Orwik

Modeling cholesterol metabolism by gene expression profiling in the hippocampus.

An important part of the challenge of building models of biochemical reactions is determining reaction rate constants that transform substrates into products. We present a method to derive enzymatic kinetic values from mRNA expression levels for mode... expand abstractling biological networks without requiring further tuning. The core metabolic reactions of cholesterol in the brain, particularly in the hippocampus, were simulated. To build the model the baseline mRNA expression levels of genes involved in cholesterol metabolism were obtained from the Allen Mouse Brain Atlas. The model is capable of replicating the trends of relative cholesterol levels in Alzheimer's and Huntington's diseases; and reliably simulated SLOS, desmosterolosis, and Dhcr14/Lbr knockout studies. A sensitivity analysis correctly uncovers the Hmgcr, Idi2 and Fdft1 sites that regulate cholesterol homeostasis. Overall, our model and methodology can be used to pinpoint key reactions, which, upon manipulation, may predict altered cholesterol levels and reveal insights into potential drug therapy targets under diseased conditions. collapse abstract

Role of metal dyshomeostasis in Alzheimer's disease.

Despite serving a crucial purpose in neurobiological function, transition metals play a sinister part in the aging brain, where the abnormal accumulation and distribution of reactive iron, copper, and zinc elicit oxidative stress and macromolecular d... expand abstractamage that impedes cellular function. Alzheimer's disease (AD), an age-related neurodegenerative condition, presents marked accumulations of oxidative stress-induced damage, and increasing evidence points to aberrant transition metal homeostasis as a critical factor in its pathogenesis. Amyloid-β oligomerization and fibrillation, considered by many to be the precipitating factor underlying AD onset and development, is also induced by abnormal transition metal activity. We here elaborate on the roles of iron, copper, and zinc in AD and describe the therapeutic implications they present. collapse abstract

Insulin-resistant brain state: the culprit in sporadic Alzheimer's disease?

Severe abnormalities in brain glucose/energy metabolism and insulin signaling have been documented to take a pivotal role in early sporadic Alzheimer's disease (sAD) pathology. Indeed, the "insulin-resistant brain state" has been hypothesized to form... expand abstract the core of the neurodegenerative events that occur in sAD. In this vein, intracerebroventricular administration of subdiabetogenic doses of streptozotocin (STZ) in rats can induce an insulin-resistant brain state, which is proposed as a suitable experimental model of sAD. This review highlights the involvement of disturbed brain insulin metabolism in sAD etiopathogenesis. Furthermore, current knowledge demonstrates that central STZ administration produces brain pathology and behavioral changes that resemble changes found in sAD patients. The STZ-intracerebroventricularly treated rat represents a promising experimental tool in this field by providing new insights concerning early brain alterations in sAD, which can be translated in novel etiopathogenic and therapeutic approaches in this disease. collapse abstract

Mark Anthony Smith (1965-2010): Visionary, Alzheimer Researcher, and Editor-in-Chief of the Journal of Alzheimer's Disease.

Drug Discovery for Neurodegenerative Diseases: Challenges and Novel Biochemical TargetsDedicated to the memory of Mark A. Smith for his inspiring contribution to Alzheimer's disease.

Widespread distribution of reticulon‐3 in various neurodegenerative diseases

No abstract is available for this article.

CD3 in Lewy pathology: does the abnormal recall of neurodevelopmental processes underlie Parkinson's disease.

CD3ζ is a subunit of the CD3 molecule that, until recently, appeared restricted to T cells and natural killer cells. However, experimental studies have demonstrated a role of CD3ζ in dendritic outgrowth in the visual system as well as in synaptic pla... expand abstractsticity. Given the increasing evidence for uncharacteristic recapitulation of neurodevelopmental processes in neurodegenerative diseases, in this study, we evaluated brains from subjects with Parkinson's disease and Lewy body dementia for evidence of aberrant CD3 expression. Our data shows marked CD3ζ in association with the α-synuclein containing pathological lesions, i.e., Lewy bodies and Lewy neurites, in the brains of subjects with Parkinson's disease and Lewy body dementia. This finding raises the novel concept of CD3 dysregulation in these disorders as a pathogenic factor and also furthers the increasing evidence that the recall of aberrant neurodevelopmental processes underlies the pathogenesis of neurodegenerative diseases. collapse abstract

Potential role of iron in a Mediterranean-style diet.

