Search PubMed⌕ Search

Biomedical subjects

George Perry

Publications and source records attributed to George Perry.

At least 127 records · Page 7Linked to original sources
PubMed2003

Role of vascular hypoperfusion-induced oxidative stress and mitochondria failure in the pathogenesis of Azheimer disease.

Chronic vascular hypoperfusion induces oxidative stress and brain energy failure, and leads to neuronal death, which manifests as cognitive impairment and the development of brain pathology as in Alzheimer disease (AD). It is becoming more widely accepted that AD is characterized by impairments in energy metabolism. We hypothesize that hypoperfusion-induced mitochondrial failure plays a central role in the generation of reactive oxygen species, resulting in oxidative damage to brain cellular compartments, especially in the vascular endothelium and neuronal cell bodies in AD. All of these changes have been found to occur before pathology and coexist during the progression of AD. In this review we have summarized recent evidence and our own knowledge regarding the relationship between the hypoperfusion-induced vascular damage that initiates oxidative stress and mitochondrial abnormalities that appear to be a key target for the development of AD pathology. Future investigations into both the mechanisms behind amyloid beta (Abeta) deposition and the possible accelerating effects of environmental factors, such as chronic hypoxia/reperfusion may open the door for effective pharmacological treatments of AD. We hypothesize that an imbalance between endothelium derived vasoconstrictors and vasodilators, along with an antioxidant system deficiency and mitochondria lesions are prominent in AD. Future studies examining the importance of mitochondrial pathophysiology in different brain cellular compartments may provide insight not only into neurodegenerative and/or cerebrovascular disease pathobiology but may also provide targets for treating these conditions.

Alzheimer Disease↗
PubMed2003

Microtubule reduction in Alzheimer's disease and aging is independent of tau filament formation.

Biochemical studies show that phosphorylated tau, like that found in paired helical filaments (PHFs), does not promote microtubule assembly leading to the view that PHF formation leads to microtubule deficiency in Alzheimer's disease (AD). However, although this issue is one of the most important aspects to further understanding the cell biology of AD, no quantitative examination of microtubule diminution in AD and its relationship with PHFs has been performed. To examine this issue directly, we undertook a morphometric study of brain biopsy specimens from AD and control cases. Ultrastructural analysis of neurons was performed to compare the microtubule assembly state in neurons of diseased and control cases and to examine the effect of PHF accumulation. We found that both number and total length of microtubules were significantly and selectively reduced in pyramidal neurons from AD in comparison to control cases (P = 0.000004) but that this decrement in microtubule density was surprisingly unrelated to PHFs (P = 0.8). Further, we found a significant age-dependent decrease in microtubule density with aging in the control cases (P = 0.016). These findings suggest that reduction in microtubule assembly is not dependent on tau abnormalities of AD and aging.

Aged↗
PubMed2003

Amyloid-beta: a chameleon walking in two worlds: a review of the trophic and toxic properties of amyloid-beta.

Although much maligned, the amyloid-beta (Abeta) protein has been shown to possess a number of trophic properties that emanate from the protein's ability to bind Cu, Fe and Zn. Abeta belongs to a group of proteins that capture redox metal ions (even under mildly acidotic conditions), thereby preventing them from participating in redox cycling with other ligands. The coordination of Cu appears to be crucial for Abeta's own antioxidant activity that has been demonstrated both in vitro as well as in the brain, cerebrospinal fluid and plasma. The chelation of Cu by Abeta would therefore be predicted to dampen oxidative stress in the mildly acidotic and oxidative environment that accompanies acute brain trauma and Alzheimer's disease (AD). Given that oxidative stress promotes Abeta generation, the formation of diffuse amyloid plaques is likely to be a compensatory response to remove reactive oxygen species. This review weighs up the evidence supporting both the trophic and toxic properties of Abeta, and while evidence for direct Abeta neurotoxicity in vivo is scarce, we postulate that the product of Abeta's antioxidant activity, hydrogen peroxide (H(2)O(2)), is likely to mediate toxicity as the levels of this oxidant rise with the accumulation of Abeta in the AD brain. We propose that metal ion chelators, antioxidants, antiinflammatories and amyloid-lowering drugs that target the reduction of H(2)O(2) and/or Abeta generation may be efficacious in decreasing neurotoxicity. However, given the antioxidant activity of Abeta, we suggest that the excessive removal of Abeta may prevent adequate chelation of metal ions and removal of O(2)(-z.ccirf;), leading to enhanced, rather than reduced, neuronal oxidative stress.

