heparitin-sulfate and Neurodegenerative-Diseases

This review comes as a part of the special issue "Emerging frontiers in GAGs and mimetics". Our interest is in the manipulation of heparan sulfate (HS) turnover by employing HS mimetics/heparin derivatives that exert pleiotropic effects and are interesting for interfering at multiple levels with pathways in which HS is implicated. Due to the important role of heparanase in HS post-biosynthetic modification and catabolism, we focus on the possibility to target heparanase, at both extracellular and intracellular levels, a strategy that can be applied to many conditions, from inflammation to cancer and neurodegeneration.

Topics: Biomimetic Materials; Glucuronidase; Heparitin Sulfate; Humans; Inflammation; Neoplasms; Neurodegenerative Diseases

Heparin and heparan sulfate glycosaminoglycans are long, linear polysaccharides that are made up of alternating dissacharide sequences of sulfated uronic acid and amino sugars. Unlike heparin, which is only found in mast cells, heparan sulfate is ubiquitously expressed on the cell surface and in the extracellular matrix of all animal cells. These negatively-charged glycans play essential roles in important cellular functions such as cell growth, adhesion, angiogenesis, and blood coagulation. These biomolecules are also involved in pathophysiological conditions such as pathogen infection and human disease. This review discusses past and current methods for targeting these complex biomolecules as a novel therapeutic strategy to treating disorders such as cancer, neurodegenerative diseases, and infection.

Topics: Animals; Glycosaminoglycans; Heparin; Heparitin Sulfate; Humans; Infections; Neoplasms; Neurodegenerative Diseases; Small Molecule Libraries

A number of neurodegenerative disorders have been linked directly to the accumulation of amyloid fibres. These fibres are made up of proteins or peptides with altered structures and which join together in vivo in association with heparan sulphate-type polysaccharides.. To examine the most recent concepts in the biology of heparan sulphates and their role in the aggregation of the peptide Abeta, of tau protein, of alpha-synuclein and of prions. The study also seeks to analyse their implications in neurodegenerative disorders such as Alzheimer's and Parkinson's disease and prion diseases.. In vitro, heparan sulphates have played an important role in the process of oligomerisation and fibrillation of amyloidogenic proteins or peptides, in the stabilisation of these bodies and their resistance to proteolysis, thereby participating in the formation of a wide range of amyloid fibres. Heparan sulphates have also been related to the internalisation of pro-amyloid fibres during the process of intercellular propagation (spreading), which is considered to be crucial in the development of proteinopathies, the best example of which is Alzheimer's disease.. This study suggests that the fine structures of heparan sulphates, their localisation in cells and tissues, together with their local concentration, may regulate the amyloidosis processes. The advances made in the understanding of this area of glyconeurobiology will make it possible to improve the understanding of the cell and molecular mechanisms underlying the neurodegenerative process.. Heparan sulfatos, amiloidosis y neurodegeneracion.. Introduccion. Numerosos trastornos neurodegenerativos se han asociado directamente a la acumulacion de fibras amiloides. Estas fibras estan formadas por proteinas o peptidos con conformaciones alteradas y que se agregan in vivo en asociacion con polisacaridos de tipo heparan sulfatos. Objetivos. Examinar los conceptos mas recientes sobre la biologia de los heparan sulfatos y su papel en la agregacion del peptido Abeta, de la proteina tau, de la alfa-sinucleina y de los priones, y analizar sus implicaciones en trastornos neurodegenerativos como las enfermedades de Alzheimer y de Parkinson y las enfermedades prionicas. Desarrollo. In vitro, los heparan sulfatos han desempeñado un papel importante en el proceso de oligomerizacion y fibrilacion de proteinas o peptidos amiloidogenos, en la estabilizacion de estos cuerpos y su resistencia a la proteolisis, participando asi en la formacion de una gran variedad de fibras amiloides. Los heparan sulfatos se han relacionado tambien con el proceso de internalizacion de fibras proamiloides durante el proceso de propagacion intercelular (spreading) considerado como central en la evolucion de las proteinopatias, cuyo mejor ejemplo es la enfermedad de Alzheimer. Conclusion. Este trabajo sugiere que las estructuras finas de los heparan sulfatos, sus localizaciones celulares y tisulares, asi como sus concentraciones locales, pueden regular los procesos de amiloidosis. Avances en la comprension de esta area de la gliconeurobiologia permitiran mejorar la comprension de los mecanismos celulares y moleculares del proceso neurodegenerativo.

