(2008) Neuropathology and Applied Neurobiology 34, 131-144 Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology Elimination of interstitial fluid and solutes plays a role in homeostasis in the brain, but the pathways are unclear. Previous work suggests that interstitial fluid drains along the walls of arteries. Aims: to define the pathways within the walls of capillaries and arteries for drainage of fluid and solutes out of the brain. Methods: Fluorescent soluble tracers, dextran (3 kDa) and ovalbumin (40 kDa), and particulate fluospheres (0.02 mm and 1.0 mm in diameter) were injected into the corpus striatum of mice. Brains were examined from 5 min to 7 days by immunocytochemistry and confocal microscopy. Results: soluble tracers initially spread diffusely through brain parenchyma and then drain out of the brain along basement membranes of capillaries and arteries. Some tracer is taken up by vascular smooth muscle cells and by perivascular macrophages. No perivascular drainage was observed when dextran was injected into mouse brains following cardiac arrest. Fluospheres expand perivascular spaces between vessel walls and surrounding brain, are ingested by perivascular macrophages but do not appear to leave the brain even following an inflammatory challenge with lipopolysaccharide or kainate. Conclusions: capillary and artery basement membranes act as 'lymphatics of the brain' for drainage of fluid and solutes; such drainage appears to require continued cardiac output as it ceases following cardiac arrest. This drainage pathway does not permit migration of cells from brain parenchyma to the periphery. Amyloid-b is deposited in basement membrane drainage pathways in cerebral amyloid angiopathy, and may impede elimination of amyloid-b and interstitial fluid from the brain in Alzheimer's disease. Soluble antigens, but not cells, drain from the brain by perivascular pathways. This atypical pattern of drainage may contribute to partial immune privilege of the brain and play a role in neuroimmunological diseases such as multiple sclerosis.

We performed a 15-year post-mortem neuropathological follow-up of patients in the first trial of amyloid-β immunotherapy for Alzheimer’s disease. Twenty-two participants of a clinical trial of active amyloid-β42 immunization (AN1792, Elan Pharmaceuticals) or placebo were studied. Comprehensive post-mortem neuropathological assessments were performed from 4 months to 15 years after the trial. We analysed the relationships between the topographical distribution of amyloid-β removal from the cerebral cortex and tau pathology, cerebrovascular territories, plasma anti-AN1792 antibody titres and late cognitive status. Seventeen of 22 (77%) participants had Alzheimer’s neuropathological change, whereas 5 of 22 (23%) had alternative causes for dementia (progressive supranuclear palsy = 1, Lewy body disease = 1, vascular brain injury = 1, and frontotemporal lobar degeneration = 2). Nineteen of the 22 participants had received the active agent, three the placebo. Fourteen of 16 (88%) patients with Alzheimer’s disease receiving the active agent had evidence of plaque removal (very extensive removal = 5, intermediate = 4, very limited = 5, no removal = 2). Of particular note, two Alzheimer’s patients who died 14 years after immunization had only very sparse or no detectable plaques in all regions examined. There was a significant inverse correlation between post-vaccination peripheral blood anti-AN1792 antibody titres and post-mortem plaque scores (ρ = − 0.664, P = 0.005). Cortical foci cleared of plaques contained less tau than did cortex with remaining plaques, but the overall distribution of tangles was extensive (Braak V/VI). In conclusion, patients with Alzheimer’s disease actively immunized against amyloid-β can remain virtually plaque-free for 14 years. The extent of plaque removal is related to the immune response. This long duration of efficacy is important in support of active immunization protocols as therapy for, or potentially prevention of, neurodegeneration-associated protein accumulations. Inclusion of patients without Alzheimer’s disease in Alzheimer’s therapy trials is a problem for assessing the efficacy of treatment. Despite modification of Alzheimer’s pathology, most patients had progressed to severe dementia, notably including the five with very extensive plaque removal, possibly due to continued tau propagation. Neuropathology follow-up of patients in therapeutic trials provides valuable information on the causes of dementia and effects of treatment.

In the dark, whereas the virescent mutants displayed reduced CAB expression and the lowest levels of POR protein, the other mutants expressed CAB and accumulated POR at near wild-type levels. All of the mutants, with the exception of cue6, were compromised in their ability to derepress CAB expression in response to phytochrome activation. Based on these results, we propose that the previously postulated plastidderived signal is closely involved in the pathway through which phytochrome regulates the expression of nuclear genes encoding plastid proteins.

