fibrin and Parkinson-Disease

The thrombin-induced polymerisation of fibrinogen to form fibrin is well established as a late stage of blood clotting. It is known that Parkinson's Disease (PD) is accompanied by dysregulation in blood clotting, but it is less widely known as a coagulopathy. In recent work, we showed that the presence of tiny amounts of bacterial lipopolysaccharide (LPS) in healthy individuals could cause clots to adopt an amyloid form, and this could be observed via scanning electron microscopy (SEM) or via the fluorescence of thioflavin-T. This could be prevented by the prior addition of lipopolysaccharide-binding protein (LBP). We had also observed by SEM this unusual clotting in the blood of patients with Parkinson's Disease. We hypothesised, and here show, that this too can be prevented by LBP in the context of PD. This adds further evidence implicating inflammatory microbial cell wall products as an accompaniment to the disease, and may be part of its aetiology. This may lead to novel treatment strategies in PD designed to target microbes and their products.

Topics: Acute-Phase Proteins; Aged; Amyloid; Blood Coagulation; Carrier Proteins; Drug Discovery; Female; Fibrin; Humans; Lipopolysaccharides; Male; Membrane Glycoproteins; Middle Aged; Parkinson Disease

Many chronic diseases, including those classified as cardiovascular, neurodegenerative, or autoimmune, are characterized by persistent inflammation. The origin of this inflammation is mostly unclear, but it is typically mediated by inflammatory biomarkers, such as cytokines, and affected by both environmental and genetic factors. Recently circulating bacterial inflammagens such as lipopolysaccharide (LPS) have been implicated. We used a highly selective mouse monoclonal antibody to detect bacterial LPS in whole blood and/or platelet poor plasma of individuals with Parkinson's Disease, Alzheimer's type dementia, or Type 2 Diabetes Mellitus. Our results showed that staining is significantly enhanced (P < 0.0001) compared to healthy controls. Aberrant blood clots in these patient groups are characterized by amyloid formation as shown by the amyloid-selective stains thioflavin T and Amytracker™ 480 or 680. Correlative Light-Electron Microscopy (CLEM) illustrated that the LPS antibody staining is located in the same places as where amyloid fibrils may be observed. These data are consistent with the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis in which bacterial inflammagens such as LPS are responsible for anomalous blood clotting as part of the aetiology of these chronic inflammatory diseases.

Topics: Aged; Alzheimer Disease; Amyloid; Blood Coagulation; Blood Specimen Collection; Diabetes Mellitus, Type 2; Female; Fibrin; Humans; Inflammation; Lipopolysaccharides; Male; Microscopy, Electron; Middle Aged; Parkinson Disease; Protein Binding

Individuals with neurodegenerative disorders or brain injury have few treatment options and it has been proposed that endogenous adult neural stem cells can be harnessed to repopulate dysfunctional nonneurogenic regions of the brain. We have accomplished this through the development of rationally designed hydrogel implants that recruit endogenous cells from the adult subventricular zone to create new relatively long tracts of neuroblasts. These implants are biocompatible and biodegradable cylindrical hydrogels consisting of fibrin and immobilized neurotrophic factors. When implanted into rat brain such that the cylinder intersected the migratory path of endogenous neural progenitors (the rostral migratory stream) and led into the nonneurogenic striatum, we observed a robust neurogenic response in the form of migrating neuroblasts with long (>100 μm) complex neurites. The location of these new neural cells in the striatum was directly coincident with the original track of the fibrin implant, which itself had completely degraded, and covered a significant area and distance (>2.5 mm). We also observed a significant number of neuroblasts in the striatal region between the implant track and the lateral ventricle. When these fibrin cylinders were implanted into hemiparkinson rats, correction of parkinsonian behavior was observed. There were no obvious behavioral, inflammatory or tumorigenic sequelae as a consequence of the implants. In conclusion, we have successfully engineered neural tissue in vivo, using neurogenic biomaterials cast into a unique cylindrical architecture. These results represent a novel approach to efficiently induce neurogenesis in a controlled and targeted manner, which may lead toward a new therapeutic modality for neurological disorders.

Topics: Aging; Animals; Behavior, Animal; Biocompatible Materials; Brain; Cell Movement; Female; Fibrin; Hydrogels; Immunohistochemistry; Implants, Experimental; Mammals; Neurites; Neurogenesis; Oxidopamine; Parkinson Disease; Rats, Sprague-Dawley; Rotation; Tissue Engineering

Topics: Blood Coagulation; Blood Viscosity; Fibrin; Hemophilia A; Hemophilia B; Humans; Kinetics; Multiple Sclerosis; Parkinson Disease; Polymers; Thrombelastography