Novel therapeutics for Alzheimer's disease: an update.

As the most prevalent form of dementia worldwide, Alzheimer's disease (AD) continues to be a burden for patients and their families. In addition, with the global population of aged individuals increasing exponentially, AD represents a significant economic burden to society. The development of an effective approach for the treatment of AD is thus of major importance, as current treatment strategies are limited to agents that attenuate disease symptomatology without addressing the causes of disease.

Treatment advances in Alzheimer's disease based on the oxidative stress model.

Effective therapy for Alzheimer's disease (AD), up to this point, has been hampered by our inability to diagnose the disease in its early stages, before the occurrence of significant neurodegeneration and clinical symptoms. Because AD historically has been defined by neuropathologic criteria, treatment strategies have been aimed at diminishing the pathologic end result of the disease process, namely neurodegenerative changes associated with extracellular amyloid-beta-containing plaques, as well as intracellular neurofibrillary tangles of the hyper-phosphorylated microtubule protein, tau. While these avenues continue to be pursued, results thus far have been disappointing.

L-arginine and Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia, is characterized by progressive neurodegeneration and loss of cognitive and memory functions. Although the exact causes of AD are still unclear, evidence suggests that atherosclerosis, redox stress, inflammation, neurotransmitter dysregulation, and impaired brain energy metabolism may all be associated with AD pathogenesis. Herein, we explore a possible role for L-arginine (L-arg) in AD, taking into consideration known functions for L-arg in atherosclerosis, redox stress and the inflammatory process, regulation of synaptic plasticity and neurogenesis, and modulation of glucose metabolism and insulin activity.

Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease.

The essential metals iron, zinc and copper deposit near the Abeta (amyloid beta-peptide) plaques in the brain cortex of AD (Alzheimer's disease) patients. Plaque-associated iron and zinc are in neurotoxic excess at 1 mM concentrations. APP (amyloid precursor protein) is a single transmembrane metalloprotein cleaved to generate the 40-42-amino-acid Abetas, which exhibit metal-catalysed neurotoxicity.

Prospects for redox-based therapy in neurodegenerative diseases.

Accumulating evidence supports a primary role for perturbations in redox metabolism in the pathogenesis of many neurodegenerative diseases. This evidence derives mainly from molecular genetic analysis, direct observation from post-mortem human brain, and biochemical, pathologic, and therapeutic studies in transgenic and other animal models of neurodegeneration. We review here the evidence for redox-mediated pathogenesis in neurodegenerative diseases.

Alzheimer disease beta-amyloid activity mimics cholesterol oxidase.

The abnormal accumulation of amyloid beta-peptide (Abeta) in the form of senile (or amyloid) plaques is one of the main characteristics of Alzheimer disease (AD). Both cholesterol and Cu2+ have been implicated in AD pathogenesis and plaque formation. Abeta binds Cu2+ with very high affinity, forming a redox-active complex that catalyzes H2O2 production from O2 and cholesterol.

Neuronal zinc exchange with the blood vessel wall promotes cerebral amyloid angiopathy in an animal model of Alzheimer's disease.

Cerebral amyloid angiopathy (CAA) is common in Alzheimer's disease (AD) and may contribute to dementia and cerebral hemorrhage. Parenchymal beta-amyloid deposition is dependent on the activity of zinc transporter 3 (ZnT3), a neocortical synaptic vesicle membrane protein that causes enrichment of exchangeable Zn2+ in the vesicle, which is externalized on neurotransmission. However, the contribution of zinc to vascular beta-amyloid deposition remains unclear.

BCL-2 improves oxidative phosphorylation and modulates adenine nucleotide translocation in mitochondria of cells harboring mutant mtDNA.

Members of the BCL-2-related antiapoptotic family of proteins have been shown previously to regulate ATP/ADP exchange across the mitochondrial membranes and to prevent the loss of coupled mitochondrial respiration during apoptosis. We have found that BCL-2/BCL-x(L) can also improve mitochondrial oxidative phosphorylation in cells harboring pathogenic mutations in mitochondrial tRNA genes. The effect of BCL-2 overexpression in mutated cells was independent from apoptosis and was presumably associated with a modulation of adenine nucleotide exchange between mitochondria and cytosol.

Creatine increase survival and delays motor symptoms in a transgenic animal model of Huntington's disease.

