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Amyloid Load (amyloid + load)
Selected AbstractsLaminar specific loss of isocortical presenilin 1 immunoreactivity in Alzheimer's disease.NEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 2 2000Correlations with the amyloid load, the density of tau-positive neurofibrillary tangles Presenilin 1 has been shown to be mutated in a high proportion of cases of familial Alzheimer's disease. Immunoreactive epitopes of the protein have been found mainly in neurones devoid of neurofibrillary tangles , an observation that has led to the conclusion that presenilin 1 could have a protective role. In this study, the relationship between deposits of A, peptide (both the 40 and 42 isoforms), tau positive neurofibrillary tangles and presenilin 1-positive neuronal profiles were analysed in three cases of presenilin 1 mutation, four cases of sporadic Alzheimer's disease and five controls. Immunohistochemistry was performed in a sample from the supramarginal gyrus. The proportion of volume occupied by the A,1,40 and A,1,42 deposits (amyloid load) was evaluated by a point-counting technique. Tau-positive neurofibrillary tangles, and presenilin 1-positive neuronal profiles were directly counted. The location of the lesions in the thickness of the cortex was recorded. The density of PS1-positive neuronal profiles in Alzheimer's disease cases was lower than in the controls. The deficit was significant only in the upper layers of the cortex. The density of presenilin 1 neuronal profiles was negatively correlated with A,1,40 and A,1,42 loads, and with the density of tau-positive neurofibrillary tangles. Multivariate analysis showed that the A,1,42 load was the best determinant of the decrease in presenilin 1-positive neuronal profiles. Presenilin 1-positive neurones appear to be lost rather than protected in the course of Alzheimer disease. [source] Cathepsin protease activity modulates amyloid load in extracerebral amyloidosisTHE JOURNAL OF PATHOLOGY, Issue 4 2006C Röcken Abstract In cerebral amyloidoses, such as Alzheimer's disease, proteolytic processing of the precursor protein is a fundamental mechanism of the disease, since it generates the amyloid protein. However, the putative significance of proteases in extracerebral amyloidoses is less well defined. In this study, we investigated the biological significance of cathepsin (Cath) B, CathK, and CathL in the pathology and pathogenesis of extracerebral amyloidoses by using the murine model of reactive or secondary AA amyloidosis with three different cathepsin-deficient mouse strains. Extracerebral AA amyloid was induced by injecting amyloid-enhancing factor and silver nitrate into CathB,/,, CathK,/,, and CathL,/, mice. Wild-type mice served as a control. CathK,/, mice deposited over 90% more amyloid and CathL,/, mice 60% less amyloid than the control (p < 0.0001). The amyloid load in CathB,/, mice did not differ from that in wild-type mice. In vitro degradation experiments with recombinant human and murine serum amyloid A (SAA) 1.1 and CathK and CathL showed that CathL generates a large number of differently sized SAA cleavage products. One of these fragments spans the heparin/heparan sulphate binding site and the neutral cholesterol ester hydrolase activating region of SAA. CathK showed only endoproteolytic activity and did not generate any AA amyloid-like peptides. This study provides unequivocal evidence that proteases modulate amyloid load in extracerebral amyloidosis. CathL was identified as an amyloid-promoting and CathK as an amyloid-retarding cysteine protease. CathB may only modulate the primary structure of the amyloid peptide without affecting amyloid load. Copyright © 2006 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. [source] Effect of apolipoprotein E on biomarkers of amyloid load and neuronal pathology in Alzheimer diseaseANNALS OF NEUROLOGY, Issue 3 2010Prashanthi Vemuri PhD Objective To study the effect of apolipoprotein E ,4 status on biomarkers of neurodegeneration (atrophy on magnetic resonance imaging [MRI]), neuronal injury (cerebrospinal fluid [CSF] t-tau), and brain A, amyloid load (CSF A,1,42) in cognitively normal subjects (CN), amnestic subjects with mild cognitive impairment (aMCI), and patients with Alzheimer disease (AD). Methods We included all 399 subjects (109 CN, 192 aMCI, 98 AD) from the Alzheimer's Disease Neuroimaging Initiative study with baseline CSF and MRI scans. Structural Abnormality Index (STAND) scores, which reflect the degree of AD-like anatomic features on MRI, were computed for each subject. Results A clear ,4 allele dose effect was seen on CSF A,1,42 levels within each clinical group. In addition, the proportion of the variability in A,1,42 levels explained by APOE ,4 dose was significantly greater than the proportion of