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Biomedical subjects

George Perry

Publications and source records attributed to George Perry.

175 records · Page 10Linked to original sources
PubMed1998

Reactive Oxygen Species Mediate Cellular Damage in Alzheimer Disease.

The two most striking features of Alzheimer disease are (i) the multitude of abnormalities affecting essentially every system and (ii) the strict age dependence. Recent work suggests that both features are linked to increased oxidative stress that damages lipids, proteins and nucleic acids and results in redox-active metal accumulations, mitochondrial damage and formation of advanced glycation endproducts. Interestingly, beta-protein precursor, amyloid-beta, presenilins, and apolipoprotein E have all been linked to reactive oxygen species production or apoptosis, a process intimately associated with oxidative stress. In therapeutics, the commonality between a number of efficacious agents appears to be oxidative stress reduction. Therefore, we contend that oxidative stress is the element that links the multitude of changes in Alzheimer disease and that a reduction of oxidative stress will have a dramatic effect on reducing the incidence or progression of Alzheimer disease.

Journal Article↗
PubMedDate not supplied

P38 activation mediates amyloid-beta cytotoxicity.

Amyloid-beta is a leading candidate factor in the development of Alzheimer disease (AD), however the mechanisms involved are unclear. As such, there has been considerable interest in evidence showing that the neuronal damage caused by amyloid-beta is mediated by oxidative stress. Notably, oxidative stress leads to activation of stress-activated protein kinases, which we and others have shown are also involved in AD pathogenesis. One SAPK in particular, p38, appears to be crucial in AD and therefore, in the current study, we investigated the role of p38 activation in amyloid-beta cytotoxicity. Our data showed p38 activation was induced by amyloid-beta in a concentration-dependent manner in M17 human neuroblastoma cells. Notably, amyloid-beta toxicity was significantly decreased by inhibition of p38 activity by overexpressing dominant negative p38. Consistent with this, in primary cortical neurons amyloid-beta also induced p38 activation and amyloid-beta toxicity was significantly diminished when p38 was inhibited by its specific inhibitor, SB203580. Taken together, these data suggest that p38 is a key downstream effector of amyloid-beta-induced neuronal death and blocking this pathway may be of therapeutic value.

Amyloid beta-Peptides↗
PubMedDate not supplied

Cerebral amyloid angiopathy: major contributor or decorative response to Alzheimer's disease pathogenesis.

Amyloid deposition within cerebral vessels, or cerebral amyloid angiopathy (CAA), is common in advanced age and even more common in Alzheimer's disease. CAA may be complicated by lobar intracerebral hemorrhage, while rare kindreds of autosomal dominant CAA also show propensity for intracerebral hemorrhage, due to germline mutations in specific amyloidogenic precursor proteins and apparent compromise of structural integrity of the blood vessel wall due to marked amyloid deposition. The relationship between cerebral amyloid angiopathy and cognitive dysfunction, however, is less clear. While cognitive dysfunction in familial CAA is likely related to prodigious amyloid deposits and vascular luminal compromise (e.g., hereditary cerebral hemorrhage with angiopathy-Dutch type (HCHWA-D)), cerebral amyloid angiopathy with intracerebral hemorrhage often presents sporadically in cognitively intact elderly patients. Moreover, while about 80% of subjects with Alzheimer's disease have demonstrable amyloid beta within blood vessel walls at autopsy, the vast majority of these fail to suffer clinically relevant intracerebral hemorrhage during life. The remaining 20% manage to progress and die of their disease with virtual no amyloid within blood vessels. Thus, the role of amyloid beta deposits in cerebral vessels as regards cognitive function on the one hand, and tendency for hemorrhage on the other, remain to be resolved for sporadic late onset Alzheimer's disease and CAA. Recent studies on transgenic APP23 mice suggest a relationship between passive immunization and amyloid angiopathy-associated cerebral hemorrhage, although the mechanism of hemorrhage was unclear from the data presented. We suggest that amyloid accumulation represents a response to chronic stress, and that the neurodegenerative process occurs at the neuronal level, encompassing oxidative stress and aberrant cell cycle activation. As such, CAA represents tissue homeostasis, such that an abrupt perturbation of this balance (e.g., amyloid beta immunization) is deleterious.

