The aggregation propensity of Tau and amyloid-β in Alzheimer's disease.

Memory loss in Alzheimer's disease: are the alterations in the UPR network involved in the cognitive impairment?

Caspase-3 Is Enriched in Postsynaptic Densities and Increased in Alzheimer's Disease

Alzheimer’s disease (AD) is a degenerative neurological disease that primarily affects the elderly. Drug therapy is the main strategy for AD treatment, but current treatments suffer from poor efficacy and a number of side effects. Non-drug therapy is attracting more attention and may be a better strategy for treatment of AD. Hypoxia is one of the important factors that contribute to the pathogenesis of AD. Multiple cellular processes synergistically promote hypoxia, including aging, hypertension, diabetes, hypoxia/obstructive sleep apnea, obesity, and traumatic brain injury. Increasing evidence has shown that hypoxia may affect multiple pathological aspects of AD, such as amyloid-beta metabolism, tau phosphorylation, autophagy, neuroinflammation, oxidative stress, endoplasmic reticulum stress, and mitochondrial and synaptic dysfunction. Treatments targeting hypoxia may delay or mitigate the progression of AD. Numerous studies have shown that oxygen therapy could improve the risk factors and clinical symptoms of AD. Increasing evidence also suggests that oxygen therapy may improve many pathological aspects of AD including amyloid-beta metabolism, tau phosphorylation, neuroinflammation, neuronal apoptosis, oxidative stress, neurotrophic factors, mitochondrial function, cerebral blood volume, and protein synthesis. In this review, we summarized the effects of oxygen therapy on AD pathogenesis and the mechanisms underlying these alterations. We expect that this review can benefit future clinical applications and therapy strategies on oxygen therapy for AD.

The pathologic hallmarks of Alzheimer's disease (AD) include senile plaque, neurofibrillary tangles (NFTs), synaptic loss, and neurodegeneration. Senile plaque and NFTs are formed by accumulation of amyloid-β (Aβ) and hyperphosphorylated tau, respectively. Progressive synaptic dysfunction and loss closely correlate with cognitive deficits in AD. Based on studies of the genes responsible for familial AD and temporal patterns of pathologic changes in AD brains, the Aβ accumulation is thought to be a primary event that influences other AD pathologies in the developmental cascade of AD. However, the details of Aβ effects on the other AD pathologies remain poorly understood. In this review, we provide an overview of the effects of Aβ in AD brains, especially focusing on synaptic dysfunction and microglia. We have recently found abnormal accumulation of a key molecule for actin assembly in NFTs of AD brains, and it was revealed that the accumulation requires not only tau pathology but also an Aβ burden in a study using transgenic mouse models of AD. Synaptic integrity is morphologically maintained by the precise regulation of actin assembly. Therefore, the results suggest the possibility that Aβ may promote NFT maturation and induce synaptic dysfunction through the disturbance of actin assembly. Thus Aβ seems to be a promoting factor in brain aging. On the other hand, we have studied microglial phagocytic ability for a compensatory pathologic reaction to Aβ accumulation. Further studies on the Aβ-dependent AD pathologies may contribute to determining novel mechanisms of AD development and new therapeutic targets in AD.

Aberrant Protein S-Nitrosylation in Neurodegenerative Diseases

A specific polymorphism in the hemochromatosis (HFE) gene, H63D, is over-represented in neurodegenerative disorders such as amyotrophic lateral sclerosis and Alzheimer disease. Mutations of HFE are best known as being associated with cellular iron overload, but the mechanism by which HFE H63D might increase the risk of neuron degeneration is unclear. Here, using an inducible expression cell model developed from a human neuronal cell line SH-SY5Y, we reported that the presence of the HFE H63D protein activated the unfolded protein response (UPR). This response was followed by a persistent endoplasmic reticulum (ER) stress, as the signals of UPR sensors attenuated and followed by up-regulation of caspase-3 cleavage and activity. Our in vitro findings were recapitulated in a transgenic mouse model carrying Hfe H67D, the mouse equivalent of the human H63D mutation. In this model, UPR activation was detected in the lumbar spinal cord at 6 months then declined at 12 months in association with increased caspase-3 cleavage. Moreover, upon the prolonged ER stress, the number of cells expressing HFE H63D in early apoptosis was increased moderately. Cell proliferation was decreased without increased cell death. Additionally, despite increased iron level in cells carrying HFE H63D, it appeared that ER stress was not responsive to the change of cellular iron status. Overall, our studies indicate that the HFE H63D mutant protein is associated with prolonged ER stress and chronically increased neuronal vulnerability.

