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Biomedical subjects

Mark A Smith

Publications and source records attributed to Mark A Smith.

At least 37 records · Page 2Linked to original sources
PubMed2006

Neuropathology in Alzheimer's disease: awaking from a hundred-year-old dream.

For one hundred years after Alois Alzheimer's first report of Alzheimer's disease (AD) in 1906, the pathological hallmarks of the disease, senile plaques and neurofibrillary tangles (NFTs), have been attractive targets for researchers. Therefore, not surprisingly, efforts to understand disease mechanisms have concentrated on the cell biology of amyloid-beta (Abeta) deposition as senile plaques or on the phosphorylation and aggregation of tau as NFTs. However, it now appears that this focus on pathology as a central contributor to disease may be misguided. Indeed, neurons associated with Abeta and NFTs in AD brain show a decrease in oxidative damage relative to those in vulnerable but morphologically intact areas of the brain, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. That Abeta and tau accumulations indicate an age-related physiological reaction to chronic stress calls into question the rationale of current therapeutic efforts targeted toward lesion removal. Moreover, if this concept holds true for pathology in other neurodegenerative diseases, we may need to restructure our thinking and undergo a paradigm shift before substantial progress can be made in therapeutic intervention.

Alzheimer Disease↗
PubMed2006

Neuropathology of Alzheimer disease: pathognomonic but not pathogenic.

Neuropathological changes in subjects with dementia are, by definition, end-stage phenomena. While such changes allow case characterization and lend themselves to disease classification and modeling, the lesions themselves are not etiological. This truth would appear to be self-evident, yet the medical and scientific literature suggests otherwise. Indeed it is now customary to view amyloid plaques in Alzheimer disease as primary etiological, neurotoxic lesions and, hence, removing them (e.g., by immunotherapy) is believed to lead to clinical improvement. The foundation for this line of thinking lies in the existence of rare kindreds with mutations in amyloid-beta, or mutations believed to be involved in the processing of amyloid-beta, and then the extrapolation of the inherited condition to sporadic disease. We believe that this overall construct ignores early events that are more critical to onset and progression of sporadic disease. Likewise, we have studied subjects with sporadic Alzheimer disease, as well as early onset familial Alzheimer disease and Down's syndrome, over a spectrum of ages, and have found that markers of oxidative stress precede amyloid deposits in all three conditions. Amyloid and neurofibrillary pathology in the Alzheimer brain show a decrease in oxidative stress relative to vulnerable but morphologically intact neurons, suggesting that neurodegenerative lesions are compensatory phenomena, and thus manifestations of cellular adaptation. The pathology of neurodegenerative diseases should be viewed as the end-stage consequence, as opposed to cause, of the disease processes, so that early disease processes that are amenable to intervention can be properly recognized and treated.

Alzheimer Disease↗
PubMed2006

Alpha-synuclein facilitates the toxicity of oxidized catechol metabolites: implications for selective neurodegeneration in Parkinson's disease.

Free radicals, including dopamine (DA)-oxidized metabolites, have long been implicated in pathogenesis of Parkinson's disease (PD). However, the relationships between such oxidative stresses and alpha-synuclein (alpha-S), a major constituent of Lewy bodies, remain unknown. In this study, we established neuronal cells that constitutively express alpha-S and tetracycline-regulated tyrosinase. While tyrosinase overexpression induced apoptosis, co-expression of wild type or A53T mutant human alpha-S with tyrosinase further exacerbated cell death. In this process, the formation of alpha-S oligomers and the reduction in mitochondrial membrane potential were demonstrated. This cellular model may reconstitute the pathological metabolism of alpha-S in the synucleinopathy and provide a useful tool to explore possible pathomechanisms of nigral degeneration in PD.

Apoptosis↗
PubMed2006

The (un)balance between metabolic and oxidative abnormalities and cellular compensatory responses in Alzheimer disease.

Compelling evidence supports the importance of metabolic abnormalities in Alzheimer disease pathogenesis. Indeed, that oxidative mechanisms are involved in the neuropathology associated with Alzheimer disease is evidenced by the large number of metabolic signs of oxidative stress as well as by specific markers of oxidative damage. However, in the initial stages of disease development, neurons adapt to the oxidative environment through the development of compensatory responses resulting in a shift of neuronal priority from normal function to basic survival.

