseases?

In less than a decade, beginning with the demonstration by Floyd, Stadtman, Markesbery et al. of increased reactive carbonyls in the brains of patients with Alzheimer's disease (AD), oxidative damage has been established as a feature of the disease. Here, we review the types of oxidative damage seen in AD, sites involved, possible origin, relationship to lesions, and compensatory changes, and we also consider other neurodegenerative diseases where oxidative stress has been implicated. Although much data remain to be collected, the broad spectrum of changes found in AD are only seen, albeit to a lesser extent, in normal aging with other neurodegenerative diseases showing distinct spectrums of change.

Alzheimer Disease↗
PubMed2002

Neuronal RNA oxidation is a prominent feature of dementia with Lewy bodies.

An approach was used to identify the oxidized nucleoside, 8-hydroxyguanosine in brains of dementia with Lewy bodies. Neurons with marked immunoreaction of 8-hydroxyguanosine in the cytoplasm were widely distributed in the hippocampal region and temporal neocortex. Relative intensity measurements of neuronal 8-hydroxyguanosine immunoreactivity showed that there was a significant increase in nucleic acid oxidation in dementia with Lewy bodies compared with controls. Treatment with nuclease (DNase or RNase) before the immunostaining demonstrated that RNA was a major site of nucleic acid oxidation. Together with the previously reported RNA oxidation in vulnerable neurons in Alzheimer and Parkinson diseases, neuronal RNA oxidation in dementia with Lewy bodies might represent one of the fundamental abnormalities in age-associated neurodegenerative diseases.

Aged↗
PubMed2002

Role of mitochondrial dysfunction in Alzheimer's disease.

Abnormalities in mitochondrial function relate to the spectrum of pathological changes seen in Alzheimer's disease. Here we review the causes and consequences of mitochondrial disturbances in Alzheimer's disease as well as how this information might impact on therapeutic approaches to this disease.

Alzheimer Disease↗
PubMed2002

Elevated luteinizing hormone expression colocalizes with neurons vulnerable to Alzheimer's disease pathology.

In individuals with Alzheimer's disease (AD), there is a two-fold elevation in the serum concentrations of the gonadotropins, luteinizing hormone (LH), and follicle stimulating hormone compared to age-matched controls. Whether this plays a role in disease pathogenesis is unclear. Nonetheless, gonadotropins are known to cross the blood brain barrier and the highest density of gonadotropin receptors in the brain are found within the hippocampus. We report for the first time the localization of LH in the cytoplasm of pyramidal neurons. In addition, we find a significant increase in LH in the cytoplasm of pyramidal neurons and neurofibrillary tangles of AD brain compared to age-matched control brain. Whereas the functional consequences of increased neuronal LH are unknown, it is notable that LH is primarily localized to those neurons that are known to be vulnerable to Alzheimer's disease-related neurodegeneration. Elevated serum and cortical neuron levels of LH, coupled with the decline in sex steroid production, could play important roles in the pathogenesis of AD.

Aged↗
PubMed2002

Amyloid-beta and tau serve antioxidant functions in the aging and Alzheimer brain.

Historically, amyloid-beta and tau (tau), the major components of senile plaques and neurofibrillary tangles, respectively, have been considered central mediators of the pathogenesis of Alzheimer disease. Therefore, efforts to understand disease mechanisms have concentrated on understanding either the processes involved in amyloid-beta deposition as senile plaques or on the phosphorylation and aggregation of tau as neurofibrillary tangles. However, in light of recent evidence, such "lesion-centric" approaches look to be inappropriate. In fact, rather than initiators of disease pathogenesis, the lesions occur consequent to oxidative stress and function as a primary line of antioxidant defense. Given this, it is perhaps not surprising that the increased sensitivity to oxidative stress in the aged brain, even in control individuals, is invariably marked by the appearance of both amyloid-beta and tau. Additionally, in Alzheimer disease, where chronic oxidative stress persists and is superimposed upon an age-related vulnerable environment, one would predict, and there is, an increased lesion load. The notion that amyloid-beta and tau function as protective components brings into serious question the rationale of current therapeutic efforts targeted toward lesion removal.

Aging↗
PubMed2002

Mitochondrial abnormalities and oxidative imbalance in neurodegenerative disease.

An increasing body of evidence now suggests the involvement of mitochondrial abnormalities in the etiology of neurodegenerative diseases, such as Parkinson's disease (PD) and Alzheimer disease. In this Perspective, we describe a recent study that shows that treatment of human patients with the antioxidant coenzyme Q(10'), which functions in concert with certain mitochondrial enzymes, reduced the worsening of symptoms associated with PD. These findings are consistent with the hypothesis that mitochondrial dysfunction plays a role in the pathogenesis of PD and that treatments that target mitochondrial biochemistry might ameliorate the functional decline observed in patients suffering from PD.

Coenzymes↗
PubMed2002

Cholesterol, oxidative stress, and Alzheimer's disease: expanding the horizons of pathogenesis.

