Home About us Contact
|
Home About us Contact | ||
|
|
||
Dystrophic Neurites (dystrophic + neurite)
Selected AbstractsAdvanced glycation endproducts and pro-inflammatory cytokines in transgenic Tg2576 mice with amyloid plaque pathologyJOURNAL OF NEUROCHEMISTRY, Issue 2 2003Gerald Münch Abstract Increased expression and altered processing of the amyloid precursor protein (APP) and generation of ,-amyloid peptides is important in the pathogenesis of amyloid plaques in Alzheimer's disease (AD). Transgenic Tg2576 mice overexpressing the Swedish mutation of human APP exhibit ,-amyloid deposition in the neocortex and limbic areas, accompanied by gliosis and dystrophic neurites. However, murine plaques appear to be less cross-linked and the mice show a lower degree of inflammation and neurodegeneration than AD patients. ,Advanced glycation endproducts (AGEs)', formed by reaction of proteins with reactive sugars or dicarbonyl compounds, are able to cross-link proteins and to activate glial cells, and are thus contributing to plaque stability and plaque-induced inflammation in AD. In this study, we analyze the tissue distribution of AGEs and the pro-inflammatory cytokines IL-1, and TNF-, in 24-month-old Tg2576 mice, and compare the AGE distribution in these mice with a younger age group (13 months old) and a typical Alzheimer's disease patient. Around 70% of the amyloid plaque cores in the 24-month-old mice are devoid of AGEs, which might explain their solubility in physiological buffers. Plaque associated glia, which express IL-1, and TNF-,, contain a significant amount of AGEs, suggesting that plaques, i.e. A, as its major component, can induce intracellular AGE formation and the expression of the cytokines on its own. In the 13-month-old transgenic mice, AGEs staining can neither be detected in plaques nor in glial cells. In contrast, AGEs are present in high amounts in both plaques and glia in the human AD patient. The data obtained in this show interesting differences between the transgenic mouse model and AD patients, which should be considered using the transgenic approach to test therapeutical strategies to eliminate plaques or to attenuate the inflammatory response in AD. [source] Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathyNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 6 2010K. Bhaskar K. Bhaskar, G. A. Hobbs, S-H. Yen and G. Lee (2010) Neuropathology and Applied Neurobiology36, 462,477 Tyrosine phosphorylation of tau accompanies disease progression in transgenic mouse models of tauopathy Aim: Tau protein is a prominent component of paired helical filaments in Alzheimer's disease (AD) and other tauopathies. While the abnormal phosphorylation of tau on serine and threonine has been well established in the disease process, its phosphorylation on tyrosine has only recently been described. We previously showed that the Src family non-receptor tyrosine kinases (SFKs) Fyn and Src phosphorylate tau on Tyr18 and that phospho-Tyr18-tau was present in AD brain. In this study, we have investigated the appearance of phospho-Tyr18-tau, activated SFK and proliferating cell nuclear antigen (PCNA) during disease progression in a mouse model of human tauopathy. Methods: We have used JNPL3, which expresses human tau with P301L mutation, and antibodies specific for phospho-Tyr18-tau (9G3), ser/thr phosphorylated tau (AT8), activated SFK and PCNA. Antibody staining was viewed by either epifluorescence or confocal microscopy. Results: Phospho-Tyr18-tau appeared concurrently with AT8-reactive tau as early as 4 months in JNPL3. Some 9G3-positive cells also contained activated SFKs and PCNA. We also investigated the triple transgenic mouse model of AD and found that unlike the JNPL3 model, the appearance of 9G3 reactivity did not coincide with AT8 in the hippocampus, suggesting that the presence of APP/presenilin influences tau phosphorylation. Also, Thioflavin S-positive plaques were 9G3-negative, suggesting that phospho-Tyr18-tau is absent from the dystrophic neurites of the mouse triple transgenic brain. Conclusions: Our results provide evidence for the association of tyrosine-phosphorylated tau with mechanisms of neuropathogenesis and indicate that SFK activation and cell cycle activation are also involved in JNPL3. [source] LRRK2 is a component of granular alpha-synuclein pathology in the brainstem of Parkinson's diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 3 2008J. Alegre-Abarrategui Classical Parkinson's disease (PD) is characterized by the appearance of Lewy bodies (LBs) in affected brain regions, showing mostly compact alpha-synuclein deposition, in contrast with punctate or granular deposition, hypothesized to represent early stages of aggregation. Leucine-rich repeat kinase 2 (LRRK2) is the commonest mutated gene in