Alzheimer Disease↗
PubMed2003

Cerebrovascular requirement for sealant, anti-coagulant and remodeling molecules that allow for the maintenance of vascular integrity and blood supply.

The integrity of the vasculature and the maintenance of the blood supply to the brain are crucial for the survival of higher vertebrates. However, peripheral mechanisms of sealing the vasculature that rely on the clotting of blood and platelet aggregation around the site of a 'leak' would lead to decreased cerebral perfusion and compromise the viability of terminally differentiated and irreplaceable neurons. Therefore, in higher organisms it is likely that a sealant/anti-coagulant system that maintains vascular supply has evolved as a necessity to life. We propose that one such system involves the amyloid-beta precursor protein (AbetaPP) and its cleavage product Abeta since (1) both AbetaPP/Abeta are known to deposit in the media of the cerebrovasculature wall following localized injury, (2) Abeta is generated from AbetaPP, a known acute phase reactant, (3) Abeta's physiochemical properties allow it to span between the extracellular matrix and the (endothelial) cell membrane and under inflammatory conditions aggregate to form an intracranial 'scab', thereby maintaining structural integrity of the blood brain barrier, (4) AbetaPP/Abeta together act as an anti-coagulant, (5) Abeta promotes vascular/neuronal remodeling, and (6) Abeta deposits resolve after injury. These properties are consistent with the acute phase generation and rapid cortical deposition of AbetaPP/Abeta following injury (either sustained by trauma or stresses associated with aging) that would be an important compensatory response aimed at limiting the loss of terminally differentiated neurons. Such a system would allow the maintenance of blood supply to the brain by sealing vascular lesions, preventing hemorrhagic stroke while at the same time inhibiting the coagulation cascade from blocking capillaries. Obviously, strategies to remove Abeta would have serious consequences for the integrity of the blood-brain barrier. Indeed, recent in vivo evidence demonstrates that the removal of deposited Abeta from the vasculature leads to increased cerebral microhemorrhage and strongly support the above mentioned functions of AbetaPP/Abeta. These insights also explain the root cause of the encephalitis and meningitis suffered by individuals in immunotherapy trials as being directly associated with the removal of Abeta from the vasculature, i.e. immunological responses to Abeta vaccination do not discriminate between physiologically purposive deposits of Abeta (vascular deposits) and pathological deposits of Abeta (senile plaques).

Amyloid beta-Peptides↗
PubMed2003

Apoptotic promoters and inhibitors in Alzheimer's disease: Who wins out?

A spectrum of apoptotic mediators are seen in neurons that are vulnerable in Alzheimer's disease (AD), leading many investigators to suggest that neuronal death in AD is mediated by an apoptotic process. Indeed, the environment of the AD brain is awash with proapoptotic mediators including amyloid-beta, oxidative stress, hydroxynonenal oxidants and metabolic alterations with concomitant energy failures. However, the phenotype that defines the terminal events that are pathogonomic of apoptosis, such as chromatin condensation, apoptotic bodies and membrane blebbing, are not seen in AD. Therefore, we speculated that, although AD presents with a proapoptotic environment, apoptosis does not proceed to completion. In this regard, we found that while the initiator phases of apoptosis were engaged, this does not lead to the activation of the terminal commitment phase necessary for apoptotic cell death. In other words, in AD, there is a lack of effective apoptotic signal propagation to distal effectors. This is a novel phenomenon (which we term abortosis) that represents an inhibition of apoptosis at the postinitiator stage in neurons that survive in AD.

Alzheimer Disease↗
PubMed2003

Adventiously-bound redox active iron and copper are at the center of oxidative damage in Alzheimer disease.

