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

Elizabeta B Mukaetova-Ladinska,Charles R Harrington,Ross Jakes,Carol Brayne,William G Honer,Eugene S Paykel,Felicia A Huppert,John H Xuereb,Richard Hills,Magnus A Mcgee,Herman-J Gertz,Francisco Garcia-Sierra,Jenny Hurt,Claude M Wischik

doi:10.1100/tsw.2009.151

Abstract

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.

Highlights

Cytoplasmic Lewy bodies (LBs) occur in a range of neurodegenerative disorders associated with dopaminergic neuronal degeneration, including Parkinson’s disease and dementia with Lewy bodies (DLB)
We demonstrate that individuals with Lewy body variant of AD (LBV) have substantially lower levels of t-SNARE complex synaptic proteins in the frontal and temporal neocortices, as well as SNAP-25, MAP2, and αsynuclein proteins in their medial temporal lobes compared to control and Alzheimer’s disease (AD) subjects
LBV is generally regarded as a subgroup of AD lacking neurofibrillary tangles, and one in which the Braak pathological stage is lower at the time of death[5,21]

Summary

Introduction

Cytoplasmic Lewy bodies (LBs) occur in a range of neurodegenerative disorders associated with dopaminergic neuronal degeneration, including Parkinson’s disease and dementia with Lewy bodies (DLB). LBs are seen in smaller numbers in older people with no cognitive impairment[1] and in other neurodegenerative disorders, including Down syndrome and Alzheimer’s disease (AD). In a recent neuropathological survey, the LBV was confirmed in 18% of the autopsy material[7]. Both AD and LBV appear to share similar genetic risk factors (including family history of dementia or APOE 4 allele frequency)[8], as well as clinical characteristics and course (e.g., age at onset, duration, extent of cognitive impairment, or performance on activities of daily living)[8,9]. Despite a majority of studies that report a similar extent of cognitive decline and mortality rate between AD and LBV, faster cognitive decline and accelerated mortality in LBV have been described[16,17]

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