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Soluble Amyloid (soluble + amyloid)

Distribution by Scientific Domains

Medical Sciences	57%
Life Sciences	28%

Selected Abstracts

Higher Soluble Amyloid , Concentration in Frontal Cortex of Young Adults than in Normal Elderly or Alzheimer's Disease

BRAIN PATHOLOGY, Issue 4 2010
Zoë Van Helmond
Abstract Little is known about the relationship between soluble amyloid , (A,) and age. We have measured soluble and insoluble A, by enzyme-linked immunosorbent assay (ELISA) in post-mortem frontal cortex in normal brains (16,95 years) and AD. Insoluble A, increased with age, and was significantly higher in Alzheimer's disease (AD) than age-matched controls. However, levels of soluble A, declined with age and were significantly greater in younger adults than older adults with or without AD. In AD, insoluble : soluble A, ratio was much higher than in age-matched controls. The high levels of soluble A, in young adults included oligomeric species of A,1-42. These observations do not preclude A, oligomers as neurotoxic mediators of AD but suggest that if they are, the toxicity may be restricted to certain species (eg, ,-pleated protofibrillar species not detected by our assay) or takes decades to manifest. The dramatically increased insoluble : soluble A, in AD points to an altered dynamic equilibrium of A, in AD, reflecting both enhanced aggregation and continued overproduction or impaired removal of the soluble peptide in older age, when the concentration of this peptide should be declining. [source]

Age-dependent cognitive decline in the APP23 model precedes amyloid deposition

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 2 2003
Debby Van Dam
Abstract Heterozygous APP23 mice, expressing human amyloid-precursor protein with the Swedish double mutation and control littermates, were subjected to behavioral and neuromotor tasks at the age of 6,8 weeks, 3 and 6 months. A hidden-platform Morris-type water maze showed an age-dependent decline of spatial memory capacities in the APP23 model. From the age of 3 months onwards, the APP23 mice displayed major learning and memory deficits as demonstrated by severely impaired learning curves during acquisition and impaired probe trial performance. In addition to the cognitive deficit, APP23 mice displayed disturbed activity patterns. Overnight cage-activity recording showed hyperactivity in the transgenics for the three age groups tested. However, a short 2-h recording during dusk phase demonstrated lower activity levels in 6-month-old APP23 mice as compared to controls. Moreover, at this age, APP23 mice differed from control littermates in exploration and activity levels in the open-field paradigm. These findings are reminiscent of disturbances in circadian rhythms and activity observed in Alzheimer patients. Determination of plaque-associated human amyloid-,1,42 peptides in brain revealed a fivefold increase in heterozygous APP23 mice at 6 months as compared to younger transgenics. This increase coincided with the first appearance of plaques in hippocampus and neocortex. Spatial memory deficits preceded plaque formation and increase in plaque-associated amyloid-,1,42 peptides, but probe trial performance did correlate negatively with soluble amyloid-, brain concentration in 3-month-old APP23 mutants. Detectable plaque formation is not the (only) causal factor contributing to memory defects in the APP23 model. [source]

Docosahexaenoic acid stabilizes soluble amyloid-, protofibrils and sustains amyloid-,-induced neurotoxicity in vitro

FEBS JOURNAL, Issue 4 2007
Ann-Sofi Johansson
Enrichment of diet and culture media with the polyunsaturated fatty acid docosahexaenoic acid has been found to reduce the amyloid burden in mice and lower amyloid-, (A,) levels in both mice and cultured cells. However, the direct interaction of polyunsaturated fatty acids, such as docosahexaenoic acid, with A,, and their effect on A, aggregation has not been explored in detail. Therefore, we have investigated the effect of docosahexaenoic acid, arachidonic acid and the saturated fatty acid arachidic acid on monomer oligomerization into protofibrils and protofibril fibrillization into fibrils in vitro, using size exclusion chromatography. The polyunsaturated fatty acids docosahexaenoic acid and arachidonic acid at micellar concentrations stabilized soluble A,42 wild-type protofibrils, thereby hindering their conversion to insoluble fibrils. As a consequence, docosahexaenoic acid sustained amyloid-,-induced toxicity in PC12 cells over time, whereas A, without docosahexaenoic acid stabilization resulted in reduced toxicity, as A, formed fibrils. Arachidic acid had no effect on A, aggregation, and neither of the fatty acids had any protofibril-stabilizing effect on A,42 harboring the Arctic mutation (A,E22G). Consequently, A,Arctic-induced toxicity could not be sustained using docosahexaenoic acid. These results provide new insights into the toxicity of different A, aggregates and how endogenous lipids can affect A, aggregation. [source]

Soluble oligomers from a non-disease related protein mimic A,-induced tau hyperphosphorylation and neurodegeneration