the variability explained by clinical diagnosis. On the other hand, the proportion of the variability in CSF t-tau and MRI atrophy explained by clinical diagnosis was greater than the proportion of the variability explained by APOE ,4 dose; however, this effect was only significant for STAND scores. Interpretation Low CSF A,1,42 (surrogate for A, amyloid load) is more closely linked to the presence of APOE ,4 than to clinical status. In contrast, MRI atrophy (surrogate for neurodegeneration) is closely linked with cognitive impairment, whereas its association with APOE ,4 is weaker. The data in this paper support a model of AD in which CSF A,1,42 is the earliest of the 3 biomarkers examined to become abnormal in both APOE carriers and noncarriers. ANN NEUROL 2010;67:308,316 [source] Relationship between atrophy and ,-amyloid deposition in Alzheimer diseaseANNALS OF NEUROLOGY, Issue 3 2010Gaël Chételat PhD Objective Elucidating the role of aggregated ,-amyloid in relation to gray matter atrophy is crucial to the understanding of the pathological mechanisms of Alzheimer disease and for the development of therapeutic trials. The present study aims to assess this relationship. Methods Brain magnetic resonance imaging and [11C]Pittsburgh compound B (PiB)-positron emission tomography scans were obtained from 94 healthy elderly subjects (49 with subjective cognitive impairment), 34 patients with mild cognitive impairment, and 35 patients with Alzheimer disease. The correlations between global and regional neocortical PiB retention and atrophy were analyzed in each clinical group. Results Global and regional atrophy were strongly related to ,-amyloid load in participants with subjective cognitive impairment but not in patients with mild cognitive impairment or Alzheimer disease. Global neocortical ,-amyloid deposition correlated to atrophy in a large brain network including the hippocampus, medial frontal and parietal areas, and lateral temporoparietal cortex, whereas regional ,-amyloid load was related to local atrophy in the areas of highest ,-amyloid load only, that is, medial orbitofrontal and anterior and posterior cingulate/precuneus areas. Interpretation There is a strong relationship between ,-amyloid deposition and atrophy very early in the disease process. As the disease progresses to mild cognitive impairment and Alzheimer disease clinical stages, pathological events other than, and probably downstream from, aggregated ,-amyloid deposition might be responsible for the ongoing atrophic process. These findings suggest that antiamyloid therapy should be administered very early in the disease evolution to minimize synaptic and neuronal loss. ANN NEUROL 2010;67:317,324 [source] Greasing the wheels of A, clearance in Alzheimer's Disease: The role of lipids and apolipoprotein EBIOFACTORS, Issue 3 2009Jianjia Fan Abstract Although apolipoprotein E (apoE) is the most common genetic risk factor for Alzheimer's Disease (AD), how apoE participates in AD pathogenesis remains incompletely understood. ApoE is also the major carrier of lipids in the brain. Here, we review studies showing that the lipidation status of apoE influences the metabolism of A, peptides, which accumulate as amyloid deposits in the neural parenchyma and cerebrovasculature. One effect of apoE is to inhibit the transport of A, across the blood-brain-barrier (BBB), particularly when apoE is lipidated. A second effect is to facilitate the proteolytic degradation of A, by neprilysin and insulin degrading enzyme (IDE), which is enhanced when apoE is lipidated. We also describe how apoE becomes lipidated and how this impacts A, metabolism. Specifically, genetic loss of the cholesterol transporter ABCA1 impairs apoE lipidation and promotes amyloid deposition in AD mouse models. ABCA1 catalyses the ATP-dependent transport of cholesterol and phospholipids from the plasma membrane to lipid-free apolipoproteins including apoE. Conversely, selective overexpression of ABCA1 increases apoE lipidation in the central nervous system (CNS) and eliminates the formation of amyloid plaques in vivo. Deficiency of Liver-X-Receptors (LXRs), transcription factors that stimulate ABCA1 and apoE expression, exacerbates AD pathogenesis in vivo, whereas treatment of AD mice with synthetic LXR agonists reduces amyloid load and improves cognitive performance. These studies provide new insights into the mechanisms by which apoE affects A, metabolism, and offer opportunities to develop novel therapeutic approaches to reduce the leading cause of dementia in the elderly. © 2009 International Union of Biochemistry and Molecular Biology, Inc. [source] One-year longitudinal evaluation of sensorimotor functions in APP751SL transgenic miceGENES, BRAIN AND BEHAVIOR, Issue 2008C. 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] | |||||||||||||