Aged↗
PubMed2006

Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice.

Until recently, the study of hormonal influences in Alzheimer disease was limited to the role of sex steroids. Despite numerous epidemiological studies supporting a protective role for estrogen in Alzheimer disease, recent studies show that estrogen administration in elderly women increases the risk of disease. Reconciling these contradictory reports, we previously hypothesized that other hormones of the hypothalamic-pituitary-gonadal axis, such as luteinizing hormone, may be involved in the onset and development of the disease. In this regard, luteinizing hormone is elevated in Alzheimer disease and is known to modulate amyloidogenic processing of amyloid-beta protein precursor. Therefore, in this study, to evaluate the therapeutic potential of luteinizing hormone ablation, we administered a gonadotropin-releasing hormone analogue, leuprolide acetate, to an aged transgenic mouse model of Alzheimer disease (Tg 2576) and measured cognitive Y-maze performance and amyloid-beta deposition after 3 months of treatment. Our data indicate that luteinizing hormone ablation significantly attenuated cognitive decline and decreased amyloid-beta deposition as compared to placebo-treated animals. Importantly, leuprolide acetate-mediated reduction of amyloid-beta correlated with improved cognition. Since both cognitive loss and amyloid-beta deposition are features of Alzheimer disease, leuprolide acetate treatment may prove to be a useful therapeutic strategy for this disease.

Alzheimer Disease↗
PubMed2006

Clusterin up-regulation following sub-lethal oxidative stress and lipid peroxidation in human neuroblastoma cells.

Clusterin/apolipoprotein J is a multifunctional protein up-regulated during various pathophysiological states. Since oxidative stress plays an important role in brain aging, and in many neurodegenerative disorders, to further understand the mechanistic underpinnings of clusterin expression, in this study, we examined clusterin expression in human neuroblastoma cells under conditions of increased production of reactive oxygen species and lipid peroxidation. Specifically, we analyzed clusterin mRNA and protein levels in human neuroblastoma IMR-32 and SH-SY5Y cells following exposure to sub-lethal amounts of iron-ascorbate to induce an increase in reactive oxygen species generation and lipid peroxidation. Under such conditions, we observed a time-dependent up-regulation of clusterin protein and mRNA levels, detected by immunoblot analysis and RT-PCR, respectively. Given the known roles of clusterin, the results of the present study support the notion that an increase in clusterin expression may be a physiological defence mounted to reduce cell damage and maintain cell viability during periods of increased oxidative stress.

Alzheimer Disease↗
PubMed2006

Ectopic expression of phospho-Smad2 in Alzheimer's disease: uncoupling of the transforming growth factor-beta pathway?

Transforming growth factor-beta (TGF-beta), a multifunctional cytokine, has been widely suggested to play a role in the pathogenesis of Alzheimer's disease. Supporting this, levels of TGF-beta are elevated in the cerebrospinal fluid, sera, and brain of patients with Alzheimer's disease. Since TGF-beta is neuroprotective, whereas Alzheimer's disease is typified by neurodegeneration, we speculated that defects in TGF-beta signaling might abrogate its neuroprotective properties. Consistently with an increase in TGF-beta in Alzheimer's disease, we found significant increases in phospho-Smad2, a major downstream signaling molecule of TGF-beta, in hippocampal neurons of Alzheimer's disease compared with age-matched control patients. However, in contrast to an expected nuclear localization, phosphorylated Smad2 in Alzheimer's disease was predominantly, and ectopically, found in the neuronal cytoplasm, specifically colocalized with neurofibrillary tangles and granulovacuolar degeneration. Given that a nuclear localization is required to regulate the transcription of TGF-beta target genes to afford neuroprotection, the ectopic localization of phosphorylated Smad2 suggests a defect in the Smad-mediated signaling pathway of TGF-beta in Alzheimer's disease and consequent loss of neuroprotective function.

Aged↗
PubMed2006

Overexpression of GRK2 in Alzheimer disease and in a chronic hypoperfusion rat model is an early marker of brain mitochondrial lesions.

