Abstract
Dementia with Lewy bodies (DLB) accounts for 15-20% of the millions of people worldwide with dementia. In the current work we investigate the association between proteasome dysfunction and the development of cortical Lewy body pathology. Analysis of post-mortem cortical tissue indicated levels of the alpha-subunit of the 20S proteasome were significantly reduced in DLB cortex, but not Alzheimer's, in comparison to control and this reduction correlated with both the severity and duration of dementia. Application of proteasome inhibitors to rodent cortical primary neurones in vitro and by direct injection onto rodent cholinergic forebrain neurons in vivo gave rise to dose dependent neuronal death and in rodent cortex -- marked cholinergic deficits accompanied by the accumulation of inclusions that stained positive for alpha-synuclein and ubiquitin. These findings suggest that proteasomal abnormalities are present within cortical Lewy body disease and the experimental inhibition of proteasomal function mirrors the neuropathological changes seen within the disorder.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Acetylcholine / metabolism
-
Acetylcysteine / analogs & derivatives
-
Acetylcysteine / toxicity
-
Aged
-
Aged, 80 and over
-
Animals
-
Basal Nucleus of Meynert / drug effects
-
Basal Nucleus of Meynert / metabolism*
-
Basal Nucleus of Meynert / pathology
-
Cell Death / drug effects
-
Cell Death / physiology
-
Cells, Cultured
-
Cerebral Cortex / drug effects
-
Cerebral Cortex / metabolism*
-
Cerebral Cortex / pathology
-
Cholinergic Fibers / drug effects
-
Cholinergic Fibers / metabolism*
-
Cholinergic Fibers / pathology
-
Disease Models, Animal
-
Dose-Response Relationship, Drug
-
Enzyme Inhibitors / toxicity*
-
Female
-
Humans
-
Lewy Bodies / drug effects
-
Lewy Bodies / metabolism
-
Lewy Bodies / pathology
-
Lewy Body Disease / chemically induced
-
Lewy Body Disease / metabolism*
-
Lewy Body Disease / pathology
-
Male
-
Nerve Degeneration / chemically induced
-
Nerve Degeneration / metabolism
-
Nerve Degeneration / pathology
-
Nerve Tissue Proteins / metabolism
-
Neural Pathways / drug effects
-
Neural Pathways / metabolism
-
Neural Pathways / pathology
-
Oligopeptides / toxicity
-
Proteasome Endopeptidase Complex / metabolism*
-
Proteasome Inhibitors
-
Rats
-
Rats, Sprague-Dawley
-
Ubiquitin / drug effects
-
Ubiquitin / metabolism
-
alpha-Synuclein / drug effects
-
alpha-Synuclein / metabolism
Substances
-
Enzyme Inhibitors
-
Nerve Tissue Proteins
-
Oligopeptides
-
Proteasome Inhibitors
-
Ubiquitin
-
alpha-Synuclein
-
lactacystin
-
Proteasome Endopeptidase Complex
-
Acetylcholine
-
Acetylcysteine
-
epoxomicin