Alzheimer Disease: Ohio

Savarin-Vuaillat C, Ransohoff RM. · Neuroinflammation Research Center, Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 44195, USA. · Neurotherapeutics. · Pubmed #17920540 No free full text.

Abstract: Chemokines and chemokine receptors comprise a large number of molecules implicated in a wide range of physiological and pathological functions. Numerous studies have demonstrated the roles of chemokines and chemokine receptors: 1) during development, by regulating hematopoiesis, cardiogenesis, and vascular and cerebellar development; 2) during tumor biology, by controlling cell proliferation, angiogenesis, and metastasis; and 3), especially during leukocyte migration, by acting on firm adhesion, locomotion, diapedesis, and chemotaxis. This review focuses on chemokine and chemokine receptor involvement in diverse neurological diseases and their therapeutic potentials. Because of its induction or upregulation during CNS pathologies, members of the chemokine system can be used as biological markers. CXCR4 and CXCL12, by the correlation between their expression and the glioblastoma tumor progression, could be a marker to grade this type of CNS tumor. CCR1, by virtue of specific expression in Abeta plaques, may be a marker for Alzheimer pathology. Downregulation of CCL2 in cerebrospinal fluid may be a candidate to characterize multiple sclerosis (MS), but needs additional investigation. Moreover, chemokines and chemokine receptors represent interesting therapeutic targets. Using chemokine receptor antagonists, several studies provided exciting findings for potential neurological disease treatment. Chemokine receptor antagonists reduce disease severity in animal models of MS. In glioblastoma, a CXCR4 antagonist (AMD3100) showed an inhibition of tumor growth. Inhibition of chemokine receptor signaling is not the only therapeutic strategy: for example, CXCR4-CXCL12 has anti-inflammatory properties and CX3CL1-CX3CR1 controls neurotoxicity. Thus, chemokine biology suggests several approaches for treating neurological disease.

Farooqui T. · Department of Entomology, The Ohio State University, Columbus, Ohio 43210, USA. · Neuroscientist. · Pubmed #17644763 No free full text.

Abstract: Biogenic amines, such as norepinephrine (in vertebrates) and octopamine (in invertebrates), have structural and functional similarities. These amines play crucial roles in animal behavior by modifying the synaptic output of relevant neurons. Increased levels of norepinephrine in the olfactory bulb preferentially increase mitral cell excitatory responses to olfactory nerve inputs, suggesting its critical role in modulating olfactory function including memory formation and/or recall of specific olfactory memories. Increased levels of octopamine in the antennal lobe play an important role in a reinforcement pathway involved in olfactory learning and memory in honeybees. Similar to adrenergic receptors in the human brain, activation of octopaminergic receptors in the honeybee brain induces specific second messenger pathways that change protein phosphorylation and/or gene expression, altering the activity and/or abundance of proteins responsible for neuronal signaling leading to changes in olfactory behavior. The author's studies in honeybees Apis mellifera indicate that oxidative stress plays a major role in olfactory dysfunction. A similar mechanism has been proposed for olfactory abnormalities in patients of Alzheimer disease and Parkinson disease. Due to similarities in cellular and molecular processes, which govern neuronal plasticity in humans and honeybees, the author proposes that the honeybee can be used as a potential and relatively simple model system for understanding human olfactory dysfunction during aging and in neurodegenerative diseases.

Zhu X, Su B, Wang X, Smith MA, Perry G. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio, USA. · Cell Mol Life Sci. · Pubmed #17605000 No free full text.

Abstract: Oxidative stress is one of the earliest events of Alzheimer disease (AD), with implications as an important mediator in the onset, progression and pathogenesis of the disease. The generation of reactive oxygen species (ROS) and its consequent cellular damage/response contributes to much of the hallmark AD pathology seen in susceptible neurons. The sources of ROS-mediated damage appear to be multi-faceted in AD, with interactions between abnormal mitochondria, redox transition metals, and other factors. In this review, we provide an overview of these potential causes of oxidative stress in AD.

Whitehouse PJ, Waller S. · Department of Neurology, Case Western Reserve University, Cleveland, Ohio, USA. · Neurotherapeutics. · Pubmed #17599723 No free full text.