There is substantial evidence for bioenergetic defects in Huntington's disease (HD). Creatine administration increases brain phosphocreatine levels and it stabilizes the mitochondrial permeability transition. We examined the effects of creatine administration in a transgenic mouse model of HD produced by 82 polyglutamine repeats in a 171 amino acid N-terminal fragment of huntingtin (N171-82Q).

Effects of an inhibitor of poly(ADP-ribose) polymerase, desmethylselegiline, trientine, and lipoic acid in transgenic ALS mice.

The development of transgenic mouse models of amyotrophic lateral sclerosis (ALS) allows the testing of neuroprotective agents. We evaluated the effects of five agents in transgenic mice with the G93A Cu,Zn superoxide dismutase mutation. A novel inhibitor of poly(ADP-ribose) polymerase showed no effects on survival.

Activation of neuronal extracellular receptor kinase (ERK) in Alzheimer disease links oxidative stress to abnormal phosphorylation.

Responses to increased oxidative stress may be the common mechanism responsible for the varied cytopathology of Alzheimer disease (AD). A possible link in support of this hypothesis is that one of the most striking features of AD, the abnormal accumulation of highly phosphorylated tau and neurofilament proteins, may be brought about by extracellular receptor kinase (ERK) whose activation is a common response to oxidative stress. In this study, we demonstrate that activated ERK is specifically increased in the same vulnerable neurons in AD that are the site of oxidative damage and abnormal phosphorylation.

Involvement of free oxygen radicals in beta-amyloidosis: an hypothesis.

Compelling evidence suggests that cerebral deposition of aggregating beta-amyloid protein may trigger the neurodegenerative cascades of Alzheimer's disease, Down syndrome, and, to a lesser degree, normal aging. We propose further that free oxygen radicals are critically involved in beta-amyloidosis. Apart from the established role of free radicals in other amyloidoses, our proposal is consistent with a large number of findings.

Regional differences in pulmonary vascular resistance in the same patient. A study of partial anomalous pulmonary venous return, intact atrial septum, and mitral stenosis before and after surgical correction.

Using hemodynamic and radionuclide perfusion data, we measured regional pulmonary vascular resistances in a patient with mitral stenosis and anomalous pulmonary venous drainage with intact atrial septum before and after surgical correction. Pulmonary vascular resistance in the right upper lung region that had anomalous drainage to a normal-pressure right atrium was compared to resistance of a region in the left upper lung similar in size that had normal drainage to a high-pressure left atrium. Preoperatively, pulmonary vascular resistance in both regions was elevated but was considerably higher in the left upper lung region.

Valve replacement for aortic regurgitation: long-term follow-up with factors influencing the results.

One hundred consecutive cases of valve replacement for aortic regurgitation performed between 1967--1971 were analyzed to identify and quantitate factors related to a favorable result. Of 83 perioperative survivors, 78% (n = 65) became asymptomatic and 58% (n = 48) were alive 5--9 years postoperatively. The cause of aortic regurgitation affected both the speed of progression of symptoms and the postoperative result.

Influence of etiology of atrial fibrillation on incidence of systemic embolism.

Atrial fibrillation is well known to increase greatly the risk of systemic arterial embolism in patients with mitral valve disease. In light of the clinical frequency of embolism in patients with atrial fibrillation due to other types of heart disease, a study was made of embolic occurrences in 333 autopsy patients with atrial fibrillation associated with various kinds of heart disease. Considering only symptomatic emboli with pathologic or surgical confirmation, embolism occurred in 41% of patients with mitral valve disease, 35% of those with ischemic heart disease, 35% of those with coexisting mitral and ischemic heart disease and 17% of those with "other" types of heart disease.

Survival following free rupture of left ventricular aneurysm: report of a case.

A 50-year-old man sustained free rupture of the left ventricle four weeks following a massive anterior myocardial infarction. The rupture occurred at the junction between a bulging left ventricular aneurysm that was not yet fibrotic and normal myocardium without evidence of fresh myocardial infarction. Accurate preoperative diagnosis aided by echocardiography and right heart catheterization made possible a planned surgical approach.

Pulmonary atresia with ventricular septal defect: report of the oldest known surviving case.

The case of a 54-year-old housewife, oldest published survivor with pulmonary atresia and a ventricular septal defect (pseudotruncus arteriosus), is reported. Her remarkably favorable course is likely related to the absence of progressive hemodynamic changes, with moderate pulmonary flow adequate for nearly normal arterial oxygenation yet without increasing pulmonary vascular resistance. This case reemphasizes the relationship of longevity to pulmonary blood flow volume with this defect.