Lewy body variant of Alzheimer's disease: selective neocortical loss of t-SNARE proteins and loss of MAP2 and alpha-synuclein in medial temporal lobe.
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 alpha-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 alpha-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.
Mukaetova-Ladinska
Elizabeta B
EB
Institute for Ageing and Health, Newcastle University, UK. Elizabeta.Mukaetova-Ladinska@ncl.ac.uk
Xuereb
John H
JH
Garcia-Sierra
Francisco
F
Hurt
Jenny
J
Gertz
Herman-J
HJ
Hills
Richard
R
Brayne
Carol
C
Huppert
Felicia A
FA
Paykel
Eugene S
ES
McGee
Magnus A
MA
Jakes
Ross
R
Honer
William G
WG
Harrington
Charles R
CR
Wischik
Claude M
CM
D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016631:Lewy Bodies / Q000378:metabolism; D020961:Lewy Body Disease / Q000378:metabolism*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000032:analysis*; D019579:Neocortex / Q000737:chemistry* / Q000473:pathology; D010766:Phosphorylation; D050600:SNARE Proteins / Q000032:analysis*; D013574:Synaptosomes / Q000378:metabolism; D013702:Temporal Lobe / Q000737:chemistry*; D051844:alpha-Synuclein / Q000032:analysis*; D016875:tau Proteins / Q000378:metabolism
C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins; D050600:SNARE Proteins; D051844:alpha-Synuclein; D016875:tau Proteins