Abstract: Understanding why we produce labels for neuropsychiatric conditions, such as Alzheimer's disease (AD), and how we use those words to tell stories about our brain, as well as which groups control such diagnostic discourse, is important to a wise understanding of our cognitive abilities, their limitations, and even our very human nature. Here, we explore the history and current focus of a newly emerging field called neuroethics and explore its relationship (or lack thereof) to a newly created clinical syndrome called involuntary emotional expressive disorder (IEED). The main argument concerns the lack of neuroethical discussion of issues pertinent to social influences on disease and the construction of professional specialization. We are critical of the processes associated with the creation of both the field and the syndrome, and express concern about their eventual outcomes. The interaction of social, political, and business institutions, the inherent interests of the advancement of larger research projects (and the individuals that compose them), their potential for profit, and other incentives to enhance marketability and public attention toward certain research programs will be examined as we discuss the development of the field of neuroethics. Similarly, we argue that these social factors and forces are instrumental in the development of IEED as a recognizable category and condition. Our critique is guided by the hope that through such analyses we can improve our understanding of how we go about our academic activities in cognitive neuroscience and also improve our efforts to help people suffering from neuropsychiatric conditions, such as dementia.

Malinski T. · Department of Chemistry and Biochemistry Ohio University, 350 W. State Street, Athens, OH 45701, USA. · J Alzheimers Dis. · Pubmed #17522445 No free full text.

Abstract: Nitric oxide is a signaling molecule produced by neurons and endothelial cells in the brain. NO is synthesized from L-arginine and oxygen by nitric oxide synthase: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS). The endothelial NO acts as a vasorelaxant in the vasculature and as a neurotransmitter when produced by neurons (under the pathological conditions of Alzheimer's disease). NO can be scavenged in a rapid reaction with superoxide (O2-) to generate peroxynitrite (ONOO-), with a half-life of < 1 s. ONOO- is a potent oxidant and the primary component of nitroxidative stress. At high concentrations (> 100 nM), ONOO- can undergo homolytic or heterolytic cleavage to produce NO2+, NO2, and OH., highly reactive oxidative species and secondary components of nitroxidative stress. The high nitroxidative stress can initiate a cascade of redox reactions which can trigger apoptosis and evoke cytotoxic effects on neurons and endothelial cells. This article reviews the functions of NO and the potential role of NO/O2-/ONOO- induced nitroxidative stress in neuronal and endothelial degeneration observed in Alzheimer's disease.

Petersen RB, Nunomura A, Lee HG, Casadesus G, Perry G, Smith MA, Zhu X. · Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA. · J Alzheimers Dis. · Pubmed #17522439 No free full text.

Abstract: It has now been established through multiple lines of evidence that oxidative stress is an early event in Alzheimer's disease, occurring prior to the canonical cytopathology. Thus, oxidative stress likely plays a key pathogenic role in the disease and is clearly involved in the cell loss and other neuropathology associated with Alzheimer's disease as demonstrated by the large number of metabolic signs of oxidative stress and by markers of oxidative damage. One puzzling observation, however, is that oxidative damage decreases with disease progression, such that levels of markers of rapidly formed oxidative damage, which are initially elevated, decrease as the disease progresses to advanced Alzheimer's disease. This finding indicates that reactive oxygen species not only cause damage to cellular structures but also provoke cellular responses, such as the compensatory upregulation of antioxidant enzymes found in vulnerable neurons in Alzheimer's disease. Not surprisingly, stress-activated protein kinase pathways, which are activated by oxidative stress, are extensively activated during Alzheimer's disease. In this review, we present the evidence of oxidative stress and compensatory responses that occur in Alzheimer's disease with a particular focus on the roles and mechanism of activation of stress-activated protein kinase pathways.

Whitehouse PJ. · University Memory and Aging Center, University Hospitals of Cleveland/Case Western Reserve University, Cleveland, OH 44120, USA. · J Altern Complement Med. · Pubmed #17480133 No free full text.

This publication has no abstract.

Zhu X, Avila J, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, 2103 Cornell Rd., Cleveland, OH 44106, USA. · Am J Pathol. · Pubmed #17456753 links to  free full text

This publication has no abstract.