Heterotrimeric guanine nucleotide-binding (G) protein-coupled receptor kinases (GRKs) are cytosolic proteins that are known to contribute to the adaptation of the heptahelical G protein-coupled receptors (GPCRs) and to regulate downstream signals through these receptors. GPCRs mediate the action of messengers that are key modulators of cardiac and vascular cell function, such as growth and differentiation. GRKs are members of a multigene family, which are classified into three subfamilies and are found in cardiac, vascular and cerebral tissues. Increasing evidence strongly supports the hypothesis that vascular damage is an early contributor to the development of Alzheimer disease (AD) and/or other pathology that can mimic human AD. Based on this hypothesis, and since kinases of this family are known to regulate numerous receptor functions both in the brain, myocardium and elsewhere, we explored cellular and subcellular localization by immunoreactivity of G protein-coupled receptor kinase 2 (GRK2), also known as beta-adrenergic receptor kinase-1(betaARK1), in the early pathogenesis of AD and in ischemia reperfusion injury models of brain hypoperfusion. In the present study, we used the two-vessel carotid artery occlusion model, namely the 2-VO system that results in chronic brain hypoperfusion (CBH) and mimics mild cognitive impairment (MCI) and vascular changes in AD pathology. Our findings demonstrate the early overexpression of GRK2 member kinase in the cerebrovasculature, especially endothelial cells (EC) following CBH, as well as in select cells from human AD tissue. We found a significant increase in GRK2 immunoreactivity in the EC of AD patients and after CBH, which preceded any amyloid deposition. Since GRK2 activity is associated with certain compensatory changes in brain cellular compartments and in ischemic cardiac tissue, our findings suggest that chronic hypoperfusion initiates oxidative stress in these conditions and appears to be the main initiating injury stimulus for disruption of brain and cerebrovascular homeostasis and metabolism.

Aged↗
PubMed2006

Involvement of oxidative stress in Alzheimer disease.

Genetic and lifestyle-related risk factors for Alzheimer disease (AD) are associated with an increase in oxidative stress, suggesting that oxidative stress is involved at an early stage of the pathologic cascade. Moreover, oxidative stress is mechanistically and chronologically associated with other key features of AD, namely, metabolic, mitochondrial, metal, and cell-cycle abnormalities. Contrary to the commonly held notion that pathologic hallmarks of AD signify etiology, several lines of evidence now indicate that aggregation of amyloid-beta and tau is a compensatory response to underlying oxidative stress. Therefore, removal of proteinaceous accumulations may treat the epiphenomenon rather than the disease and may actually enhance oxidative damage. Although some antioxidants have been shown to reduce the incidence of AD, the magnitude of the effect may be modified by individual factors such as genetic predisposition (e.g. apolipoprotein E genotype) and habitual behaviors. Because caloric restriction, exercise, and intellectual activity have been experimentally shown to promote neuronal survival through enhancement of endogenous antioxidant defenses, a combination of dietary regimen of low total calorie and rich antioxidant nutrients and maintaining physical and intellectual activities may ultimately prove to be one of the most efficacious strategies for AD prevention.

Alzheimer Disease↗
PubMed2006

The application of microarray technology to neuropathology: cutting edge tool with clinical diagnostics potential or too much information?

Microarray technology is a tremendously powerful method for simultaneously monitoring the expression of thousands of species of nucleic acids, usually cellular mRNA, producing a high-resolution representation of the genes encoded or expressed in a cell. As such, microarray technology has great potential for impacting research and clinical approaches to treatment. However, this complex technology has been challenging to apply as a result of difficulties discerning biologic variation from technologic issues, therefore slowing the application of the technology to human diagnostics. Nevertheless, significant advances in microarray technology, improvements that avoid potential pitfalls, and a wider spectrum of application are making this technology easier to apply. Indeed, microarray technology has provided valuable insights into mechanisms involving gene regulation and expression in Alzheimer disease, and it remains a powerful tool to identify biomarkers for disease diagnosis. Ultimately, the most robust markers will enable the application of more specific treatments particular to disease stages or subcategories. Currently, no widely applicable molecular test is available to identify those at risk for developing Alzheimer disease or those who have early markers of pathology but show discernible cognitive impairment. The progression of this technology will lead to earlier detection of the disease through enhanced understanding of disease onset and progression.