inherited and idiopathic PD. LRRK2 mutation carriers display a diverse neuropathology, including alpha-synuclein and tau inclusions, suggesting an upstream role for LRRK2 in protein aggregation. We studied LRRK2 expression throughout the normal human brain with three different antibodies. We also examined the pattern of LRRK2 expression in relation to alpha-synuclein aggregation and LB formation in the brainstem of sporadic LB disease. Physiological LRRK2 expression was not restricted to regions preferentially affected in PD and LRRK2 often localized to the nuclear envelope in addition to the known cytoplasmic expression. In PD, we were able to consistently detect LRRK2 in the halo of a minority (approximately 10%) of nigral LBs using three different antibodies. Only one antibody detected LRRK2 in the core of approximately 80% of classic LBs. In the lower brainstem, most notably in the dorsal motor nucleus of the vagus, we found previously unrecognized LRRK2 labelling of complex globular lesions, filled with LB-like matter showing a punctate or granular staining for alpha-synuclein. This was often accompanied by strong LRRK2 expression within dystrophic neurites. Our findings confirm widespread physiological LRRK2 expression in the human brain and suggest an association of LRRK2 with possible early-stage alpha-synuclein pathology in the brainstem of PD. [source] Selective PrP-like protein, doppel immunoreactivity in dystrophic neurites of senile plaques in Alzheimer's diseaseNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 4 2004I. Ferrer Doppel (Dpl) is a prion-like protein encoded by the gene PRND, which has been found downstream of the prion gene PRNP in several species. The present study examines by immunohistochemistry Dpl expression in brain samples from 10 patients with Alzheimer's disease (AD), three patients with Pick's disease, four patients with Parkinson's disease, eight patients with diffuse Lewy body disease (DLBD), six patients with sporadic Creutzfeldt,Jakob disease (CJD) methionine/methionine at the codon 129, two patients with sporadic CJD methionine/valine at the codon 129 and numerous kuru plaques in the cerebellum, one patient with fatal familial insomnia (FFI), and 10 age-matched controls. In the adult human brain, Dpl immunoreactivity was restricted to scattered granule cells of the cerebellum and scattered small granules in the cerebral cortex. Dpl immunoreactivity was seen around ,A4 amyloid deposits in neuritic plaques, but not in diffuse plaques, AD and the common form of DLBD. Neurofibrillary tangles, Pick bodies and Lewy bodies were not stained with anti-Dpl antibodies. No modifications in Dpl immunoreactivity were observed in CJD excepting those associated with accompanying senile plaques. No Dpl-positive deposits were seen in FFI. Whether Dpl in neuritic plaques may attenuate amyloid-induced oxidative stress and participate in the glial response around amyloid cores is discussed in light of the few available data on Dpl functions. [source] The p53 homologue p73 accumulates in the nucleus and localizes to neurites and neurofibrillary tangles in Alzheimer disease brainNEUROPATHOLOGY & APPLIED NEUROBIOLOGY, Issue 1 2004C. Wilson The molecular mechanisms that regulate neuronal survival vs. death during Alzheimer disease (AD) remain unclear. Nonetheless, a number of recent studies indicate that increased expression or altered subcellular distribution of numerous cell cycle proteins during AD may contribute to disease pathogenesis. Because homologues of p53, a key regulatory protein in the cell cycle, such as p73, have been identified and shown to participate in cellular differentiation and death pathways, we examined the expression and distribution of p73 in the hippocampus of eight control and 16 AD subjects. In control subjects, hippocampal pyramidal neurones exhibit p73 immunoreactivity that is distributed predominately in the cytoplasm. In AD hippocampus, increased levels of p73 are located in the nucleus of pyramidal neurones and p73 is located in dystrophic neurites and cytoskeletal pathology. Immunoblot analysis confirmed the presence of p73 in the hippocampus. These data indicate that p73 is expressed within hippocampal pyramidal neurones and exhibits altered subcellular distribution in AD. [source] Olfactory epithelium amyloid-, and paired helical filament-tau pathology in Alzheimer diseaseANNALS OF NEUROLOGY, Issue 4 2010Steven E. Arnold MD Objective Olfactory dysfunction is common in Alzheimer disease (AD) and other neurodegenerative diseases. Paired helical filament (PHF)-tau, ,-synuclein, and amyloid-, lesions occur early and severely in cerebral regions of the olfactory system, and they have also been observed in olfactory epithelium (OE). However, their frequency, abundance, and disease