Landreth G. · Department of Neurosciences, Case Western Reserve University, School of Medicine, 10900 Euclid Ave., Cleveland, OH 44106, USA. · Curr Alzheimer Res. · Pubmed #17430241 No free full text.

Abstract: Alzheimer's disease (AD) is a devastating neurodegenerative disease for which there are no highly effective therapies. A novel therapeutic approach to the treatment of AD is the use of agonists of the nuclear receptor, peroxisome proliferators-activated receptor gamma (PPARgamma). PPARgamma is a ligand activated transcription factor whose best described roles are to regulate lipid metabolism and inflammation. Agonists of PPARgamma have been shown to ameliorate AD-related pathology in animal models of AD and improve cognition. A number of potential mechanisms have been advanced to account for these effects. PPARgamma agonists act as insulin sensitizers, facilitating insulin action. In addition, PPARgamma agonists have been shown to inhibit inflammatory gene expression, alter Abeta homeostasis and exhibit neuroprotective effects. Importantly, recent clinical trials of FDA approved PPARgamma agonists have been shown to improve cognition and memory in AD patients. Thus, PPARgamma agonists represent a new and potentially efficacious treatment of AD.

Farooqui AA, Horrocks LA, Farooqui T. · Department of Molecular and Cellular Biochemistry, Ohio State University, Columbus, Ohio 43210, USA. · J Neurosci Res. · Pubmed #17393491 No free full text.

Abstract: The neural membranes contain phospholipids, sphingolipids, cholesterol, and proteins. Glycerophospholipids and sphingolipids are precursors for lipid mediators involved in signal transduction processes. Degradation of glycerophospholipids by phospholipase A(2) (PLA(2)) generates arachidonic acid (AA) and docosahexaenoic acids (DHA). Arachidonic acid is metabolized to eicosanoids and DHA is metabolized to docosanoids. The catabolism of glycosphingolipids generates ceramide, ceramide 1-phosphate, sphingosine, and sphingosine 1-phosphate. These metabolites modulate PLA(2) activity. Arachidonic acid, a product derived from glycerophospholipid catabolism by PLA(2), modulates sphingomyelinase (SMase), the enzyme that generates ceramide and phosphocholine. Furthermore, sphingosine 1-phosphate modulates cyclooxygenase, an enzyme responsible for eicosanoid production in brain. This suggests that an interplay and cross talk occurs between lipid mediators of glycerophospholipid and glycosphingolipid metabolism in brain tissue. This interplay between metabolites of glycerophospholipid and sphingolipid metabolism may play an important role in initiation and maintenance of oxidative stress associated with neurologic disorders as well as in neural cell proliferation, differentiation, and apoptosis. Recent studies indicate that PLA(2) and SMase inhibitors can be used as neuroprotective and anti-apoptotic agents. Development of novel inhibitors of PLA(2) and SMase may be useful for the treatment of oxidative stress, and apoptosis associated with neurologic disorders such as stroke, Alzheimer disease, Parkinson disease, and head and spinal cord injuries.

Casadesus G, Moreira PI, Nunomura A, Siedlak SL, Bligh-Glover W, Balraj E, Petot G, Smith MA, Perry G. · Department of Neuroscience, Case Western Reserve University, Cleveland, OH, USA. · Neurochem Res. · Pubmed #17342408 No free full text.

Abstract: Metabolic alterations are a key player involved in the onset of Alzheimer disease pathophysiology and, in this review, we focus on diet, metabolic rate, and neuronal size differences that have all been shown to play etiological and pathological roles in Alzheimer disease. Specifically, one of the earliest manifestations of brain metabolic depression in these patients is a sustained high caloric intake meaning that general diet is an important factor to take in account. Moreover, atrophy in the vasculature and a reduced glucose transporter activity for the vessels is also a common feature in Alzheimer disease. Finally, the overall size of neurons is larger in cases of Alzheimer disease than that of age-matched controls and, in individuals with Alzheimer disease, neuronal size inversely correlates with disease duration and positively associates with oxidative stress. Overall, clarifying cellular and molecular manifestations involved in metabolic alterations may contribute to a better understanding of early Alzheimer disease pathophysiology.