A mechanistic insight into the mechanical role of the stratum corneum during stretching and compression of the skin. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.www.elsevier.com/locate/jmbbm 1 A mechanistic insight into the mechanical role of the stratum corneum during stretching and compression of the skin. AbstractThe study of skin biophysics has largely been driven by consumer goods, biomedical and cosmetic industries which aim to design products that efficiently interact with the skin and/or modify its biophysical properties for health or cosmetic benefits. The skin is a hierarchical biological structure featuring several layers with their own distinct geometry and mechanical properties. Up to now, no computational models of the skin have simultaneously accounted for these geometrical and material characteristics to study their complex biomechanical interactions under particular macroscopic deformation modes.The goal of this study was, therefore, to develop a robust methodology combining histological sections of human skin, image-processing and finite element techniques to address fundamental questions about skin mechanics and, more particularly, about how macroscopic strains are transmitted and modulated through the epidermis and dermis. The work hypothesis was that, as skin deforms under macroscopic loads, the stratum corneum does not experience significant strains but rather folds/unfolds during skin extension/compression.A sample of fresh human mid-back skin was processed for wax histology. Sections were stained and photographed by optical microscopy. The multiple images were stitched together to produce a larger region of interest and segmented to extract the geometry of the stratum corneum, viable epidermis and dermis. From the segmented structures a 2D finite element mesh of the skin composite model was created and geometrically non-linear plane-strain finite element analyses were conducted to study the sensitivity of the model to variations in mechanical properties.The hybrid experimental-computational methodology has offered valuable insights into the simulated mechanics of the skin, and that of the stratum corneum in particular, by providing qualitative and quantitative information on strain magnitude and distribution. Through a complex non-linear interplay, the geometry and mechanical characteristics of the skin layers (and their relative balance), play a critical role in conditioning the skin mechanical response to macroscopic in-plane compression and extension. Topographical features of the skin surface such as furrows were shown to act as an efficient means to deflec...

It has been hypothesised that tau protein, when hyper-phosphorylated as in AD, does not bind effectively to microtubules and is no longer able to stabilize them, thus microtubules break down and axonal transport can no longer proceed efficiently in affected brain regions in AD and related tauopathies (tau-microtubule hypothesis). We have used Drosophila models of tauopathy to test all components of this hypothesis in vivo. We have previously shown that upon expression of human 0N3R tau in Drosophila motor neurons it becomes highly phosphorylated, resulting in disruptions to both axonal transport and synaptic function which culminate in behavioural phenotypes. We now show that the mechanism by which the human tau mediates these effects is two-fold: firstly, as predicted by the tau-microtubule hypothesis, the highly phosphorylated tau exhibits significantly reduced binding to microtubules, and secondly, it participates in a pathogenic interaction with the endogenous normal Drosophila tau and sequesters it away from microtubules. This causes disruption of the microtubular cytoskeleton as evidenced by a reduction in the numbers of intact correctly aligned microtubules, and the appearance of microtubules that are not correctly oriented within the axon. These deleterious effects of human tau are phosphorylation dependent, because treatment with LiCl to suppress tau phosphorylation increases microtubule binding of both human and Drosophila tau and restores cytoskeletal integrity. Notably, all these phospho-tau mediated phenotypes occur in the absence of tau filament/ neurofibrillary tangle formation or neuronal death, and may thus constitute the mechanism by which hyper-phosphorylated tau disrupts neuronal function and contributes to cognitive impairment prior to neuronal death in the early stages of tauopathies.KEYWORDS: Alzheimer's disease, tauopathy, axonal transport, lithium, neurofibrillary tangles. It has been speculated that the axonal microtubular cytoskeleton may be compromised in Alzheimer's disease (AD) and other tauopathies because the microtubule associated protein tau, which usually stabilises this cytoskeleton, is abnormal in these conditions. In all tauopathies tau is atypically hyper-phosphorylated, misfolded and aggregated into filaments and tangles (reviewed in [20]. The idea that some of these aberrations of tau may result in defects in cytoskeletal integrity first came forth when it was demonstrated that microtubule assembly, in an in vitro assay, was defective in extracts from AD brains when compared to those obtained from age matched control brains [19]. It was shown that this was not due to dysfunctional tubulin proteins in the AD brains, but due to the hyper-phosphorylated state of the tau protein which, the authors speculated, affected its microtubule binding properties [14]. Subsequently, various studies analysed the effect of tau phosphorylation on its microtubule binding function, and showed that hyper-phosphorylation of tau reduces its binding to tubulin in vitro [4,12,27,41] leadi...