Alzheimer Disease↗
PubMed2006

Heme deficiency in Alzheimer's disease: a possible connection to porphyria.

Mechanisms that cause Alzheimer's disease (AD), an invariably fatal neurodegenerative disease, are unknown. Important recent data indicate that neuronal heme deficiency may contribute to AD pathogenesis. If true, factors that contribute to the intracellular heme deficiency could potentially alter the course of AD. The porphyrias are metabolic disorders characterized by enzyme deficiencies in the heme biosynthetic pathway. We hypothesize that AD may differ significantly in individuals possessing the genetic trait for an acute hepatic porphyria. We elaborate on this hypothesis and briefly review the characteristics of the acute hepatic porphyrias that may be relevant to AD. We note the proximity of genes encoding enzymes of the heme biosynthesis pathway to genetic loci linked to sporadic, late-onset AD. In addition, we suggest that identification of individuals carrying the genetic trait for acute porphyria may provide a unique resource for investigating AD pathogenesis and inform treatment and management decisions.

Journal Article↗
PubMed2006

Targeting gonadotropins: an alternative option for Alzheimer disease treatment.

Recent evidence indicates that, alongside oxidative stress, dysregulation of the cell cycle in neurons susceptible to degeneration in Alzheimer disease may play a crucial role in the initiation of the disease. As such, the role of reproductive hormones, which are closely associated with the cell cycle both during development and after birth, may be of key import. While estrogen has been the primary focus, the protective effects of hormone replacement therapy on cognition and dementia only during a crucial period led us to expand the study of hormonal influences to other members of the hypothalamic pituitary axis. Specifically, in this review, we focus on luteinizing hormone, which is not only increased in the sera of patients with Alzheimer disease but, like estrogen, is modulated by hormone replacement therapy and also influences cognitive behavior and pathogenic processing in animal models of the disease. Targeting gonadotropins may be a useful treatment strategy for disease targeting multiple pleiotropic downstream consequences.

Journal Article↗
PubMed2006

Oxidative damage to RNA in neurodegenerative diseases.

Since 1999, oxidative damage to RNA molecules has been described in several neurological diseases including Alzheimer's disease, Parkinson's disease, Down syndrome, dementia with Lewy bodies, prion disease, subacute sclerosing panencephalitis, and xeroderma pigmentosum. An early involvement of RNA oxidation of vulnerable neuronal population in the neurodegenerative diseases has been demonstrated, which is strongly supported by a recent observation of increased RNA oxidation in brains of subjects with mild cognitive impairment. Until recently, little is known about consequences and cellular handling of the RNA damage. However, increasing body of evidence suggests detrimental effects of the RNA damage in protein synthesis and the existence of several coping mechanisms including direct repair and avoiding the incorporation of the damaged ribonucleotides into translational machinery. Further investigations toward understanding of the consequences and cellular handling mechanisms of the oxidative RNA damage may provide significant insights into the pathogenesis and therapeutic strategies of the neurodegenerative diseases.

Journal Article↗
PubMed2006

Therapeutic options in Alzheimer's disease.

Alzheimer's disease (AD) places an enormous burden on individuals, families and society. Consequently, a tremendous effort is being devoted to the development of drugs that prevent or delay neurodegeneration. Current pharmacological treatments are based on the use of acetylcholinesterase inhibitors or memantine, a N-methyl-D-aspartate channel blocker. However, new therapeutic approaches, including those more closely targeted to the pathogenesis of the disease, are being developed. These potentially disease-modifying therapeutics include secretase inhibitors, cholesterol-lowering drugs, amyloid-beta immunotherapy, nonsteroidal anti-inflammatory drugs, hormonal modulation and the use of antioxidants. The possibility that oxidative stress is a primary event in AD indicates that antioxidant-based therapies are perhaps the most promising weapons against this devastating neurodegenerative disorder.

Alzheimer Disease↗