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Alterations in choroid plexus gene expression in Alzheimer’s disease provide inferences for CSF composition and dynamics Miles C Miller, Edward G Stopa, Elena V Nikonova, Keith Q Tanis, Alexei A Podtelezhnikov, Eva M Finney, David J Stone, Luiz M Camargo, Lisan Parker, Ajay Verma, Andrew Baird, John E Donahue, Ana Maria Gonzalez, Brian Eliceiri, Gerald D Silverberg, Petra M Klinge, Conrad E Johanson

ss Open Acce Oral presentation Microglial downregulation in a double transgenic mouse model associated with early-onset Alzheimer's disease (AD) after intraventricular implantation of alginate encapsulated Glukagon-like-peptide-1 (GLP-1) producing human mesenchymal stem-cells Kathrin Harmening1, Anna Heile1, Miles Miller2, Conrad E Johanson2, Christine Wallrapp3, Thomas Brinker1, Gerald D Silverberg2 and Petra M Klinge*2

Background Cognitive deficits in aging, NPH and Alzheimer's disease (AD) are exacerbated by compromised neurogenesis in the dentate gyrus (DG) and subventricular zone (SVZ). We previously found beta-amyloid (Aβ) retention in cortex and hippocampus of aged rats and diseased humans, due to greater RAGE and lesser LRP-1 expression of microvascular transporters for Aβ. Now we focus on the periventricular DG and SVZ that harbor stem cells convertible to new neurons in adults. Working hypothesis: Aβ retention in neurogenic zones harms neural stem cells, leading to reduced cognition.

Background Previous studies in aging animals have shown that amyloid-beta protein (Aβ) accumulates and its transporters, low-density lipoprotein receptor-related protein-1 (LRP-1) and the receptor for advanced glycation end products (RAGE) are impaired during hydrocephalus. Furthermore, correlations between astrocytes and Aβ have been found in human cases of normal pressure hydrocephalus (NPH) and Alzheimer's disease (AD). Because hydrocephalus occurs frequently in children, we evaluated the expression of Aβ and its transporters and reactive astrocytosis in animals with neonatal hydrocephalus. Methods Hydrocephalus was induced in neonatal rats by intracisternal kaolin injections on post-natal day one, and severe ventriculomegaly developed over a three week period. MRI was performed on post-kaolin days 10 and 21 to document ventriculomegaly. Animals were sacrificed on post-kaolin day 21. For an age-related comparison, tissue was used from previous studies when hydrocephalus was induced in a group of adult animals at either 6 months or 12 months of age. Tissue was processed for immunohistochemistry to visualize LRP-1, RAGE, Aβ, and glial fibrillary acidic protein (GFAP) and with quantitative real time reverse transcriptase polymerase chain reaction (qRT-PCR) to quantify expression of LRP-1, RAGE, and GFAP. Results When 21-day post-kaolin neonatal hydrocephalic animals were compared to adult (6–12 month old) hydrocephalic animals, immunohistochemistry demonstrated levels of Aβ, RAGE, and LRP-1 that were substantially lower in the younger animals; in contrast, GFAP levels were elevated in both young and old hydrocephalic animals. When the neonatal hydrocephalic animals were compared to age-matched controls, qRT-PCR demonstrated no significant changes in Aβ, LRP-1 and RAGE. However, immunohistochemistry showed very small increases or decreases in individual proteins. Furthermore, qRT-PCR indicated statistically significant increases in GFAP. Conclusion Neonatal rats with and without hydrocephalus had low expression of Aβ and its transporters when compared to adult rats with hydrocephalus. No statistical differences were observed in Aβ and its transporters between the control and hydrocephalic neonatal animals.

Hydrocephalus 2008 was held 17–20 September in Hannover, Germany, at the invitation of Petra M Klinge (President), co-hosted by Joachim K. Krauss (Vice President), and Madjid Samii (Honorary President). This meeting was a successor to Hydrocephalus 2006 held in Göteborg, Sweden, organised by Past-President, Carsten Wikkelso. The conference began with a general introductory session of six talks including three invited lectures, followed by eighteen parallel sessions. Subjects covered were hydrocephalus signs, symptoms and diagnosis, especially in normal pressure hydrocephalus; cerebrospinal fluid (CSF) physics and dynamics; CSF function and modelling of function; dementia and quality of life, economy, health care and rehabilitation; neuropsychology, cognition and outcome assessment; neuroimaging, functional imaging and non-invasive diagnostics; paediatric and adolescent hydrocephalus; intelligent shunt and valve design (e.g. telemetry, adjustable and antimicrobial shunts); endoscopic third ventriculostomy; technical advances and image-guided surgical approaches in the treatment of hydrocephalus; brain metabolism, biomarkers and biophysics; co-morbidity, classification and aetiology; epidemiology, registries and clinical trials; experimental hydrocephalus; and pharmaceutical modulation of central nervous system function (CNS drug delivery). Each session began with introductory talks from the invited chairpersons followed by six to eight submitted oral presentations. Overall, 136 oral presentations and 18 posters were presented, the abstracts of which were published elsewhere 1. We present here an account of the introductory session, the invited chairperson's talks and the concluding remarks by Anthony Marmarou.

Background Little is known about the cerebellum in NPH. Studies show that neurotransmitter changes in the cerebellum are opposite to the cortex [1,2]. In Kaolin-induced hydrocephalus, increases of A-beta peptides at cortical and hippocampal microvessels were found [3]. Reciprocal changes in BBB receptors, LRP-1, which transports A-beta out of, and RAGE, which transports A-beta into the brain, indicated a defective clearance might be causal. We looked at LRP-1 and RAGE expression changes in the cerebellum vs. the cortex in hydrocephalic and aged rats.

