Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0752347 (Dementia with Lewy bodies)
 1,653 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The nature of Lewy bodies (LBs) in the brain stem and cerebral cortex in five cases of diffuse Lewy body disease and one case of Parkinson's disease with dementia were investigated immunocytochemically with various antibodies to cytoskeletal proteins, paired helical filaments (PHF) and ubiquitin. Antibodies to 200-kDa component of neurofilament, tau and PHF showed no significant reactions with most of LBs. Antibodies to high-molecular weight microtubule-associated proteins (HMWMAPs) moderately stained the periphery of a few of LBs. A monoclonal antibody to PHF (DF2) which recognizes ubiquitin, and polyclonal antibodies to ubiquitin immunostained virtually all of the typical and cortical LBs as intensely as Alzheimer's neurofibrillary tangles and senile plaque neurites: the periphery of LBs was darkly stained, whereas the central core of typical LBs and central zone of cortical LBs were less intensely stained or remained unstained. Immunoelectron microscopy of the LBs with DF2 revealed that immune reaction products were located on the filaments exclusively in the periphery of LBs, but not on those in the center. These findings suggest that both types of LBs are immunocytochemically indistinguishable despite some structural differences, and that peripherally located filaments in LBs are tagged with ubiquitin, an element required for the ATP-dependent proteolysis system in the cell. Antibodies to ubiquitin are the most useful marker of LBs ever known.
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PMID:Lewy bodies are ubiquitinated. A light and electron microscopic immunocytochemical study. 336 59

Cytochrome oxidase (CO) is the terminal complex of the mitochondrial respiratory chain which generates ATP by oxidative phosphorylation. We have measured CO activity in six different brain regions of patients with senile dementia of Alzheimer type (SDAT, n = 10), presenile dementia of Alzheimer type (PDAT, n = 10), Lewy body dementia with SDAT (LBD, n = 5), cerebrovascular dementia (CVD, n = 10), Parkinson dementia (PD, n = 5), and in controls (n = 8), as all confirmed by neuropathological evaluation. CO activity was lower in the frontal and parietal cortex of SDAT patients compared to controls. Patients with PDAT, LBD, CVD or PD showed no significant reduction of the enzymatic activity in the six regions studied. Our results show that reduced CO activity might play a role in the physiopathology of senile dementia of Alzheimer type.
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PMID:Distribution of brain cytochrome oxidase activity in various neurodegenerative diseases. 760 32

The ATP-ubiquitin-dependent proteolytic pathway (ubiquitin pathway) is believed to be involved in the formation of various neuronal inclusion bodies including Lewy bodies (LBs), a pathological hallmark of Parkinson disease and diffuse Lewy body disease (DLBD). Since multicatalytic proteinase (MCP) is involved in the ubiquitin pathway, an investigation of whether MCP is involved in neuronal inclusion bodies would provide a clue to the mechanism underlying the formation of neuronal inclusion bodies as well as to the pathogenesis of degenerative neurological disorders. In this study, we investigated detailed immunolocalization of MCP in LBs in DLBD brains using light and electron microscopy. We raised three different monoclonal antibodies against purified human MCP. Each of them recognized different sets of MCP subunits on Western blotting. Immunohistochemically, anti-MCP antibodies recognized all ubiquitin-positive cortical LBs in situ as well as those isolated from frozen DLBD cortices, suggesting that MCP is present in LBs as a whole molecule exhibiting protease activity. In electron microscopy, MCP immunoreactivity (MCP-IR) was exclusively localized on a characteristic oval structure with an approximate diameter of 100 nm. This structure was distributed throughout the LBs and was devoid of ubiquitin immunoreactivity. Treatment of isolated LBs with 2% SDS, but not with 0.5% Triton X-100, removed this structure from LBs in which fibrous materials predominated. Ubiquitin immunoreactivity was also decreased in isolated LBs treated with 2% SDS, suggesting that the fibrous structures in LBs were not ubiquitinated in situ. Thus, it is suggested that LBs are subjected to a proteolytic process in which MCP plays a role via processing of specific components of LBs.
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PMID:Multicatalytic proteinase is associated with characteristic oval structures in cortical Lewy bodies: an immunocytochemical study with light and electron microscopy. 802 94