Zhu X, Smith MA, Honda K, Aliev G, Moreira PI, Nunomura A, Casadesus G, Harris PL, Siedlak SL, Perry G. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neurol Sci. · Pubmed #17337008 links to  free full text

Abstract: Alzheimer disease and cerebrovascular dementia are two common causes of dementia and, by present diagnostic criteria, are mutually exclusive using vascular pathology as an arbitrary demarcation in differential diagnosis. However, evidence from epidemiological, neuropathological, clinical, pharmacological, and functional studies suggest considerable overlap in risk factors and pathological changes suggesting shared common pathogenic mechanisms between these two diseases such that vascular factors play a vital role in the pathogenesis of Alzheimer disease. A high energy demand and lack of an endogenous fuel reserve make the brain highly dependent upon a continuous blood supply where disruption of cerebral blood vessels and blood flow can have serious consequences on neural activities. Indeed, many studies implicate metabolic defects in Alzheimer disease, such a reduced brain metabolism is one of the best documented abnormalities in the disease. Notably, since endothelial reactive oxygen species such as nitric oxide act as vasodilators at low concentrations, increased production coupled with elevated reactive oxygen species scavenging of nitric oxide, can lead to reduced bioavailability of nitric oxide and increased oxidative stress that damage sensitive vascular cells. In this respect, we and others have demonstrated that oxidative stress is one of the earliest pathological changes in the brain of Alzheimer disease patients and plays a critical role in the vascular abnormalities underlying metabolic defects in Alzheimer disease. Here, we discuss vascular factors in relation to Alzheimer disease and review hypoperfusion as a potential cause by triggering mitochondrial dysfunction and increased oxidative stress initiating the pathogenic process.

Neils-Strunjas J, Groves-Wright K, Mashima P, Harnish S. · University of Cincinnati, OH, USA. · J Speech Lang Hear Res. · Pubmed #17197498 No free full text.

Abstract: PURPOSE: This article presents a critical review of literature on dysgraphia associated with Alzheimer's disease (AD). Research presented includes discussions of central and peripheral spelling impairments as well as the impact of general, nonlinguistic cognitive functions on dysgraphia associated with AD. METHOD: The studies critically reviewed were from a variety of disciplines, with emphasis on seminal work, recent literature, and the first author's research. CONCLUSIONS: Studies have shown that writing impairment is heterogeneous within the AD population; however, there are certain aspects of the writing process that are more vulnerable than others and may serve as diagnostic signs. Identifying patterns of writing impairment at different stages of AD may help to chart disease progression and assist in the development of appropriate interventions.

Ryman D, Lamb BT. · Department of Neurosciences, Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Avenue, NC30, Cleveland, OH 44195, USA. · Curr Alzheimer Res. · Pubmed #17168645 No free full text.

Abstract: As a group, strains of laboratory mice carrying Alzheimer's disease (AD)-related transgenes are currently the most widely studied animal models of AD. Many AD mouse models carrying the same or similar transgene constructs demonstrate strikingly different phenotypic responses to transgene expression, mimicking the apparent genetic complexity of AD pathogenesis seen in the human population. Genetic differences between the numerous mouse model strains used for AD research can significantly affect correct interpretation and cross-comparison of experimental findings, making genetic background an important consideration for all work in mouse models of AD. Furthermore, because of the potential for discovering novel genetic modifiers of AD pathogenesis, the effects of genetic background on AD phenotypes in the mouse can prove a worthwhile subject of study in their own right. This review discusses the implications of genetic modifiers for mouse and human AD research, and summarizes recent findings identifying significant roles for genetic background in modifying important phenotypes in AD mouse models, including premature death, amyloid deposition, tau hyperphosphorylation, and responsiveness to environmental or treatment interventions.

Yang Y, Herrup K. · Department of Neurology, University Hospitals of Cleveland, Alzheimer Research Lab, E504, Case Western Reserve University School of Medicine, 10900 Euclid Avenue Cleveland, OH 44106, USA. · Biochim Biophys Acta. · Pubmed #17158035 No free full text.