JOURNAL OF NEUROCHEMISTRY, Issue 2 2007
Marcelo N. N. Vieira
Abstract Protein aggregation and amyloid accumulation in different tissues are associated with cellular dysfunction and toxicity in important human pathologies, including Alzheimer's disease and various forms of systemic amyloidosis. Soluble oligomers formed at the early stages of protein aggregation have been increasingly recognized as the main toxic species in amyloid diseases. To gain insight into the mechanisms of toxicity instigated by soluble protein oligomers, we have investigated the aggregation of hen egg white lysozyme (HEWL), a normally harmless protein. HEWL initially aggregates into ,-sheet rich, roughly spherical oligomers which appear to convert with time into protofibrils and mature amyloid fibrils. HEWL oligomers are potently neurotoxic to rat cortical neurons in culture, while mature amyloid fibrils are little or non-toxic. Interestingly, when added to cortical neuronal cultures HEWL oligomers induce tau hyperphosphorylation at epitopes that are characteristically phosphorylated in neurons exposed to soluble oligomers of the amyloid-, peptide. Furthermore, injection of HEWL oligomers in the cerebral cortices of adult rats induces extensive neurodegeneration in different brain areas. These results show that soluble oligomers from a non-disease related protein can mimic specific neuronal pathologies thought to be induced by soluble amyloid-, peptide oligomers in Alzheimer's disease and support the notion that amyloid oligomers from different proteins may share common structural determinants that would explain their generic cytotoxicities. [source]

Vaccination as a Therapeutic Approach to Alzheimer's Disease

MOUNT SINAI JOURNAL OF MEDICINE: A JOURNAL OF PERSONALIZED AND TRANSLATIONAL MEDICINE, Issue 1 2010
Thomas Wisniewski MD
Abstract Alzheimer's disease is the most common cause of dementia worldwide. Alzheimer's disease is a member of a broad range of neurodegenerative diseases characterized pathologically by the conformational change of a normal protein into a pathological conformer with a high ,-sheet content that renders it neurotoxic. In the case of Alzheimer's disease, the normal soluble amyloid , peptide is converted into oligomeric/fibrillar amyloid ,. The oligomeric forms of amyloid , have been hypothesized to be the most toxic, whereas fibrillar amyloid , becomes deposited as amyloid plaques and congophilic angiopathy, which both serve as neuropathological markers of the disease. In addition, the accumulation of abnormally phosphorylated tau as soluble toxic oligomers and as neurofibrillary tangles is a critical part of the pathology. Numerous therapeutic interventions are under investigation to prevent and treat Alzheimer's disease. Among the most exciting and advanced of these approaches is vaccination. Immunomodulation is being tried for a range of neurodegenerative disorders, with great success being reported in most model animal trials; however, the much more limited human data have shown more modest clinical success so far, with encephalitis occurring in a minority of patients treated with active immunization. The immunomodulatory approaches for neurodegenerative diseases involve targeting a self-protein, albeit in an abnormal conformation; hence, effective enhanced clearance of the disease-associated conformer has to be balanced with the potential risk of stimulating excessive toxic inflammation within the central nervous system. The design of future immunomodulatory approaches that are more focused is dependent on addressing a number of questions, including when is the best time to start immunization, what are the most appropriate targets for vaccination, and is amyloid central to the pathogenesis of Alzheimer's disease or is it critical to target tau-related pathology also. In this review, we discuss the past experience with vaccination for Alzheimer's disease and the development of possible future strategies that target both amyloid ,,related and tau-related pathologies. Mt Sinai J Med 77:17&–31, 2010. © 2010 Mount Sinai School of Medicine [source]

Amyloid , protein toxicity mediated by the formation of amyloid-, protein precursor complexes

ANNALS OF NEUROLOGY, Issue 6 2003
Daniel C. Lu MD
The amyloid-, protein precursor, a type 1 transmembrane protein, gives rise to the amyloid ,-protein, a neurotoxic peptide postulated to be involved in the pathogenesis of Alzheimer's disease. Here, we show that soluble amyloid , protein accelerates amyloid precursor protein complex formation, a process that contributes to neuronal cell death. The mechanism of cell death involves the recruitment of caspase-8 to the complex, followed by intracytoplasmic caspase cleavage of amyloid precursor protein. In vivo, the levels of soluble amyloid , protein correlated with caspase-cleaved fragments of the amyloid precursor protein in brains of Alzheimer's disease subjects. These findings suggest that soluble amyloid , protein,induced multimerization of the amyloid precursor protein may be another mechanism by which amyloid , protein contributes to synapse loss and neuronal cell death seen in Alzheimer's disease. Ann Neurol 2003;54:781,789 [source]