New unexpected role for Wolfram Syndrome protein WFS1: a novel therapeutic target for Alzheimer's disease?

Ageing is driven by the inexorable and stochastic accumulation of damage in biomolecules vital for proper cellular function. Although this process is fundamentally haphazard and uncontrollable, senescent decline and ageing is broadly influenced by genetic and extrinsic factors. Numerous gene mutations and treatments have been shown to extend the lifespan of diverse organisms ranging from the unicellular Saccharomyces cerevisiae to primates. It is becoming increasingly apparent that most such interventions ultimately interface with cellular stress response mechanisms, suggesting that longevity is intimately related to the ability of the organism to effectively cope with both intrinsic and extrinsic stress. Here, we survey the molecular mechanisms that link ageing to main stress response pathways, and mediate age-related changes in the effectiveness of the response to stress. We also discuss how each pathway contributes to modulate the ageing process. A better understanding of the dynamics and reciprocal interplay between stress responses and ageing is critical for the development of novel therapeutic strategies that exploit endogenous stress combat pathways against age-associated pathologies.

Pathology in Alzheimer's Disease: General: 1. The Pathogenesis of Alzheimer's Disease R.D. Terry. 2. Molecular and Cellular Abnormalities of Tau in Early Alzheimer's Disease P. Davis, et al. Apoliprotein E: 3. ApoE and Memory in Alzheimer's Disease H.S. Soininen, P.J. Riekkinen, Sr. 4. Divergent Metabolism of Apolipoproteins E3 and E4 by Cells R.E. Pitas, et al. 5. APP, ApoE, and Presenilin Transgenics: Toward a Genetic Model of Alzheimer's Disease L. Pradier, et al. Apoptosis Oxidative Stress Amyloids, Inflammation and Other Defects: 8. Apoptosis in Alzheimer's Disease: Inductive Agents and Antioxidant Protective Factors C.W. Cotman, C.J. Pike. 9. Membrane Constituencies and Receptor Subtype Contribute to Age-Related Increases in Vulnerability to Oxidative Stress: Implications for Neurodegenerative Disease J.A. Joseph, et al. 10. Mitochondrial Dysfunction and Alzheimer's Disease S.S. Ghosh, et al. 11. Mitochondrial Dysfunction in Parkinson's Disease: Potential Applications for Cybrid Modeling of the Disease R.H. Swerdlow, et al. Amyloid Aggregation: 27. Amyloid-beta Hypothesis of Alzheimer's Disease M.S. Shearman. 28. Discovery and Characterization of Peptidoorganic Inhibitors of Amyloid beta-Peptide Polymerization M.A. Findeis, S.M. Molineaux. 29. Anthracyclines and Amyloidosis C. Post, et al. 30. The Amino Terminus of the beta-Amyloid Peptide Contains an Essential Epitope for Maintaining Its Solubility B. Solomon, et al. 31. Animal Models of Amyloid Aggregation and Deposition R. Kisilevsky Tau in Alzheimer's Disease: 32. The Conformations of Tau Protein and Its Aggregation into Alzheimers Paired Helical Filaments E. Mandelkow, et al. Alzheimer's Disease/Parkinsons's Disease and Related Disorders: Clinical and Etiological Aspects: 37. Different Cognitive Profiles on Memory Tests in Parkinson's Disease and Alzheimer's Disease R.F. Allegri, et al. Parkinson's Disease--Etiology, Genetics, Treatment: 56. Genetic Aspects of Parkinson's Disease Y. Mizuno, et al. Cholinergic Strategies in Alzheimer's and Parkinson's Disease: 64. The Rationale for Development of Cholinergic Therapies in AD A. Enz, P.T. Francis. Alzheimer's Disease--Muscarinic Treatment and Therapy--beta-Amyloids: 70. APP Localization and Trafficking in the Central Nervouse System J.D. Buxbaum, et al. Cholinesterase Inhibitors for Treatment of Alzheimer's Disease: 75. Crystallographic Studies on Complexes of Acetylcholinesterase with the Natural Cholinesterase Inhibitors Fasciculin and Huperzine A I. Silman, et al. Neurotrophic Factor Therapy--Neuroprotection, Neurotransplantation and Other Treatment Strategies: 86. Functional Effects of GDNF on Dopamine Neurons in Animal Models of Parkinson's Disease A.F. Hoffman, et al. Animal Models in Alzheimer's and Parkinson's Diseases: 93. Age Dependence of Muscarinic Plasticity in the Rat Hippocampus J.M. Auerbach, M. Segal. Diagnostic Too

