Alzheimer Disease: Lowe J

McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, Del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M, Anonymous00346. · Institute for Ageing and Health, University of Newcastle upon Tyne, UK. · Neurology. · Pubmed #16237129 No free full text.

Abstract: The dementia with Lewy bodies (DLB) Consortium has revised criteria for the clinical and pathologic diagnosis of DLB incorporating new information about the core clinical features and suggesting improved methods to assess them. REM sleep behavior disorder, severe neuroleptic sensitivity, and reduced striatal dopamine transporter activity on functional neuroimaging are given greater diagnostic weighting as features suggestive of a DLB diagnosis. The 1-year rule distinguishing between DLB and Parkinson disease with dementia may be difficult to apply in clinical settings and in such cases the term most appropriate to each individual patient should be used. Generic terms such as Lewy body (LB) disease are often helpful. The authors propose a new scheme for the pathologic assessment of LBs and Lewy neurites (LN) using alpha-synuclein immunohistochemistry and semiquantitative grading of lesion density, with the pattern of regional involvement being more important than total LB count. The new criteria take into account both Lewy-related and Alzheimer disease (AD)-type pathology to allocate a probability that these are associated with the clinical DLB syndrome. Finally, the authors suggest patient management guidelines including the need for accurate diagnosis, a target symptom approach, and use of appropriate outcome measures. There is limited evidence about specific interventions but available data suggest only a partial response of motor symptoms to levodopa: severe sensitivity to typical and atypical antipsychotics in approximately 50%, and improvements in attention, visual hallucinations, and sleep disorders with cholinesterase inhibitors.

Layfield R, Lowe J, Bedford L. · School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. · Essays Biochem. · Pubmed #16250904 No free full text.

Abstract: As in all other mammalian tissues, the UPS (ubiquitin-proteasome system) is fundamental to normal brain function. A consistent feature of the major human neurodegenerative disorders is the accumulation of disease-related proteins, in non-native conformations, as protein aggregates within neurons or glial cells. Often the proteins in these aggregates are post-translationally conjugated with ubiquitin, suggesting a possible link between pathological protein-aggregation events in the nervous system and dysfunction of the UPS. Genetic evidence clearly demonstrates that disruption of ubiquitin-mediated processes can lead to neurodegeneration; however, the relationship between the UPS and idiopathic neurodegenerative disorders is less clear. In the latter cases, although a number of different mechanisms could potentially contribute to dysfunction of the UPS and promote the neurodegenerative process, whether UPS dysfunction is causally related to disease pathogenesis, or alternatively arises as a result of the pathological state, and indeed whether ubiquitinated inclusions are harmful or beneficial to cells, remains to be clarified.

Lowe J. · Department of Pathology, University of Nottingham Medical School, Clifton Boulevard, Nottingham NG7 2UH, UK. · Curr Top Pathol. · Pubmed #11545053 No free full text.

This publication has no abstract.

Layfield R, Alban A, Mayer RJ, Lowe J. · Schools of Biomedical Sciences and Clinical Laboratory Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, United Kingdom. · Neuropathol Appl Neurobiol. · Pubmed #11489136 No free full text.

Abstract: The ubiquitin-proteasome system of intracellular proteolysis is essential for cell viability. We propose the concept that neurodegenerative diseases such as Alzheimer's and Parkinson's, as well as other conditions including some types of cancer, collectively represent a raft of 'ubiquitin protein catabolic disorders' in which altered function of the ubiquitin-proteasome system can cause or directly contribute to disease pathogenesis. Genetic abnormalities within the ubiquitin pathway, either in ubiquitin-ligase (E3) enzymes or in deubiquitinating enzymes, cause disease because of problems associated with substrate recognition or supply of free ubiquitin, respectively. In some cases, mutations in protein substrates of the ubiquitin-proteasome system may directly contribute to disease progression because of inefficient substrate recognition. Mutations in transcripts for the ubiquitin protein itself (as a result of 'molecular misreading') also affect ubiquitin-dependent proteolysis with catastrophic consequences. This has been shown in Alzheimer's disease and could apply to other age-associated neurodegenerative conditions. Within the nervous system, accumulation of unwanted proteins as a result of defective ubiquitin-dependent proteolysis may contribute to aggregation events, which underlie the pathogenesis of several major human neurodegenerative diseases.

Lowe J, Hand N, Mayer RJ. · School of Molecular Medical Sciences, University of Nottingham Medical School, Queens Medical Centre, Nottingham, United Kingdom. · Methods Enzymol. · Pubmed #16338351 No free full text.

Abstract: Ubiquitin immunohistochemistry has changed understanding of the pathophysiology of many diseases, particularly chronic neurodegenerative diseases. Protein aggregates (inclusions) containing ubiquitinated proteins occur in neurones and other cell types in the central nervous system in afflicted cells. The inclusions are present in all the neurological illnesses, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, polyglutamine diseases, and rarer forms of neurodegenerative disease. A new cause of cognitive decline in the elderly, "dementia with Lewy bodies," accounting for some 15-30% of cases, was initially discovered and characterized by ubiquitin immunocytochemistry. The optimal methods for carrying out immunohistochemical analyses of paraffin-embedded tissues are described, and examples of all the types of intracellular inclusions detected by ubiquitin immunohistochemistry in the diseases are illustrated. The role of the ubiquitin proteasome system (UPS) in disease progression is being actively researched globally and increasingly, because it is now realized that the UPS controls most pathways in cellular homeostasis. Many of these regulatory mechanisms will be dysfunctional in diseased cells. The goal is to understand fully the role of the UPS in the disorders and then therapeutically intervene in the ubiquitin pathway to treat these incurable diseases.

Tilley L, Morgan K, Grainger J, Marsters P, Morgan L, Lowe J, Xuereb J, Wischik C, Harrington C, Kalsheker N. · Division of Clinical Chemistry, School of Clinical Laboratory Sciences, University Hospital, Queen's Medical Centre, Nottingham, UK. · Eur J Hum Genet. · Pubmed #10482954 links to  free full text

Abstract: The E4 allele of the apolipoprotein E gene (APOE) is a major risk factor for late-onset Alzheimer's disease (LOAD) but is neither necessary nor sufficient to cause the disease. In this study, we investigated polymorphisms in the presenilin-1 (PS-1), and butyrylcholinesterase (BChE) genes, which have been implicated as risk factors for LOAD. Our data-set comprised 177 AD and 118 control patients, all of whom had been histopathologically confirmed following autopsy. We have tested homozygosity for the PS-1 allele 1 and possession of the BChE-K variant in association with APOE epsilon4 as risk factors in LOAD. Our findings support an association between the PS-1 polymorphism and LOAD, finding homozygosity for allele 1 associated with an approximately two-fold increased risk. Our data also show that in subjects greater than 75 years of age possession of both BChE-K and APOE-epsilon4 alleles is associated with an increased risk of LOAD, whilst the risk associated with APOE-epsilon4 allele alone is not significant.