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1.
Front Cell Neurosci ; 12: 479, 2018.
Article in English | MEDLINE | ID: mdl-30618629

ABSTRACT

Early diagnosis of Parkinson's disease (PD) offers perhaps, the most promising route to a successful clinical intervention, and the use of an animal model exhibiting symptoms comparable to those observed in PD patients in the early stage of the disease, may facilitate screening of novel therapies for delaying the onset of more debilitating motor and behavioral abnormalities. In this study, a rat model of pre-motor PD was used to study the etiology of hyposmia, a non-motor symptom linked to the early stage of the disease when the motor symptoms have yet to be experienced. The study focussed on determining the effect of a partial reduction of both dopamine and noradrenaline levels on the olfactory cortex. Neuroinflammation and striking structural changes were observed in the model. These changes were prevented by treatment with a neuroprotective drug, a glucagon-like peptide-1 (GLP1) receptor agonist, exendin-4 (EX-4).

2.
Ann N Y Acad Sci ; 1351: 99-113, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26200258

ABSTRACT

Multiple sclerosis (MS) is a debilitating disease characterized by demyelination of the central nervous system (CNS), resulting in widespread formation of white matter lesions (WMLs) and grey matter lesions (GMLs). WMLs are pathologically characterized by the presence of immune cells that infiltrate the CNS, whereas these immune cells are barely present in GMLs. This striking pathological difference between WMLs and GMLs raises questions about the underlying mechanism. It is known that infiltrating leukocytes contribute to the generation of WMLs; however, since GMLs show a paucity of infiltrating immune cells, their importance in GML formation remains to be determined. Here, we review pathological characteristics of WMLs and GMLs, and suggest some possible explanations for the observed pathological differences. In our view, cellular and molecular characteristics of WM and GM, and local differences within WMLs and GMLs (in particular, in glial cell populations and the molecules they express), determine the pathway to demyelination. Further understanding of GML pathogenesis, considered to contribute to chronic MS, may have a direct impact on the development of novel therapeutic targets to counteract this progressive neurological disorder.


Subject(s)
Demyelinating Diseases/physiopathology , Gray Matter/immunology , Multiple Sclerosis/pathology , White Matter/immunology , Astrocytes/immunology , Blood-Brain Barrier/physiopathology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Gray Matter/physiopathology , Humans , Inflammation/immunology , Leukoencephalopathies/immunology , Leukoencephalopathies/pathology , Microglia/immunology , Multiple Sclerosis/immunology , White Matter/physiopathology
3.
Neurobiol Aging ; 34(4): 1159-69, 2013 Apr.
Article in English | MEDLINE | ID: mdl-23122413

ABSTRACT

Cerebral amyloid angiopathy (CAA) is a key histopathological hallmark of Alzheimer's disease (AD) and hereditary cerebral hemorrhage with amyloidosis of the Dutch type (HCHWA-D). CAA is characterized by amyloid-beta (Aß) depositions and remodeling of the extracellular matrix (ECM) in brain vessels and plays an important role in the development and progression of both AD and HCHWA-D. Tissue transglutaminase (tTG) modulates the ECM by molecular cross-linking of ECM proteins. Here, we investigated the distribution pattern, cellular source, and activity of tTG in CAA in control, AD, and HCHWA-D cases. We observed increased tTG immunoreactivity and colocalization with Aß in the vessel wall in early stage CAA, whereas in later CAA stages, tTG and its cross-links were present in halos enclosing the Aß deposition. In CAA, tTG and its cross-links at the abluminal side of the vessel were demonstrated to be either of astrocytic origin in parenchymal vessels, of fibroblastic origin in leptomeningeal vessels, and of endothelial origin at the luminal side of the deposited Aß. Furthermore, the ECM proteins fibronectin and laminin colocalized with the tTG-positive halos surrounding the deposited Aß in CAA. However, we observed that in situ tTG activity was present throughout the vessel wall in late stage CAA. Together, our data suggest that tTG and its activity might play a differential role in the development and progression of CAA, possibly evolving from direct modulation of Aß aggregation to cross-linking of ECM proteins resulting in ECM restructuring.


Subject(s)
Alzheimer Disease/metabolism , Amyloidosis, Familial/metabolism , Cerebral Amyloid Angiopathy/metabolism , Cerebral Arteries/metabolism , Cerebral Hemorrhage/metabolism , Extracellular Matrix Proteins/metabolism , GTP-Binding Proteins/metabolism , Transglutaminases/metabolism , Aged, 80 and over , Cerebral Amyloid Angiopathy, Familial , Female , Humans , Male , Middle Aged , Protein Glutamine gamma Glutamyltransferase 2 , Tissue Distribution
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