Frontiers in Alzheimer’s disease therapeutics

Alzheimer’s disease (AD) is a progressive neurodegenerative disease which begins with insidious deterioration of higher cognition and progresses to severe dementia. Clinical symptoms typically involve impairment of memory and at least one other cogni... expand abstracttive domain. Owing to the exponential increase in the incidence of AD with age, the aging population across the world has seen a congruous increase in AD, emphasizing the importance of disease-altering therapy. Current therapeutics on the market, including cholinesterase inhibitors and N -methyl- D -aspartate receptor antagonists, provide symptomatic relief but do not alter progression of the disease. Therefore, progress in the areas of prevention and disease modification may be of critical interest. In this review, we summarize novel AD therapeutics that are currently being explored, and also mechanisms of action of specific drugs within the context of current knowledge of AD pathologic pathways. collapse abstract

Mitochondrial preconditioning: a potential neuroprotective strategy.

Mitochondria have long been known as the powerhouse of the cell. However, these organelles are also pivotal players in neuronal cell death. Mitochondrial dysfunction is a prominent feature of chronic brain disorders, including Alzheimer's disease (AD... expand abstract) and Parkinson's disease (PD), and cerebral ischemic stroke. Data derived from morphologic, biochemical, and molecular genetic studies indicate that mitochondria constitute a convergence point for neurodegeneration. Conversely, mitochondria have also been implicated in the neuroprotective signaling processes of preconditioning. Despite the precise molecular mechanisms underlying preconditioning-induced brain tolerance are still unclear, mitochondrial reactive oxygen species generation and mitochondrial ATP-sensitive potassium channels activation have been shown to be involved in the preconditioning phenomenon. This review intends to discuss how mitochondrial malfunction contributes to the onset and progression of cerebral ischemic stroke and AD and PD, two major neurodegenerative disorders. The role of mitochondrial mechanisms involved in the preconditioning-mediated neuroprotective events will be also discussed. Mitochondrial targeted preconditioning may represent a promising therapeutic weapon to fight neurodegeneration. collapse abstract

Mathematical Modeling of Microtubule Dynamics: Insights into Physiology and Disease.

Computer models of microtubule dynamics have provided the basis for many of the theories on the cellular mechanics of the microtubules, their polymerization kinetics, and the diffusion of tubulin and tau. In the three dimensional model presented here... expand abstract, we include the effects of tau concentration and the hydrolysis of GTP-tubulin to GDP-tubulin and observe the emergence of microtubule dynamic instability. This integrated approach simulates the essential physics of microtubule dynamics in a cellular environment. The model captures the structure of the microtubules as they undergo steady state dynamic instabilities in this simplified geometry, and also yields the average number, length, and cap size of the microtubules. The model achieves realistic geometries and simulates cellular structures found in degenerating neurons in disease states such as Alzheimer disease. Further, this model can be used to simulate microtubule changes following the addition of antimitotic drugs which have recently attracted attention as chemotherapeutic agents. collapse abstract

Cholesterol homeostasis markers are localized to mouse hippocampal pyramidal and granule layers

Changes in brain cholesterol homeostasis are associated with multiple diseases, such as Alzheimer's and Huntington's; however, controversy persists as to whether adult neurons produce their own cholesterol, or if it is outsourced to astrocytes. To ad... expand abstractdress this issue, we analyzed 25 genes most immediately involved in cholesterol homeostasis from in situ data provided by the Allen Brain Mouse Atlas. We compared the relative mRNA expression in the pyramidal and granule layers, populated with neurons, with the rest of the hippocampus which is populated with neuronal processes and glia. Comparing the expression of the individual genes to markers for neurons and astrocytes, we found that cholesterol homeostasis genes are preferentially targeted to neuronal layers. Therefore, changes in gene expression levels might affect neuronal populations directly. © 2010 Wiley-Liss, Inc. collapse abstract

Variably protease‐sensitive prionopathy: A new sporadic disease of the prion protein

No abstract is available for this article.

Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein.

OBJECTIVE: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV).... expand abstract The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). METHODS: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. RESULTS: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. INTERPRETATION: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease. collapse abstract

Indoleamine 2,3-dioxygenase and 3-hydroxykynurenine modifications are found in the neuropathology of Alzheimer's disease.