specificity, and the relationships of OE pathology to brain pathology have not been established. Methods We investigated the pathological expression of amyloid-,, PHFtau, ,-synuclein, and TDP-43 in postmortem OE of 79 cases with AD, 63 cases with various other neurodegenerative diseases, and 45 neuropathologically normal cases. Results Amyloid-, was present as punctate and small patchy aggregates in 71% of AD cases, compared with 22% of normal cases and 14% of cases with other diseases, and in greater amounts in AD than in either of the other 2 diagnostic categories. PHFtau was evident in dystrophic neurites in 55% of cases with AD, 34% with normal brains, and 39% with other neurodegenerative diseases, also at higher densities in AD. ,-Synuclein was present in dystrophic neurites in 7 cases, 6 of which also had cerebral Lewy bodies. Pathological TDP-43 inclusions were not observed in the OE in any cases. Amyloid-, and to a lesser degree, PHFtau ratings in OE significantly correlated with cortical A, and PHFtau lesion ratings in the brain. Interpretation These data demonstrate that AD pathology in the OE is present in the majority of cases with pathologically verified AD and correlates with brain pathology. Future work may assess the utility of amyloid-, and PHFtau measurement in OE as a biomarker for AD. ANN NEUROL 2010;67:462,469 [source] A1 Adenosine Receptors Accumulate in Neurodegenerative Structures in Alzheimer's Disease and Mediate Both Amyloid Precursor Protein Processing and Tau Phosphorylation and TranslocationBRAIN PATHOLOGY, Issue 4 2003Ester Angulo Immunostaining of adenosine receptors in the hippocampus and cerebral cortex from necropsies of Alzheimer's disease (AD) patients shows that there is a change in the pattern of expression and a redistribution of receptors in these brain areas when compared with samples from controls. Adenosine A1 receptor (A1R) immunoreactivity was found in degenerating neurons with neurofibrillary tangles and in dystrophic neurites of senile plaques. A high degree of colocalization for A1R and pA4 amyloid in senile plaques and for A1R and tau in neurons with tau deposition, but without tangles, was seen. Additionally, adenosine A2A receptors, located mainly in striatal neurons in controls, appeared in glial cells in the hippocampus and cerebral cortex of patients. On comparing similar samples from controls and patients, no significant change was evident for metabotropic glutamate receptors. In the human neuroblastoma SH-SY5Y cell line, agonists for A1R led to a dose-dependent increase in the production of soluble forms of amyloid precursor protein in a process mediated by PKC. A1R agonist induced p21 Ras activation and ERK1/2 phosphorylation. Furthermore, activation of A1R led to and ERK-dependent increase of tau phosphorylation and translocation towards the cytoskeleton. These results indicate that adenosine receptors are potential targets for AD. [source] Neuropathology with Clinical Correlations of Sporadic Amyotrophic Lateral Sclerosis: 102 Autopsy Cases Examined Between 1962 and 2000BRAIN PATHOLOGY, Issue 1 2003Yue-Shan Piao MD Sporadic amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder affecting adults. We studied the neuropathology and clinical correlations in 102 autopsy cases of ALS. The age at onset of the disease was significantly higher for the bulbar-onset form (30 cases) than for the limb-onset form (72 cases). Dementia was confirmed in 7 cases. These 102 cases were divided into 4 pathological subgroups: typical ALS (59 cases), lower-motor-predominant ALS (23 cases), ALS with temporal lesions (18 cases), and ALS with pallido-nigro-luysian degeneration (2 cases). The age at onset was significantly higher for lower-motor-predominant ALS and ALS with temporal lesions than for typical ALS. In the lower motor neurons, Bunina bodies were detected in 88 cases, whereas ubiquitin-immunoreactive skein and/or spherical inclusions were detected in all 102 cases. Of the 100 available cases, 50 and 16 also showed ubiquitin-immunoreactive inclusions in the neostriatal and temporal small neurons, respectively. Ubiquitin-immunoreactive dystrophic neurites were also observed in the neostriatum in 3 of the 50 cases with neostriatal inclusions, and in the temporal cortex in 4 of the 16 cases with temporal inclusions. There was a significant association between the bulbar-onset form, temporal lesions, neostriatal inclusions and temporal inclusions, and between dementia, temporal lesions and temporal inclusions. Neostriatal and temporal dystrophic neurites were associated with dementia and bulbar-onset form through temporal lesions and temporal inclusions. The present findings may be helpful for designing further studies on the mechanisms underlying the development of ALS. [source] | ||||||||||