Alzheimer Disease↗
PubMedDate not supplied

Hydroxynonenal, toxic carbonyls, and Alzheimer disease.

Cytoskeletal disruption is one of the distinguishing characteristics of the vulnerable neurons in Alzheimer disease (AD). It has been suggested that these cytoskeletal changes occur secondarily to covalent modifications of the protein components. Despite the abundance and probable importance of these changes, there has been very little data regarding the identity of the modified proteins or the precise chemistry of the modifications. Here we review a specific type of modification, namely carbonylation of proteins, which has been shown to be a common result of cellular oxidative stress. Hopefully, the following discussion will help elucidate the relationship between oxidative stress, protein modification and the pathogenesis of AD.

Aldehydes↗
PubMedDate not supplied

The p38 pathway is activated in Pick disease and progressive supranuclear palsy: a mechanistic link between mitogenic pathways, oxidative stress, and tau.

In Pick disease and progressive supranuclear palsy (PSP), accumulations of phosphorylated tau are associated with oxidative stress, although the mechanism linking these features remains unknown. However, we suspected that the oxidative stress-induced activation of mitogen-activated protein kinases might lead to tau phosphorylation and accumulation as characteristic inclusion bodies. To test this notion, we investigated whether the activation of mitogen-activated protein kinases is involved in the pathogenesis of Pick disease and PSP. Our results show that the lesions of both Pick disease and PSP are associated with the activation of the p38 pathway (phospho-MKK6 and phospho-p38), one of the best characterized of the mitogen-activated protein kinase pathways. Based on these findings, we propose that the phosphorylation of tau is a direct consequence of the oxidative stress-induced activation of mitogen-activated protein kinases, including p38.

Calcium-Calmodulin-Dependent Protein Kinases↗
PubMedDate not supplied

Gender differences in Alzheimer disease: the role of luteinizing hormone in disease pathogenesis.

Epidemiological data reporting the predisposition of women to Alzheimer disease has provided researchers with an important clue as to the identity of the driving pathogenic force and lead many to question the potential role of sex steroids, namely estrogen, in disease pathogenesis. However, while estrogen has become the primary focus of research in the field, inconclusive data regarding estrogen replacement therapy has lead some researchers to begin investigating the effects of the other hormones of the hypothalamic-pituitary-gonadal (HPG) axis on the aging brain. Certain hormones of the HPG axis, namely the gonadotropins (luteinizing hormone and follicle-stimulating hormone), are not only involved in regulating reproductive function via a complex feedback loop but are also known to cross the blood-brain barrier. Recently, we proposed that an increase in gonadotropin concentrations, not the decrease in steroid hormone (eg, estrogen) production following menopause/andropause, is a potentially primary causative factor for the development of Alzheimer disease. In this review, we examine how the gonadotropins may play a central and determining role in modulating the susceptibility to, and progression of, Alzheimer disease. Based on this, we suggest that therapeutic interventions targeted at gonadotropins may both prevent disease in those patients currently asymptomatic or may halt, and even reverse, disease in those currently afflicted.

Alzheimer Disease↗
PubMedDate not supplied

The role of mitogen-activated protein kinase pathways in Alzheimer's disease.

Given the critical role of mitogen-activated protein kinase (MAPK) pathways in regulating cellular processes that are affected in Alzheimer's disease (AD), the importance of MAPKs in disease pathogenesis is being increasingly recognized. All MAPK pathways, i.e., the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and p38 pathways, are activated in vulnerable neurons in patients with AD suggesting that MAPK pathways are involved in the pathophysiology and pathogenesis of AD. Here we review recent findings implicating the MAPK pathways in AD and discuss the relationship between these pathways and the prominent pathological processes, i.e., tau phosphorylation and amyloid-beta deposition, as well as the functional association to amyloid beta protein precursor. We suggest that regulation of these pathways may be a central facet to any potential treatment for the disease.

Alzheimer Disease↗
PubMedDate not supplied

Differential regulation of glutamate receptors in Alzheimer's disease.