Tryptophan metabolism, through the kynurenine pathway, produces neurotoxic intermediates that are implicated in the pathogenesis of Alzheimer's disease. In particular, oxidative stress via 3-hydroxykynurenine (3-HK) and its cleaved product 3-hydroxya... expand abstractnthranilic acid (3-HAA) significantly damages neuronal tissue and may potentially contribute to a cycle of neurodegeneration through consequent amyloid-beta accumulation, glial activation, and up-regulation of the kynurenine pathway. To determine the role of the kynurenine pathway in eliciting and continuing oxidative stress within Alzheimer's diseased brains, we used immunocytochemical methods to show elevated levels of 3-HK modifications and the upstream, rate-limiting enzyme indoleamine 2,3-dioxygenase (IDO-1) in Alzheimer's diseased brains when compared to controls. Importantly, the association of IDO-1 with senile plaques was confirmed and, for the first time, IDO-1 was shown to be specifically localized in conjunction with neurofibrillary tangles. As senile plaques and neurofibrillary tangles are the pathological hallmarks of Alzheimer's disease, our study provides further evidence that the kynurenine pathway is involved with the destructive neurodegenerative pathway of Alzheimer's disease. collapse abstract

Specific reaction of Met 35 in amyloid beta peptide with hypochlorous acid.

The reaction of the amyloid beta peptide (Abeta) with hypochlorous acid and hydroxyl radicals was analysed by spectrophotometry and mass spectrometry. N-acetylmethionine, Abeta25-35 and Abeta1-42 reacted rapidly with hypochlorous acid. The relative r... expand abstracteaction rates of N-acetylmethionine and Abeta with hypochlorous acid was in the order N-acetylmethionine > Abeta25-35 > Abeta1-42. While the reaction of Abeta25-35 in the presence of a slight excess of hypochlorous acid resulted in complete conversion of Met35 to Met35 sulphoxide, Abeta1-42 required more than a 4-fold excess of hypochlorous acid for complete conversion of Met35. Identical products were obtained when Abeta25-35 and Abeta1-42 were treated with a hypochlorous acid generating system. Conversion of Met35 to Met35 sulphoxide in Abeta abolished the aggregation of Abeta25-35. Reaction of Abeta with hydroxyl radicals resulted in limited conversion of Met35 to Met35 sulphoxide. The specific reaction of Met35 in Abeta with hypochlorous acid to form Met35 sulphoxide has been analysed. collapse abstract

Antioxidant approaches for the treatment of Alzheimer's disease.

Oxidative stress is an important factor, and one that acts in the earliest stages, of Alzheimer's disease (AD) pathogenesis. The reduction of oxidative stress has been tested as a therapy for AD. While the trial of vitamin E supplementation in modera... expand abstracttely severe AD is the most promising so far, it also reveals the limitations of general antioxidant therapies that simply lower oxidative stress and, therefore, the complexity of the redox system. The multiple contributing factors that foster the clinical manifestations of AD should be considered when designing antioxidative stress therapy. In this article, we discuss the multiple pathogenic mechanisms of oxidative stress in AD and the potential targeting approaches. collapse abstract

Autophagy in Alzheimer's disease.

Autophagy is a degradation pathway for the turnover of dysfunctional organelles or aggregated proteins in cells. Extensive literature exists supporting a causative role of mitochondrial dysfunction and amyloid-beta protein in the pathogenesis of Alzh... expand abstracteimer's disease (AD). Furthermore, a link between mitochondrial dysfunction, amyloid-beta levels and autophagy has been reported to occur in AD. However, it is not yet clear if autophagy plays a causative role, a protective role or is a consequence of the disease process itself. Understanding the exact role of autophagy in different stages of AD progression may help to design more effective therapeutic strategies. A central issue in developing therapies for neurodegenerative diseases involves understanding why and when responses to stress or injury can help prevent neuronal degeneration and death. collapse abstract

Elevation of beta-amyloid 1-42 autoantibodies in the blood of amnestic patients with mild cognitive impairment.

OBJECTIVE: To develop a blood-based test for screening populations at risk for Alzheimer disease. DESIGN: Case-control study. Subjects A total of 180 patients with mild cognitive impairment (MCI) and 105 age-matched, cognitively normal controls. INTE... expand abstractRVENTIONS: The titer of beta-amyloid 1-42 autoantibodies in the plasma was obtained at the time of diagnosis and evaluated by enzyme-linked immunosorbent assay before and after dissociation of the antigen-antibody complexes. A total of 107 patients with MCI were followed up for 36 months; 70 of the 107 cases progressed to Alzheimer disease. RESULTS: The average level of beta-amyloid 1-42 plasma autoantibodies in patients with MCI that progressed to Alzheimer disease, but not that of the stable cases, was significantly higher than in cognitively normal controls (P < .001). CONCLUSIONS: The results suggest that the plasma beta-amyloid 1-42 autoantibodies parallel beta-amyloid 42 deposition in the brain, which is known to precede by several years the clinical onset of Alzheimer disease. The evaluation of beta-amyloid 1-42 autoantibodies after dissociation of the complexes is a simple and inexpensive method that can be used to predict the occurrence of Alzheimer disease. collapse abstract

Alzheimer's disease: diverse aspects of mitochondrial malfunctioning.