Creatine kinase (CK) BB, a member of the CK gene family, is a predominantly cytosolic CK isoform in the brain and plays a key role in regulation of the ATP level in neural cells. CK BB levels are reduced in brain regions affected by neurodegeneration in Alzheimer's disease (AD), Pick's disease, and Lewy body dementia, and this reduction is not a result of decreased mRNA levels. This study demonstrates that posttranslational modification of CK BB plays a role in the decrease of CK activity in AD brain. The specific CK BB activity and protein carbonyl content were determined in brain extracts of six AD and six age-matched control subjects. CK BB activity per microgram of immunoreactive CK BB protein was lower in AD than in control brain extracts, indicating the presence of inactive CK BB molecules. The analysis of specific protein carbonyl levels in CK BB, performed by two-dimensional fingerprinting of oxidatively modified proteins, identified CK BB as one of the targets of protein oxidation in the AD brain. The increase of protein carbonyl content in CK BB provides evidence that oxidative posttranslational modification of CK BB plays a role in the loss of CK BB activity in AD.
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PMID:Oxidative modification of creatine kinase BB in Alzheimer's disease brain. 1082 Feb 14

Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD) are second only to Alzheimer's disease (AD) in frequency. In particular it is evident that up to 80% of people with PD will develop dementia towards the end of their life. While the neurobiology of movement disorder has been well studied in PD, much less attention has been given to mechanisms underlying the cognitive and behavioural symptoms associated with DLB and PDD. To date, the best correlate of cognitive impairment appears to be cortical Lewy bodies; however, new emphasis has been placed on small aggregates of synuclein. Furthermore, very few studies have attempted to investigate the neurochemical correlates of behavioural disorders in DLB/PDD and whether these are similar or distinct from AD. Aggregated alpha-synuclein forms the core component of Lewy bodies, a major pathological feature of Parkinson's-related conditions. The 26S proteasome is an ATP-dependent protease that catalyses the breakdown of alpha-synuclein. Previous studies have implicated alterations in the proteasome in PD. Furthermore, proteasome inhibitors have been reported to induce alpha-synuclein aggregation and Lewy body-like inclusions, resulting in neuronal loss both in vitro and in vivo. Our preliminary results indicate that selective alterations in the expression of proteosome sub-units are a feature of both DLB and PDD, while changes in activity are restricted to PDD. Depression is a common symptom in DLB/PDD, yet the evidence base for standard treatment with SSRIs is limited. In contrast to previous studies of AD, our results indicate that there is no association between depression and the 5-HT transporter, while there was a significant increase in the number of 5-HT1A receptors in those DLB/PDD patients with depression. These data may provide an insight into the lack of success of current treatments and suggest alternative approaches.
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PMID:Biochemical and pathological correlates of cognitive and behavioural change in DLB/PDD. 1971 Nov 17

Alzheimer's disease (AD) and related dementias are a major public health challenge and present a therapeutic imperative for which we need additional insight into molecular pathogenesis. We performed a genome-wide association study and analysis of known genetic risk loci for AD dementia using neuropathologic data from 4,914 brain autopsies. Neuropathologic data were used to define clinico-pathologic AD dementia or controls, assess core neuropathologic features of AD (neuritic plaques, NPs; neurofibrillary tangles, NFTs), and evaluate commonly co-morbid neuropathologic changes: cerebral amyloid angiopathy (CAA), Lewy body disease (LBD), hippocampal sclerosis of the elderly (HS), and vascular brain injury (VBI). Genome-wide significance was observed for clinico-pathologic AD dementia, NPs, NFTs, CAA, and LBD with a number of variants in and around the apolipoprotein E gene (APOE). GalNAc transferase 7 (GALNT7), ATP-Binding Cassette, Sub-Family G (WHITE), Member 1 (ABCG1), and an intergenic region on chromosome 9 were associated with NP score; and Potassium Large Conductance Calcium-Activated Channel, Subfamily M, Beta Member 2 (KCNMB2) was strongly associated with HS. Twelve of the 21 non-APOE genetic risk loci for clinically-defined AD dementia were confirmed in our clinico-pathologic sample: CR1, BIN1, CLU, MS4A6A, PICALM, ABCA7, CD33, PTK2B, SORL1, MEF2C, ZCWPW1, and CASS4 with 9 of these 12 loci showing larger odds ratio in the clinico-pathologic sample. Correlation of effect sizes for risk of AD dementia with effect size for NFTs or NPs showed positive correlation, while those for risk of VBI showed a moderate negative correlation. The other co-morbid neuropathologic features showed only nominal association with the known AD loci. Our results discovered new genetic associations with specific neuropathologic features and aligned known genetic risk for AD dementia with specific neuropathologic changes in the largest brain autopsy study of AD and related dementias.
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PMID:Genome-wide association meta-analysis of neuropathologic features of Alzheimer's disease and related dementias. 2518 41