Selective neurodegeneration is a prominent feature in Alzheimer's disease; however, the mechanism of neuronal death is still unclear. Nonetheless, the topographical distribution of different types of receptors is thought to contribute to the regional selective nature of neuronal degeneration. Specifically, since glutamatergic transmission is severely altered by the early degeneration of cortico-cortical connections and hippocampal projections in Alzheimer's disease, we suspect that glutamate receptors may play a new role in the pathophysiology of disease. Here we review the salient aspects of glutamate receptor expression in Alzheimer's disease and how their differential regulation can contribute to the selective neurodegeneration seen in the disease. Additionally, we assess the potential therapeutic value of glutamate receptors as a target for drug intervention in Alzheimer's disease.

Alzheimer Disease↗
PubMedDate not supplied

Mitochondrial failures in Alzheimer's disease.

Mitochondrial dysfunction and free radical-induced oxidative damage have been implicated in the pathogenesis of several different neurodegenerative diseases such as Parkinson disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), and Alzheimer's disease (AD). The defective adenosine triphosphate (ATP) production and increased oxygen radicals may induce mitochondria-dependent cell death because damaged mitochondria are unable to maintain the energy demands of the cell. The role of vascular hypoperfusion-induced mitochondria failure in the pathogenesis of AD now has been widely accepted. However, the exact cellular mechanisms behind vascular lesions and their relation to oxidative stress markers identified by RNA oxidation, lipid peroxidation, or mitochondrial DNA (mtDNA) deletion remain unknown. Future studies comparing the spectrum of mitochondrial damage and the relationship to oxidative stress-induced damage during the aging process or, more importantly, during the maturation of AD pathology are warranted.

Aged↗
PubMedDate not supplied

Antioxidant protection and neurodegenerative disease: the role of amyloid-beta and tau.

In Alzheimer's disease (AD), the major components of senile plaques and neurofibrillary tangles, amyloid-beta and tau, respectively, are thought by many to play a key role in disease initiation and progression. However, herein we propose that rather than being initiators of disease pathogenesis, the lesions that characterize AD, senile plaques and neurofibrillary pathology, occur consequent to oxidative stress and, importantly, function as a primary line of antioxidant defense. Importantly, this paradigm shift in thinking about the role of lesions in disease also provides an explanation for the appearance of both amyloid-beta and tau in control individuals given the increased levels of oxidative stress associated with the aged brain. In AD, oxidative stress is not only high but chronic and is superimposed upon an age-related vulnerable environment. Therefore, one would predict, successfully, an increased lesion load in patients with AD above and beyond that seen in normal aging. The notion that amyloid-beta and tau accumulations indicate adaptation and, likely, physiological processes sheds light on the pathological expression of disease and calls into question the rationale of current therapeutic efforts targeted toward lesion removal.

Alzheimer Disease↗
PubMedDate not supplied

Oxidative damage and Alzheimer's disease: are antioxidant therapies useful?

Oxidative stress is a key factor involved in the development and progression of Alzheimer's disease, and it is well documented that free radical oxidative damage, particularly of neuronal lipids, proteins, nucleic acids and sugars, is extensive in brains of Alzheimer's disease patients. However, oxidative stress may elicit compensatory responses and downstream adaptations such as amyloid-beta deposition and neurofibrillary tangle formation, which may function as "shields" to ensure that neuronal cells do not succumb to oxidative injuries. Although during the past several years our understanding of the mechanisms leading to neuronal damage and death in the course of Alzheimer's disease has improved significantly, we have not found an effective therapeutic to fight this devastating disorder. However, the results obtained in clinical trials with antioxidants are promising and propel us in the search of new and more effective antioxidant therapies.

Alzheimer Disease↗
PubMedDate not supplied

The role of nitric oxide in the pathogenesis of brain lesions during the development of Alzheimer's disease.

Nitric oxide (NO) is a key bioregulatory active molecule in the cardiovascular, immune and nervous systems, synthesized through converting L-arginine to L-citrulline by NO synthase (NOS). Research exploration supports the theory that this molecule appears to be one of the key factors for the disruption of normal brain homeostasis, which causes the development of brain lesions and pathology such as in Alzheimer's disease (AD). Especially the vascular content of NO activity appears to be a major contributor to this pathology before the overexpression of NOS activity in other brain cellullar compartments develop. We theorize that pharmacological intervention using NO donors and/or NO suppressors should delay or minimize brain lesion development and further progression of brain pathology and dementia.

Alzheimer Disease↗