Alzheimer's disease is a progressive neurodegenerative disorder, either assuming a sporadic, age-associated, late-onset form, or a familial form, with early onset, in a smaller fraction of the cases. Whereas in the familial cases several mutations ha... expand abstractve been identified in genes encoding proteins related with the pathogenesis of the disease, for the sporadic form several causes have been proposed and are currently under debate. Mitochondrial dysfunction has surfaced as one of the most discussed hypotheses acting as a trigger for the pathogenesis of Alzheimer's disease. Mitochondria assume central functions in the cell, including ATP production, calcium homeostasis, reactive oxygen species generation, and apoptotic signaling. Although their role as the cause of the disease may be controversial, there is no doubt that mitochondrial dysfunction, abnormal mitochondrial dynamics and degradation by mitophagy occur during the disease process, contributing to its onset and progression. collapse abstract

Neurodegenerative diseases: mechanisms and therapies.

A synergistic dysfunction of mitochondrial fissionfusion dynamics and mitophagy in Alzheimer's disease.

Alzheimer's disease (AD), the most common form of dementia in the elderly, can have a late-onset sporadic or an early-onset familial origin. In both cases, the neuropathological hallmarks are the same: senile plaques and neurofibrillary tangles. Desp... expand abstractite AD having a proteinopathic nature, there is strong evidence for an organelle dysfunction-related neuropathology, namely dysfunctional mitochondria. In this regard, dysfunctional mitochondria and associated exacerbated generation of reactive oxygen species are among the earliest events in the progression of the disease. Since the maintenance of a healthy mitochondrial pool is essential given the central role of this organelle in several determinant cellular processes, mitochondrial dysfunction in AD would be predicted to have profound pluripotent deleterious consequences. Mechanistically, recent reports suggest that mitochondrial fission/fusion and mitophagy are altered in AD and in in vitro models of disease, and since both processes are reported to be protective, this review will discuss the role of mitochondrial fission/fusion and mitophagy in the pathogenesis of AD. collapse abstract

Mitochondria: the missing link between preconditioning and neuroprotection.

The quote "what does not kill you makes you stronger" perfectly describes the preconditioning phenomenon - a paradigm that affords robust brain tolerance in the face of neurodegenerative insults. Over the last few decades, many attempts have been mad... expand abstracte to identify the molecular mechanisms involved in preconditioning-induced protective responses, and recent data suggests that many of these mechanisms converge on the mitochondria, positing mitochondria as master regulators of preconditioning-triggered endogenous neuroprotection. In this review, we critically discuss evidence for the involvement of mitochondria within the preconditioning paradigm. We will highlight the crucial targets and mediators by which mitochondria are integrated into neuroprotective signaling pathways that underlie preconditioning, putting focus on mitochondrial respiratory chain and mitochondrial reactive oxygen species, mitochondrial ATP-sensitive potassium channels, mitochondrial permeability transition pore, uncoupling proteins, and mitochondrial antioxidant enzyme manganese superoxide dismutase. We also discuss the role of mitochondria in the induction of hypoxia-inducible factor-1, a transcription factor engaged in preconditioning-mediated neuroprotective effects. The identification of intrinsic mitochondrial mechanisms involved in preconditioning will provide new insights which can be translated into potential pharmacological interventions aimed at counteracting neurodegeneration. collapse abstract

Mitochondria and neurodegenerative diseases.

Paraffin-embedded tissue (PET) blot method: application to Alzheimer disease.

Traditionally, immunohistochemistry, immunoblotting, and histoblot have been used to detect protein in tissue samples. However, each of these techniques has a number of disadvantages. The sensitivity of protein detection in immunohistochemistry is lo... expand abstractst due to fixation or paraffin embedding methods that modify antigenic sites. The anatomical resolution and specific cellular involvement are lost in immunoblotting. Histoblot, a hybrid of these two techniques, is able to resolve these issues, but it cannot be applied to formalin-fixed tissues. A recent technique, paraffin-embedded tissue (PET) blot, retains the superior protein detection and anatomical resolution of histoblot and is applicable to formalin-fixed tissues. Unfortunately, a major obstacle to the widespread application of PET is the lack of a detailed methodological description. In this paper, we describe a PET blotting method that was formulated from our own empirical and experimental research in Alzheimer disease and a systematic review of the current literature. From this, we conclude that PET can be applied to a variety of conditions with a wide spectrum of pathology. collapse abstract