Topics: Alzheimer Disease; Amyloidosis; Animals; Disease Models, Animal; Heparitin Sulfate; Humans; Neurodegenerative Diseases; Parkinson Disease; Prion Diseases

Alzheimer's disease (AD) is a neurodegenerative disease characterized by memory loss and cognitive impairments. Amyloid-β (Aβ) deposition and neurotoxicity play important roles in AD. It has been widely reported that heparan sulfate (HS) proteoglycans play a nonnegligible role in the release, uptake and misfolding of Aβ, resulting in the discovery of HS as a therapeutic drug for AD. In this manuscript, HS from porcine mucosa could promote Aβ fibrosis and improve the cognitive defects of APPswe/PS1ΔE9 mice. Furthermore, HS enhanced the phagocytosis of neutrophils to clear Aβ

Topics: Alzheimer Disease; Amyloid beta-Peptides; Animals; Brain; Disease Models, Animal; Heparitin Sulfate; Mice; Mice, Transgenic; Mucous Membrane; Neurodegenerative Diseases; Swine

Sanfilippo syndrome is an untreatable form of childhood-onset dementia. Whilst several therapeutic strategies are being evaluated in human clinical trials including i.v. delivery of AAV9-based gene therapy, an urgent unmet need is the availability of non-invasive, quantitative measures of neurodegeneration. We hypothesise that as part of the central nervous system, the retina may provide a window through which to 'visualise' degenerative lesions in brain and amelioration of them following treatment. This is reliant on the age of onset and the rate of disease progression being equivalent in retina and brain. For the first time we have assessed in parallel, the nature, age of onset and rate of retinal and brain degeneration in a mouse model of Sanfilippo syndrome. Significant accumulation of heparan sulphate and expansion of the endo/lysosomal system was observed in both retina and brain pre-symptomatically (by 3 weeks of age). Robust and early activation of micro- and macroglia was also observed in both tissues. There was substantial thinning of retina and loss of rod and cone photoreceptors by ~ 12 weeks of age, a time at which cognitive symptoms are noted. Intravenous delivery of a clinically relevant AAV9-human sulphamidase vector to neonatal mice prevented disease lesion appearance in retina and most areas of brain when assessed 6 weeks later. Collectively, the findings highlight the previously unrecognised early and significant involvement of retina in the Sanfilippo disease process, lesions that are preventable by neonatal treatment with AAV9-sulphamidase. Critically, our data demonstrate for the first time that the advancement of retinal disease parallels that occurring in brain in Sanfilippo syndrome, thus retina may provide an easily accessible neural tissue via which brain disease development and its amelioration with treatment can be monitored.

Topics: Animals; Asymptomatic Diseases; Brain; Disease Models, Animal; Endosomes; Genetic Therapy; Heparitin Sulfate; Humans; Hydrolases; Lysosomes; Mice; Microglia; Mucopolysaccharidosis III; Neurodegenerative Diseases; Retina; Retinal Cone Photoreceptor Cells; Retinal Degeneration; Retinal Rod Photoreceptor Cells

Intra-cerebrospinal fluid (CSF) injection of recombinant human lysosomal enzyme is a potential treatment strategy for several neurodegenerative lysosomal storage disorders including Sanfilippo syndrome (Mucopolysaccharidosis type IIIA; MPS IIIA). Here we have utilised the MPS IIIA Huntaway dog model to compare the effectiveness of the repeated intermittent bolus injection strategy being used in the trials with an alternate approach; slow, continual infusion of replacement enzyme (recombinant human sulphamidase; rhSGSH) into the spinal CSF using a SynchroMed II® pump attached to a spinal infusion cannula. The ability of each enzyme delivery strategy to ameliorate lesions in MPS IIIA brain was determined in animals treated from ∼three- to six-months of age. Controls received buffer or no treatment. Significant reductions in heparan sulphate (primary substrate) were observed in brain samples from dogs treated via either cisternal or lumbar spinal CSF bolus injection methods and also in slow intra-spinal CSF infusion-treated dogs. The extent of the reduction differed regionally. Pump-delivered rhSGSH was less effective in reducing secondary substrate (G

Topics: Animals; Cerebral Cortex; Cerebrospinal Fluid; Disease Models, Animal; Dogs; Enzyme Replacement Therapy; Heparitin Sulfate; Humans; Hydrolases; Lumbar Vertebrae; Mucopolysaccharidosis III; Neurodegenerative Diseases; Recombinant Proteins