Central to oxidative damage in Alzheimer disease is the production of metal-catalyzed hydroxyl radicals that damage every category of macromolecule. Studies on redox-competent copper and iron indicate that redox activity in Alzheimer disease resides exclusively within the cytosol of vulnerable neurons and that chelation with deferoxamine or DTPA removes this activity. We have also found that while proteins that accumulate in Alzheimer disease such as tau, amyloid beta, and apolipoprotein E possess metal-binding sites, metal-associated cellular redox activity is more dependent on metal-nucleic acid binding. Consistent with this finding is the large amount of cytoplasmic RNA in pyramidal neurons. Still, the source of metal-catalyzed redox activity is controversial. Heme oxygenase-1, an enzyme that catalyzes the conversion of heme to iron and biliverdin, is increased in Alzheimer disease suggesting increased heme turnover as a source of redox-active iron. Additionally, the role of mitochondria as a potential source of redox-active metals and oxygen radical production is assuming more prominence. In recent studies, we have found that while mitochondrial DNA and cytochrome C oxidase activity are increased in Alzheimer disease, the number of mitochondria is decreased, indicating accelerated mitochondria turnover. This finding, as well as preliminary studies demonstrating a reduction in microtubule density in neurons in Alzheimer disease suggests mitochondrial dysfunction as a potentially inseparable component of the initiation and progression of Alzheimer disease.

Alzheimer Disease↗
PubMed2003

A metabolic basis for Alzheimer disease.

Most studies of Alzheimer's disease (AD) have focused on a single precipitating alteration as the etiological event rather than global changes closely linked to aging. Recent evidence suggests that the most significant of these global changes are metabolic. Here we present data indicating that metabolic rate, nutrition, and neuronal size are all early indicators of AD. Understanding the cellular and molecular basis for these changes may open a new dimension to understanding AD.

Alzheimer Disease↗
PubMed2003

JKK1, an upstream activator of JNK/SAPK, is activated in Alzheimer's disease.

JNK/SAPK has been implicated in the pathogenesis of Alzheimer's disease, but the upstream cascade leading to JNK/SAPK activation has not been elucidated in the disease. In this study, we focused on one of the physiological activators of JNK/SAPK, JNK kinase 1 (JKK1). Although there was no significant difference in the level and distribution of total JKK1 between Alzheimer's disease (AD) and age-matched control cases, increased levels of activated phospho-JKK1 were specifically localized to neurofibrillary pathology including neurofibrillary tangles, senile plaque neurites, granulovaualar degenerations and neuropil threads in severe AD (Braak stage V-VI), considerably overlapping with its downstream effector, phospho-JNK/SAPK, suggesting both a functional and mechanistic link. Nuclear localization of phospho-JKK1 was also found in mild (Braak stage III-IV) but not in severe AD cases (Braak stage V-VI), suggesting a possible re-distribution correlating with the progress of the disease. By immunoblot analyses, phospho-JKK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the JNK/SAPK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.

Aged↗
PubMed2003

Melatonin increases survival and inhibits oxidative and amyloid pathology in a transgenic model of Alzheimer's disease.

Increased levels of a 40-42 amino-acid peptide called the amyloid beta protein (A beta) and evidence of oxidative damage are early neuropathological markers of Alzheimer's disease (AD). Previous investigations have demonstrated that melatonin is decreased during the aging process and that patients with AD have more profound reductions of this hormone. It has also been recently shown that melatonin protects neuronal cells from A beta-mediated oxidative damage and inhibits the formation of amyloid fibrils in vitro. However, a direct relationship between melatonin and the biochemical pathology of AD had not been demonstrated. We used a transgenic mouse model of Alzheimer's amyloidosis and monitored over time the effects of administering melatonin on brain levels of A beta, abnormal protein nitration, and survival of the mice. We report here that administration of melatonin partially inhibited the expected time-dependent elevation of beta-amyloid, reduced abnormal nitration of proteins, and increased survival in the treated transgenic mice. These findings may bear relevance to the pathogenesis and therapy of AD.

Alzheimer Disease↗
PubMed2003

4-hydroxynonenal contributes to NGF withdrawal-induced neuronal apoptosis.

Reactive oxygen species are a necessary triggering event for apoptosis of sympathetic neurons after nerve growth factor (NGF) withdrawal. Reactive oxygen species can lead to the generation of 4-hydroxynonenal (HNE), a highly reactive aldehyde that forms adducts with proteins. This covalent modification can activate or inhibit signal transduction pathways involved in the induction of apoptosis. This process may be clinically relevant because HNE-adduct immunoreactivity increases in several disease states. Here we evaluate the role of HNE-adducts in sympathetic neurons undergoing NGF-deprivation-induced apoptosis, a model of developmental programmed cell death. We show that HNE-adduct immunoreactivity is dramatically increased after NGF-withdrawal in an NADPH oxidase-dependent manner. Moreover, HNE-adducts appear to contribute to NGF-deprivation-induced apoptotic signal transduction because microinjected HNE-adduct antiserum protects sympathetic neurons from NGF withdrawal. In conclusion, this report suggests the direct contribution of endogenously generated HNE in the stimulation of apoptotic signal transduction in neurons.