Abstract: Cell cycle events have been documented to be associated with several human neurodegenerative diseases. This review focuses on two diseases--Alzheimer's disease and ataxia telangiectasia--as well as their mouse models. Cell cycle studies have shown that ectopic expression of cell cycle markers is spatially and regional correlated well with neuronal cell death in both disease conditions. Further evidence of ectopic cell cycling is found in both human diseases and in its mouse models. These findings suggest that loss of cell cycle control represents a common pathological root of disease, which underlies the defects in the affected brain tissues in both human and mouse. Loss of cell cycle control is a unifying hypothesis for inducing neuronal death in CNS. In the disease models we have examined, cell cycle markers appear before the more well-recognized pathological changes and thus could serve as early stress markers--outcome measures for preclinical trials of potential disease therapies. As a marker these events could serve as a new criterion in human pathological diagnosis. The evidence to date is compatible with the requirement for a second "hit" for a neuron to progress cell cycle initiation and DNA replication to death. If this were true, any intervention of blocking 'second' processes might prevent or slow the neuronal cell death in the process of disease. What is not known is whether, in an adult neuron, the cell cycle event is part of the pathology or rather a desperate attempt of a neuron under stress to protect itself.

Zhu X, Lee HG, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, OH 44106, USA. · Biochim Biophys Acta. · Pubmed #17142016 No free full text.

Abstract: Given the relative modality of single-insult models to accurately reflect Alzheimer disease pathogenesis, based on studies on mitogenic and oxidative stress signaling pathways, we proposed a two-hit hypothesis 2 years ago stating that both oxidative stress and mitogenic dysregulation are necessary and sufficient to cause the disease and suggested that it may be a common mechanism for other neurodegenerative diseases as well (X. Zhu, A.K. Raina, G. Perry, M.A. Smith, Alzheimer's disease: the two-hit hypothesis, Lancet Neurol. 3 (2004) 219-226). Recent developments in the field confirm some important predictions of the hypothesis and shed new lights on potential mechanisms regarding how steady state may be achieved in sporadic AD cases and therefore, in our opinion, strengthen the hypothesis, which will be the focus of this review.

Whitehouse PJ. · Department of Neurology, Case Western Reserve University, Cleveland, OH 44120, USA. · Alzheimer Dis Assoc Disord. · Pubmed #17132959 No free full text.

This publication has no abstract.

Kanter SJ, Factora RM, Suh TT. · Section of Geriatric Medicine, Department of General Internal Medicine, Cleveland Clinic Foundation, OH 44195, USA. · Cleve Clin J Med. · Pubmed #17128545 links to  free full text

Abstract: Primary progressive aphasia (PPA) is a distinct clinical entity in which the patient develops language deficits while other cognitive domains remain relatively preserved until late in the course of the illness. The diagnosis can be relatively clear through an appropriate diagnostic approach based on the history and physical examination. There is no cure, but speech therapy is beneficial in this illness.

McShea A, Marlatt MW, Lee HG, Tarkowsky SM, Smit M, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA. · J Neuropathol Exp Neurol. · Pubmed #17086099 No free full text.

Abstract: 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.

Webber KM, Casadesus G, Atwood CS, Bowen RL, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, Cleveland, OH, USA. · Mol Cell Endocrinol. · Pubmed #17052835 No free full text.

Abstract: While there is ample experimental evidence supporting the role of estrogen in the pathogenesis of Alzheimer disease, recent inconclusive data regarding hormone replacement therapy (HRT), specifically, the unexpected results of the Women's Health Initiative (WHI) Memory Study has raised serious questions regarding the protective effects of estrogen. Because of this and other inconsistencies in the estrogen hypothesis, we propose that another hormone of the hypothalamic-pituitary-gonadal axis, luteinizing hormone, is a major factor in the pathogenesis of Alzheimer disease. Specifically, we suspect that the increase in gonadotropin concentrations, and not the decrease in steroid hormone (e.g., estrogen) production following menopause/andropause, is a 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.

Zhu X, Raina AK, Perry G, Smith MA. · Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio 44106 USA. · Curr Alzheimer Res. · Pubmed #17017869 No free full text.