Recent epidemiological, clinical, and experimental data suggest that cholesterol may play a role in Alzheimer's disease (AD). We have recently shown that cholesterolemia has a profound effect in the development and modulation of amyloid pathology in a transgenic model of AD. This review summarizes recent advancements in our understanding of the potential role of cholesterol and the amyloid beta protein in initiating the generation of free radicals and points out their role in a chain of events that causes damage of essential macromolecules in the central nervous system and culminates in neuronal dysfunction and loss. Experimental data links cholesterol and oxidative stress with some neurodegenerative aspects of AD.

Alzheimer Disease↗
PubMed2002

Hydroxynonenal adducts indicate a role for lipid peroxidation in neocortical and brainstem Lewy bodies in humans.

Multiple lines of evidence indicate that oxidative stress is a critical pathogenic factor in Parkinson disease (PD) and diffuse Lewy body disease (DLBD). Previously, we demonstrated increased levels of redox-active iron in Lewy bodies, and that Lewy bodies accumulate advanced glycation end-products. To further characterize the role of oxidative stress in diseases with Lewy body formation, we examined immunocytochemically eight cases of PD and five cases of DLBD for adducts of the lipid peroxidation adduct 4-hydroxy-2-nonenal, and for N(epsilon)-(carboxymethyl)lysine (CML). Our findings demonstrate immunolocalization of 4-hydroxynonenal and CML to Lewy bodies in PD and DLBD. These findings not only support prior studies indicating that lipid peroxidation is increased in patients with PD and DLBD but that oxidative damage may play a critical role in Lewy body formation.

Adult↗
PubMed2002

Systemic increase of oxidative nucleic acid damage in Parkinson's disease and multiple system atrophy.

8-hydroxy-2'-deoxyguanosine (8-OHdG) or 8-hydroxyguanosine (8-OHG), a product of oxidized DNA or RNA, is a good marker of oxidative cellular damage. In this study, we measured the 8-OHdG/8-OHG levels in the serum and cerebrospinal fluid (CSF) of patients with Parkinson's disease (PD) and multiple system atrophy (MSA). Compared to age-matched controls, the mean levels of serum 8-OHdG/8-OHG were significantly higher in PD (P < 0.0001). Although no gender differences were observed in the controls, the mean values of serum 8-OHdG/8-OHG were significantly higher in female PD cases (P < 0.005) than in male patients. 8-OHdG/8-OHG levels in CSF were also increased significantly in patients with PD and MSA, however, their relative values were generally much lower than those in the serum. Together with previous studies showing increased peripheral 8-OHdG levels in Alzheimer's disease and amyotrophic lateral sclerosis, the data presented here suggest that systemic DNA/RNA oxidation is commonly observed in neurodegenerative diseases. Our results also imply that female patients with PD show higher levels of oxidative stress, which may explain the faster progression of this disease in females.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2002

Oxidative damage to nucleic acids in human prion disease.

Recently, several studies proposed a physiological role for the cellular prion protein (PrP(c)) in defense against oxidative stress. Since the pathogenesis of prion disease necessarily involves a disturbance of PrP(c) homeostasis, we hypothesized that such diseases would be associated with concomitant disturbances in oxidative balance. In support of such a notion, in this study we show increased oxidative damage to nucleic acids in affected brains of patients with Creutzfeldt-Jakob disease. These data suggest that damage by free radicals is a likely cause for neurodegeneration in human prion disease, and antioxidants are a potential therapy for these disorders. Further, our data support the hypothesis that loss of the anti-oxidant function of PrP(c) plays a key role in the pathogenesis of these disorders.

Adult↗
PubMed2002

Oxidative stress increases expression and activity of BACE in NT2 neurons.

Recently an aspartyl protease with beta-secretase activity called BACE was identified. In the present paper we showed that BACE is modulated by the oxidative stress product 4-hydroxynonenal (HNE). Exposure of NT(2) neurons to the two classical pro-oxidant stimuli ascorbate/FeSO(4) and H(2)O(2)/FeSO(4) resulted in a significant generation of HNE, which is temporally followed by an increased production of BACE protein levels. HNE mediated BACE induction is accompanied by a proportional elevation of carboxy-terminal fragments of amyloid precursor protein. Moreover, the direct relationship between BACE induction and lipid peroxidation products was strongly confirmed by the protection exerted by a short pretreatment with alpha-tocopherol, the most important antioxidant known to prevent the formation of aldehydic end-products of lipid peroxidation, including HNE. Our results support the hypothesis that oxidative stress and A beta production are strictly interrelated events and suggest that inhibition of BACE may have a therapeutic effect synergic with antioxidant compounds.

Aldehydes↗
PubMed2002

The state versus amyloid-beta: the trial of the most wanted criminal in Alzheimer disease.

Investigators studying the primary culprit responsible for Alzheimer disease have, for the past two decades, primarily focused on amyloid-beta (Abeta). Here, we put Abeta on trial and review evidence amassed by the prosecution that implicate Abeta and also consider arguments and evidence gathered by the defense team who are convinced of the innocence of their client. As in all trials, the arguments provided by the prosecution and defense revolve around the same evidence, with opposing interpretations. Below, we present a brief synopsis of the trial for you, the jury, to decide the verdict. Amyloid-beta: guilty or not-guilty?

Aging↗