Aldehydes↗
PubMed2003

Distribution, levels, and activation of MEK1 in Alzheimer's disease.

Extracellular-signal-regulated kinase (ERK) has been implicated in the pathogenesis of Alzheimer's disease (AD), but the upstream cascade leading to ERK activation has not been elucidated. In this study, we focused on one of the physiological activators of ERK, mitogen-activated protein kinase (MAPK)/ERK kinase 1 (MEK1). Although there was no significant difference in the level and distribution of total MEK1 between AD and age-matched control cases, increased levels of activated phospho-MEK1 were specifically localized to neuronal intracytoplasmic granular structures in severe AD (Braak stage V-VI). The considerable overlap between MEK1 and its downstream effector, phospho-ERK, suggests both a functional and mechanistic link. Nuclear localization of phospho-MEK1 was a prominent feature in both mild AD cases (Braak stage III-IV) and control cases with limited pathology (Braak stage I-II). Since MEK1 is normally cytoplasmic due to the active export from nucleus because of the presence of nuclear export signal in its amino-terminus, we suspect that the apparent nuclear accumulation of phospho-MEK1 in AD patients at early stages suggests that abnormal nuclear trafficking may contribute to the pathogenesis of AD. By immunoblot analyses, phospho-MEK1 was significantly increased in AD over control cases. Together, these findings lend further credence to the notion that the ERK pathway is dysregulated in AD and also indicate an active role for this pathway in disease pathogenesis.

Active Transport, Cell Nucleus↗
PubMed2003

Increased p27, an essential component of cell cycle control, in Alzheimer's disease.

A number of recent findings have demonstrated re-expression of cell cycle-related proteins in vulnerable neurones in Alzheimer's disease. We hypothesize that this attempt by neurones to re-enter mitosis is a response to external growth stimuli that leads to an abortive re-entry into the cell cycle and, ultimately, neuronal degeneration. In this study, to further delineate the role of mitotic processes in the pathogenesis of Alzheimer's disease, we investigated p27, a cyclin-dependent kinase inhibitor that plays a negatively regulatory role in cell cycle progression that, once phosphorylated at Thr187, is degraded via an ubiquitin-proteasome pathway. Here we report that both p27 and phosphorylated p27 (Thr187) show increases in the cytoplasm of vulnerable neuronal populations in Alzheimer's disease vs. age-matched control subjects. Importantly, phosphorylated p27 (Thr187) shows considerable overlap with tau-positive neurofibrillary pathology, including neurofibrillary tangles, dystrophic neurites and neuropil threads. The findings presented here suggest that dysregulation of the cell cycle plays a crucial role in the pathogenesis of Alzheimer's disease that may provide a novel mechanistic basis for therapeutic intervention.

Aged↗
PubMed2003

Oxidative stress and neuronal adaptation in Alzheimer disease: the role of SAPK pathways.

Recent evidence indicates that oxidative stress occurs early in the progression of Alzheimer disease, significantly before the development of the hallmark pathologies, namely neurofibrillary tangles and senile plaques. The interaction of abnormal mitochondria, redox transition metals, and oxidative stress response elements contributes to the generation of reactive oxygen species in diseased neurons. Oxidative damage to major cellular molecules is seen in a number of disease states that are either acute or chronic and it is apparent that without eliciting compensations that restore redox balance, cells will rapidly succumb to death. Indeed, although oxidative stress is a prominent feature in Alzheimer disease, few vulnerable neurons show clear signs of apoptosis, suggesting that the level of oxidative stress does not significantly exceed neuronal oxidative defenses. In light of this observation, we propose that neurons in Alzheimer disease are exposed to low, but chronic, levels of oxidative stress that lead neurons to elicit adaptive responses such as the activation of stress-activated protein kinase pathways.

Alzheimer Disease↗
PubMed2003

Will preventing protein aggregates live up to its promise as prophylaxis against neurodegenerative diseases?