Abstract: Neuronal cell dysfunction and death are cardinal features of Alzheimer disease and a great deal of effort is being expended not only to understand factors involved in the cause and progression of disease (i.e., disease initiators and propagators) but, ultimately, the precise mechanism by which neurons die (for want of a better word, the terminators). Understanding each and every component of the complex pathway that ultimately leads to disease (a clinical phenotype) is clearly of paramount importance for the development of effective therapeutic strategies. Of particular intrigue for many scientists, perhaps the more macabre among us, has been to decipher the final event - namely cell death. Broadly speaking, cell death falls into two categories, apoptotic and necrotic. The former, apoptosis, by definition, is a controlled event; thereby offering the potential for intervention, whereas necrosis is a more stochastic process. Since many of the propagators and exacerbators involved in Alzheimer disease are pro-apoptotic, it is not surprising that certain aspects of apoptosis are evident. However, it would be a mistake to call this apoptosis. In fact, as reviewed herein, the chronic course of disease together with the necessarily slow rate of neuronal death makes apoptotic cell death in Alzheimer disease a mathematical improbability. The numbers simply do not add up.

Perry G. · Institute of Pathology, Case Western Reserve University, Cleveland, OH, USA. · J Alzheimers Dis. · Pubmed #17004366 No free full text.

Abstract: Dissection of neurofibrillary tangles has been confounded by the insolubility of their fibers. While the majority of biochemical studies have considered tau filaments equivalent to neurofibrillary tangles, they forget that the former are soluble and the latter completely resistant to solvents. What, then, accounts for the insolubility of neurofibrillary tangles while tau filaments are soluble? Investigation of these distinctions played a critical role in our findings on proteolytic abnormalities and oxidative stress.

Beatty GE. · Liver Transplant Program, University Hospital, Cincinnati, Ohio, USA. · Nurse Pract. · Pubmed #16971831 No free full text.

This publication has no abstract.

de la Torre JC. · Institute of Pathology, Case Western Reserve School of Medicine, Gig Harbor, WA, USA. · Neurol Res. · Pubmed #16945216 No free full text.

Abstract: BACKGROUND: Heart disease and stroke are two of the major leading causes of death and disability in the world. Mainly affecting the elderly population, heart disease and stroke are important risk factors for Alzheimer's disease (AD). METHODS: This review examines the evidence linking chronic brain hypoperfusion (CBH) produced by several types of heart disease and stroke on the development of AD. RESULTS: The evidence indicates a strong association between such risk factors as coronary artery bypass surgery (CABG), atrial fibrillation, aortic/mitral valve damage, hypertension, hypotension, congestive heart failure, cerebrovascular-carotid atherosclerosis, and transient ischemic attacks in producing CBH. In people whose cerebral perfusion is already diminished by their advanced age, further cerebral blood flow reductions from heart-brain vascular-related risk factors, seemingly increases the probability of AD. The evidence also suggests that a neuronal energy crisis brought on by a relentless CBH is responsible for protein synthesis defects that later result in the classic AD neurodegenerative lesions such as the formation of excess beta-amyloid plaques and neurofibrillary tangles. CONCLUSIONS: Knowledge of how heart disease and stroke can progress to AD should provide a better understanding of the physiopathology characteristic of AD and also target more precise therapy in preventing, controlling or reversing this dementia.

Wenk GL, Parsons CG, Danysz W. · Department Psychology & Neuroscience, Ohio State University, Ohio, USA. · Behav Pharmacol. · Pubmed #16940762 No free full text.

Abstract: Glutamatergic neurotransmission is critical to normal learning and memory and when the activity of glutamate neurons becomes excessive, or the normal function of its primary receptors becomes dysfunctional, this may lead to pathological changes associated with age-related neurodegenerative diseases. Anomalous glutamatergic activity associated with Alzheimer's disease may be due to a postsynaptic receptor and downstream defects that produce inappropriately timed or sustained glutamate activation of N-methyl-D-aspartate receptors, leading to neuronal injury and death and cognitive deficits associated with dementia. The mechanisms leading to the condition of chronically depolarized membranes on vulnerable neurons in the Alzheimer's disease brain are likely due to a complex interaction between oxidative stress, mitochondrial failure, chronic brain inflammation and the presence of amyloid-beta and hyperphosphorylated-tau; each of these factors are highly interrelated with each other and are discussed with an emphasis upon potential therapeutic mechanisms underlying the neuroprotective actions of memantine.