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Amyloid Burden (amyloid + burden)

Distribution by Scientific Domains

Medical Sciences	60%

Selected Abstracts

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]

One-year longitudinal evaluation of sensorimotor functions in APP751SL transgenic mice

GENES, BRAIN AND BEHAVIOR, Issue 2008
C. Le Cudennec
Intracerebral amyloid-beta (A,) peptide deposition is considered to play a key role in Alzheimer's disease and is designated as a principal therapeutic target. The relationship between brain A, levels and clinical deficits remains, however, unclear, both in human patients and in animal models of the disease. The purpose of the present study was to investigate, in a transgenic mouse model of brain amyloidosis, the consequences of A, deposition on basic neurological functions using a longitudinal approach. Animals were phenotyped at different ages corresponding to graded neuropathological stages (from no extracellular A, deposition to high amyloid loads). Sensory functions were evaluated by assessing visual and olfactory abilities and did not show any effects of the amyloid precursor protein (APP) transgene. Motor functions were assessed using multiple experimental paradigms. Results showed that motor strength was considerably reduced in APP transgenic mice compared with control animals. No deficit was noted in a motor coordination test although APP transgenic mice displayed decreased locomotion on a stationary beam. Hypolocomotion was also observed in the standard open-field test. Measures of anxiety obtained in the elevated plus-maze show some evidence of hyperanxiety in 15-month-old transgenic mice. Some of the neurological impairments showed by APP mice had an early onset and worsened with progressive aging, in parallel to gradual accumulation of A, in brain parenchyma. Relationships between neuropathologically assessed amyloid loads and behavioral deficits were further explored, and it was observed that motor strength deficits were correlated with cortical amyloid burden. [source]

Imaging of amyloid burden and distribution in cerebral amyloid angiopathy

ANNALS OF NEUROLOGY, Issue 3 2007
Keith A. Johnson MD
Objective Cerebrovascular deposition of ,-amyloid (cerebral amyloid angiopathy [CAA]) is a major cause of hemorrhagic stroke and a likely contributor to vascular cognitive impairment. We evaluated positron emission tomographic imaging with the ,-amyloid,binding compound Pittsburgh Compound B (PiB) as a potential noninvasive method for detection of CAA. We hypothesized that amyloid deposition would be observed with PiB in CAA, and based on the occipital predilection of CAA pathology and associated hemorrhages, that specific PiB retention would be disproportionately greater in occipital lobes. Methods We compared specific cortical PiB retention in 6 nondemented subjects diagnosed with probable CAA with 15 healthy control subjects and 9 patients with probable Alzheimer's disease (AD). Results All CAA and AD subjects were PiB-positive, both by distribution volume ratio measurements and by visual inspection of positron emission tomographic images. Global cortical PiB retention was significantly increased in CAA (distribution volume ratio 1.18 ± 0.06) relative to healthy control subjects (1.04 ± 0.10; p = 0.0009), but was lower in CAA than in AD subjects (1.41 ± 0.17; p = 0.002). The occipital-to-global PiB ratio, however, was significantly greater in CAA than in AD subjects (0.99 ± 0.07 vs 0.86 ± 0.05; p = 0.003). Interpretation We conclude that PiB-positron emission tomography can detect cerebrovascular ,-amyloid and may serve as a method for identifying the extent of CAA in living subjects. Ann Neurol 2007 [source]

Neuropathology and Pathogenesis of Encephalitis following Amyloid , Immunization in Alzheimer's Disease

BRAIN PATHOLOGY, Issue 1 2004
Isidre Ferrer
Immunizing transgenic PDAPP mice, which overexpress mutant APP and develop ,-amyloid deposition resembling plaques in Alzheimer's disease (AD), results in a decrease of amyloid burden when compared with non treated transgenic animals im-munization with amyloid , peptide has been initiated in a randomised pilot study in AD. Yet a minority of patients developed a neurological complication consistent with meningoencephalitis and one patient died; the trial has been stopped. Neuropathological examination in that patient showed meningoencephalitis and focal atypically low numbers of diffuse and neuritic plaques but not of vascular amyloid nor regression of tau pathology in neurofibrillary tangles and neuropil threads. The present neuropathological study reports the second case of menigoencephalitis following immunization with amyloid-, peptide in AD, and has been directed toward exploring mechanisms underlying decreased tau pathology in relation- with amyliod deposit regression, and possible molecular bases involved in the inflammatory response following immunization. Inflammatory infiltrates were composed of CD8+, CD3+, CD5+ and, rarely, CD7+ lymphocytes, whereas B lymphocytes and T cytotoxic cells CD16, CD57, TIA and graenzyme were negative. Characteristic neuropathological findings were focal depletion of diffuse and neuritic plaques, but not of amyloid angiopathy, and the presence of small numbers of extremely dense(collapsed) plaques surrounded by active microglia, and multinucleated giant cells filled with dense A,42and A,40, in addition to severe small cerebral blood Reduced amyloid burden was accompanied by low amyloid-associated oxidative stress responses (reduced superoxide dismutase-1:SOD-1 expression) and by local inhibition of the stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) and p38 kinase which are involved in tau phosphorylation. These results support the amyloid cascade of tau phosphorylation in AD regarding phosphorylation of tau in neurofibrillary tangles and ,-amyloid deposition in neuritic plaques, but not of tau in neurofibrillary tangles and threads. Furthermore, amyloid reduction was accompanied by increased expression of the PA28,/, inductor, and of LMP7, LMP2 and MECL1 subunits of the immunopro-teasome in microglial and inflammatory cells surrounding collapsed plaques, and in multinucleated giant cells.Immunoproteasome subunit expression was accompanied by local presentation of MHC class molecules. Release of antigenic peptides derived from ,-amyloid processing may enhance T-cell inflammatory responses accounting for the meningoencephalitis following amyloid-, peptide immunization [source]

Relationship of the extended tau haplotype to tau biochemistry and neuropathology in progressive supranuclear palsy

ANNALS OF NEUROLOGY, Issue 4 2001
Wan-Kyng Liu PhD
Two extended haplotypes of the tau gene (H1 and H2) have been described. The frequency of H1 haplotype is increased in progressive supranuclear palsy (PSP). PSP is associated with filamentous tau lesions in neurons and glia, which are reportedly composed exclusively of tau isoforms with four repeats in the microtubule-binding domain (4R tau). To determine the influence of the tau haplotype on tau isoform composition and neuropathology, we studied 25 PSP cases and 6 Alzheimer's disease patients matched for age, sex, and postmortem delay. In the basal ganglia, tau and amyloid burdens were determined to see if there was an effect of concurrent Alzheimer-type pathology, and the ratio of 4R to 3R tau was measured in detergent-insoluble tau fractions. Insoluble tau from PSP was not composed exclusively of 4R tau. All brains had a mixture of 4R and 3R tau, but the ratio was different in Alzheimer's disease and PSP. In Alzheimer's disease there was less 4R than 3R tau, whereas the ratio was reversed in PSP. In PSP cases with concurrent Alzheimer-type pathology, the ratio of 4R to 3R was intermediate between Alzheimer's disease and PSP. The H1 haplotype had no effect on the 4R to 3R ratio or on tau and amyloid burdens. In summary, the H1 haplotype does not have a major influence on the pathological or biochemical phenotype of PSP. [source]