Protein aggregation and misfolding characterize most age-related neurodegenerative diseases including Alzheimer, Parkinson and Huntington diseases. Protein aggregation has generally been assumed to be responsible for neurodegeneration in these disorders due to association and genetics. However, protein aggregation may, in fact, be an attempt to protect neurons from the stress resulting from the disease etiology. In this review, we weigh the evidence of whether removal of amyloids, aggregates and neuronal inclusions represent a reasonable strategy for protecting neurons.

Amyloid↗
PubMed2003

Mitochondria and vascular lesions as a central target for the development of Alzheimer's disease and Alzheimer disease-like pathology in transgenic mice.

Accumulating evidence strongly suggests that the AD brain is characterized by impairments in energy metabolism, and vascular hypoperfusion, whereby oxidative stress appears to be an especially important contributor to neuronal death and development of AD pathology. We hypothesized that mitochondria play a key role in the generation of reactive oxygen species, resulting in oxidative damage to neuronal cell bodies, as well as other cellular compartments in the AD brain. All of these changes have been found to accompany AD pathology. In this review we have outlined recent evidence from the literature and our own original studies concerning the role of mitochondrial abnormalities and vascular damage in the pathogenesis of AD and AD-like pathology in transgenic mice (as a model for human AD). We examined ultrastructural features of vascular lesions and mitochondria from vascular wall cells in human AD brain biopsies, in human short post-mortem brain tissues and in yeast artificial chromosome (YAC) and C57B6/SJL transgenic positive (Tg+) mice overexpressing amyloid beta precursor protein (A beta PP). In situ hybridization using mitochondrial DNA (mtDNA) probes for human wild type, 5kb deleted and mouse mtDNA was performed along with immunocytochemistry using antibodies against amyloid beta precursor protein (A beta PP), 8-hydroxy-2'-guanosine (8OHG) and cytochrome C oxidase (COX) were studied at the electron microscopic levels. There was a higher degree of amyloid deposition in the vascular walls of the human AD, YAC and C57B6/SJL Tg(+) mice compared to aged-matched controls. In addition, vessels with more severe lesions showed immunopositive staining for APP and possessed large, lipid-laden vacuoles in the cytoplasm of endothelial cells (EC). Significantly more mitochondrial abnormalities were seen in human AD, YAC and C57B6/SJL Tg(+) mouse microvessels where lesions occurred. In situ hybridization using wild and chimera (5 kB) mtDNA probes revealed positive signals in damaged mitochondria from the vascular endothelium and in perivascular cells of lesioned microvessels close to regions of large amyloid deposition. These features were absent in undamaged regions of human AD tissues, YAC and C57B6/SJL Tg(+) mouse tissues and in aged-matched control subjects. In addition, vessels with atherosclerotic lesions revealed endothelium and perivascular cells possessing clusters of wild and deleted mtDNA positive probes. These mtDNA deletions were accompanied by increased amounts of immunoreactive APP, 8OHG and COX in the same cellular compartment. Our observations first time demonstrate that vascular wall cells, especially their mitochondria, appear to be a central target for oxidative stress induced damage.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2003

Amyotrophic lateral sclerosis: a novel hypothesis involving a gained 'loss of function' in the JNK/SAPK pathway.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neurodegenerative disease that mainly affects motor neurons. Despite intensive research efforts inspired by the mile-stone discovery linking the Cu/Zn superoxide dismutase 1 (SOD1) gene to a subset of familial cases, the mechanisms underlying disease pathogenesis are still largely unknown. Nonetheless, the recent finding of a second gene associated with familial form of the disease, ALS2, is likely to be of great help in elucidating the key pathways involved in motor neuron degeneration. Here, we provide evidence that the JNK/SAPK pathway plays a critical neuroprotective role in susceptible motor neurons in ALS. The involvement of the JNK/SAPK pathway integrates our knowledge about these two known genetic factors into a single pathogenic pathway involved in both sporadic and familial ALS.

Amyotrophic Lateral Sclerosis↗
PubMed2003

Tipping the apoptotic balance in Alzheimer's disease: the abortosis concept.

The mechanisms underlying the selective neuronal death in Alzheimer's disease are largely unresolved. Nonetheless, it is apparent that the environment of the diseased brain is extremely rich in pro-apoptotic stimuli and that these lead to an activation of the apoptotic death cascade. However, there is surprisingly little evidence for the completion of the death pathway indicating that the apoptotic death program is terminated by a mechanism termed abortosis. This review discusses the concept of abortosis in relation to Alzheimer's disease.

Alzheimer Disease↗