Neurodegenerative metabolic disorders such as mucopolysaccharidosis IIIB (MPSIIIB or Sanfilippo disease) accumulate undegraded substrates in the brain and are often unresponsive to enzyme replacement treatments due to the impermeability of the blood brain barrier to enzyme. MPSIIIB is characterised by behavioural difficulties, cognitive and later motor decline, with death in the second decade of life. Most of these neurodegenerative lysosomal storage diseases lack effective treatments. We recently described significant reductions of accumulated heparan sulphate substrate in liver of a mouse model of MPSIIIB using the tyrosine kinase inhibitor genistein.. We report here that high doses of genistein aglycone, given continuously over a 9 month period to MPSIIIB mice, significantly reduce lysosomal storage, heparan sulphate substrate and neuroinflammation in the cerebral cortex and hippocampus, resulting in correction of the behavioural defects observed. Improvements in synaptic vesicle protein expression and secondary storage in the cerebral cortex were also observed.. Genistein may prove useful as a substrate reduction agent to delay clinical onset of MPSIIIB and, due to its multimodal action, may provide a treatment adjunct for several other neurodegenerative metabolic diseases.

Topics: Animals; Blood-Brain Barrier; Brain; Disease Models, Animal; Gene Expression Regulation; Genistein; Heparitin Sulfate; Heterozygote; Immunohistochemistry; Liver; Lysosomes; Mice; Mice, Inbred C57BL; Mucopolysaccharidosis III; Neurodegenerative Diseases; Neurons; Protein Kinase Inhibitors

Recent studies have begun to investigate the role of agrin in brain and suggest that agrin's function likely extends beyond that of a synaptogenic protein. Particularly, it has been shown that agrin is associated with the pathological lesions of Alzheimer's disease (AD) and may contribute to the formation of beta-amyloid (Abeta) plaques in AD. We have extended the analysis of agrin's function in neurodegenerative diseases to investigate its role in Parkinson's disease (PD). Alpha-synuclein is a critical molecular determinant in familial and sporadic PD, with the formation of alpha-synuclein fibrils being enhanced by sulfated macromolecules. In the studies reported here, we show that agrin binds to alpha-synuclein in a heparan sulfate-dependent (HS-dependent) manner, induces conformational changes in this protein characterized by beta-sheet structure, and enhances insolubility of alpha-synuclein. We also show that agrin accelerates the formation of protofibrils by alpha-synuclein and decreases the half-time of fibril formation. The association of agrin with PD lesions was also explored in PD human brain, and these studies shown that agrin colocalizes with alpha-synuclein in neuronal Lewy bodies in the substantia nigra of PD brain. These studies indicate that agrin is capable of accelerating the formation of insoluble protein fibrils in a second common neurodegenerative disease. These findings may indicate shared molecular mechanisms leading to the pathophysiology in these two neurodegenerative disorders.

Topics: Agrin; alpha-Synuclein; Alzheimer Disease; Animals; Antibodies, Monoclonal; Brain; Cell Death; Chickens; Circular Dichroism; Electrophoresis, Polyacrylamide Gel; Enzyme-Linked Immunosorbent Assay; Heparitin Sulfate; Humans; Immunoblotting; Immunohistochemistry; Lewy Bodies; Microscopy, Electron, Transmission; Neurodegenerative Diseases; Neurons; Parkinson Disease; Prions; Protein Binding; Protein Conformation; Recombinant Proteins; Solubility; Substantia Nigra; Synucleins; Time Factors

Microtubule-associated protein tau forms neurofibrillary lesions in Alzheimer's disease and several other neurodegenerative disorders, such as Niemann-Pick disease type C, subacute sclerosing panencephalitis, argyrophilic grain disease, myotonic dystrophy and motor neuron disease with neurofibrillary tangles. In this study we have compared the characteristics of tau pathology in these diseases using immunohistochemistry and phosphorylation-dependent and phosphorylation-independent anti-tau antibodies. The pattern of staining for heparan sulphate and alpha-synuclein was also investigated. We show that in all of these diseases tau deposits were stained by all anti-tau antibodies used, with the exception of argyrophilic grains which do not stain with antibody 12E8, confirming our previous findings. Heparan sulphate staining was present to a variable extent in all of these diseases, with the exception of subacute sclerosing panencephalitis, in which no staining was observed. Heparan sulphate staining coexisted with tau staining. In some cases it was more extensive than the tau staining. Alpha-synuclein staining was present in presynaptic terminals with the exception of one case of Alzheimer's disease, in which alpha-synuclein-positive Lewy bodies were observed in the hippocampal formation. These findings indicate that tau deposits are antigenically similar in several neurodegenerative diseases and that tau staining is often associated with heparan sulphate staining, supporting the concept that heparan sulphate may be involved in the assembly of tau protein into filaments.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; alpha-Synuclein; Dementia; Female; Heparitin Sulfate; Humans; Immunohistochemistry; Male; Microtubule-Associated Proteins; Nerve Tissue Proteins; Neurodegenerative Diseases; Neurofibrils; Synucleins; tau Proteins