Background Reduced CSF formation in chronic hydrocephalus (NPH) prompts the question of how the expression of choroid epithelial transporters is altered when flow is disrupted. In the Kaolin model of communicating hydrocephalus, we previously demonstrated that choroid plexus chloride transport (proportional to CSF production) is significantly decreased [1]. To investigate the expression of other choroidal transporters that effect CSF homeostasis, we have now analyzed the time course of LRP-1 expression in the plexus at various stages of hydrocephalus. LRP-1 is a transporter that mediates efflux of A-Beta peptide from the CSF. We postulate that LRP-1 in choroid plexus has a key absorptive role that stabilizes A-Beta in the CNS.

This review integrates eight aspects of cerebrospinal fluid (CSF) circulatory dynamics: formation rate, pressure, flow, volume, turnover rate, composition, recycling and reabsorption. Novel ways to modulate CSF formation emanate from recent analyses of choroid plexus transcription factors (E2F5), ion transporters (NaHCO3 cotransport), transport enzymes (isoforms of carbonic anhydrase), aquaporin 1 regulation, and plasticity of receptors for fluid-regulating neuropeptides. A greater appreciation of CSF pressure (CSFP) is being generated by fresh insights on peptidergic regulatory servomechanisms, the role of dysfunctional ependyma and circumventricular organs in causing congenital hydrocephalus, and the clinical use of algorithms to delineate CSFP waveforms for diagnostic and prognostic utility. Increasing attention focuses on CSF flow: how it impacts cerebral metabolism and hemodynamics, neural stem cell progression in the subventricular zone, and catabolite/peptide clearance from the CNS. The pathophysiological significance of changes in CSF volume is assessed from the respective viewpoints of hemodynamics (choroid plexus blood flow and pulsatility), hydrodynamics (choroidal hypo- and hypersecretion) and neuroendocrine factors (i.e., coordinated regulation by atrial natriuretic peptide, arginine vasopressin and basic fibroblast growth factor). In aging, normal pressure hydrocephalus and Alzheimer's disease, the expanding CSF space reduces the CSF turnover rate, thus compromising the CSF sink action to clear harmful metabolites (e.g., amyloid) from the CNS. Dwindling CSF dynamics greatly harms the interstitial environment of neurons. Accordingly the altered CSF composition in neurodegenerative diseases and senescence, because of adverse effects on neural processes and cognition, needs more effective clinical management. CSF recycling between subarachnoid space, brain and ventricles promotes interstitial fluid (ISF) convection with both trophic and excretory benefits. Finally, CSF reabsorption via multiple pathways (olfactory and spinal arachnoidal bulk flow) is likely complemented by fluid clearance across capillary walls (aquaporin 4) and arachnoid villi when CSFP and fluid retention are markedly elevated. A model is presented that links CSF and ISF homeostasis to coordinated fluxes of water and solutes at both the blood-CSF and blood-brain transport interfaces. Outline 1 Overview 2 CSF formation 2.1 Transcription factors 2.2 Ion transporters 2.3 Enzymes that modulate transport 2.4 Aquaporins or water channels 2.5 Receptors for neuropeptides 3 CSF pressure 3.1 Servomechanism regulatory hypothesis 3.2 Ontogeny of CSF pressure generation 3.3 Congenital hydrocephalus and periventricular regions 3.4 Brain response to elevated CSF pressure 3.5 Advances in measuring CSF waveforms 4 CSF flow 4.1 CSF flow and brain metabolism 4.2 Flow effects on fetal germinal matrix 4.3 Decreasing CSF flow in aging CNS 4.4 Refinement of non-invasive flow measurements 5 CSF volume 5.1 Hemodynamic factors 5.2 Hydrodynamic factors 5.3 Neuroendocrine factors 6 CSF turnover rate 6.1 Adverse effect of ventriculomegaly 6.2 Attenuated CSF sink action 7 CSF composition 7.1 Kidney-like action of CP-CSF system 7.2 Altered CSF biochemistry in aging and disease 7.3 Importance of clearance transport 7.4 Therapeutic manipulation of composition 8 CSF recycling in relation to ISF dynamics 8.1 CSF exchange with brain interstitium 8.2 Components of ISF movement in brain 8.3 Compromised ISF/CSF dynamics and amyloid retention 9 CSF reabsorption 9.1 Arachnoidal outflow resistance 9.2 Arachnoid villi vs. olfactory drainage routes 9.3 Fluid reabsorption along spinal nerves 9.4 Reabsorption across capillary aquaporin channels 10 Developing translationally effective models for restoring CSF balance 11 Conclusion

Background The Leksell Gamma Knife® has been used for several decades as a relatively non-invasive, highly effective and precise therapeutic tool for brain disorders ranging from tumors to vascular malformations. It has a very benign side effect profile. To date many animal hydrocephalus models have been surgically or chemically invasive. Our exploratory model uses gamma knife to induce a lesion with the aim of increasing CSF outflow resistance at the cerebral aqueduct.

Address: 1Division of Pediatric Neurosurgery, 100 North Medical Drive, Suite 1475, Salt Lake City, UT 84113, USA, 2Department of Neurosurgery (Anatomy and Cell Biology), Wayne State University, 550 East Canfield St., Lande MRB 048, Detroit, MI 48201, USA, 3Neurosurgical Department, International Neuroscience Institute Hannover, Alexis-Carrel-Str. 4, Hannover, 30625, Germany, 4Department of Neurosurgery, Stanford University, 300 Pasteur Dr. Rm. 155, Palo Alto, CA 94304, USA and 5Department of Neurosurgery, Rhode Island Hospital and, Brown University, 593 Eddy Street, Providence, RI 02903, USA