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Volume 9, Pages 1463-1475
Research Article

Lewy Body Variant of Alzheimer's Disease: Selective Neocortical Loss of t-SNARE Proteins and Loss of MAP2 and α-Synuclein in Medial Temporal Lobe

1Institute for Ageing and Health, Newcastle University, United Kingdom
2Department of Pathology, University of Cambridge, United Kingdom
3Cambridge Brain Bank Laboratory, MRC Centre, Cambridge, UK
4Department of Cell Biology, CINVESTAV - I.P.N., Mexico City, Mexico
5Department of Psychiatry, University of Leipzig, Germany
6Department of Public Health, University of Cambridge, UK
7Department of Psychiatry, University of Cambridge, UK
8Department of Public Health and General Practice, Christchurch School of Medicine and Health Sciences, University of Otago, Dunedin, New Zealand
9Laboratory of Molecular Biology, MRC Centre, Cambridge, UK
10Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada
11Division of Applied Health Sciences, University of Aberdeen, UK

Received 17 July 2009; Revised 17 November 2009; Accepted 17 November 2009

Academic Editor: Rudy Tanzi

Copyright © 2009 Elizabeta B Mukaetova-Ladinska et al.


Lewy bodies (LBs) appear in the brains of nondemented individuals and also occur in a range of neurodegenerative disorders, such as dementia with Lewy bodies (DLB) and Parkinson's disease. A number of people with a definite diagnosis of Alzheimer's disease (AD) also exhibit these intraneuronal inclusions in allo- and/or neocortical areas. The latter, referred to as Lewy body variant of AD (LBV), bears a clinical resemblance to AD in terms of age at onset, duration of illness, cognitive impairment, and illness severity. Since the presence of LBs is accompanied by neuronal cytoskeleton changes, it is possible that the latter may influence neuronal connectivity via alterations to the synaptic network. To address this, we examined the expression of synaptic proteins (synaptophysin, syntaxin, SNAP-25, and α-synuclein) and two cytoskeletal proteins (tau and MAP2) in the brain tissue of subjects enrolled in a population-based autopsy study (n = 47). They were divided into groups with no memory problems (control group, n = 15), LBV (n = 5), AD devoid of LBs (n = 17), cerebrovascular dementia (n = 3), and mixed dementia (n = 7). The LBV and AD groups had a similar degree of cognitive impairment and neuropathological staging in terms of Braak staging and CERAD score. In comparison with the control group and the dementia groups without LBs, the LBV group had significantly lower levels of syntaxin and SNAP-25 (23%) in the neocortex, and depletion of MAP2 (64%), SNAP-25 (34%), and α-synuclein (44%) proteins in the medial temporal lobes. These findings suggest that the t-SNARE complex deficit present in LBV may be associated with the presence of LB-related pathology and may explain the more profound cholinergic loss seen in these patients.