Tau Pathology Generated by Overexpression of Tau

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

The cellular response to aggregated proteins associated with human disease.

Lack of Tau Proteins Rescues Neuronal Cell Death and Decreases Amyloidogenic Processing of APP in APP/PS1 Mice

Amyloid plaques and neurofibrillary tangles are the major pathological hallmarks of Alzheimer's disease. Neurofibrillary tangles are composed of filaments and paired helical filaments containing polymerized hyperphosphorylated tau protein. Derlin proteins are a family of proteins that are conserved in all eukaryotes, in which they function in endoplasmic reticulum-associated degradation. Protein disulfide isomerase (PDI) is a member of the thioredoxin superfamily and is believed to accelerate the folding of disulfide-bonded proteins in the luminal space of the endoplasmic reticulum. In this study, we found that derlin-1 and PDI were colocalized in neurofibrillary tangles in the brain of patients with Alzheimer's disease. Derlin-1 and PDI may work as partners to avoid the accumulation of unfolded proteins in Alzheimer's disease. Furthermore, we found that derlin-1 was immunopositive for neurofibrillary tangles and upregulated in Alzheimer's disease and that derlin-1 may play an important role in endoplasmic reticulum-associated degradation during the pathogenesis of Alzheimer's disease. We hypothesize that derlin-1 was upregulated to avoid the aggregation of unfolded proteins. Despite the upregulation of derlin-1, the functions of chaperone proteins and Alzheimer tau protein were lost and these proteins were also accumulated. Finally, they were involved in neurofibrillary tangles. These results suggest that derlin-1 may be associated with endoplasmic reticulum stress in neuronal cells in Alzheimer's disease.

Previous studies demonstrated that selenium in the form of sodium selenate reduces neurofibrillary tangle formation in Alzheimer's disease models. Hyperphosphorylation of tau, which leads to formation of neurofibrillary tangles in Alzheimer's disease, is increased by endoplasmic reticulum (ER) stress. Selenoprotein S (SelS) is part of an ER membrane complex that removes misfolded proteins from the ER as ameans to reduce ER stress. Selenate, as with other forms of selenium, will increase selenoprotein expression. We therefore proposed that increased SelS expression by selenate would contribute to the beneficial actions of selenate in Alzheimer's disease. SelS expression increased with ER stress and decreased under conditions of elevated glucose concentrations in the SH-SY5Y neuronal cell line. Reducing expression of SelS with siRNA promoted cell death in response to ER stress. Selenate increased SelS expression, which significantly correlated with decreased tau phosphorylation. Restricting SelS expression during ER stress conditions increased tau phosphorylation, and also promoted aggregation of phosphorylated tau in neurites and soma. In human postmortem brain, SelS expression coincided with neurofibrillary tangles, but not with amyloid-β plaques. These results indicate that selenate can alter phosphorylation of tau by increasing expression of SelS in Alzheimer's disease and potentially other neurodegenerative disorders.