Abstract
Abnormally accumulated α-synuclein (α-syn) is a pathological hallmark of Lewy body-related disorders such as Parkinson's disease (PD) and dementia with Lewy body disease (DLB). However, it is not well understood whether and how abnormal accumulation of α-syn leads to cognitive impairment or dementia in PD and DLB. Furthermore, it is not known whether targeted removal of α-syn pathology can reverse cognitive decline. Here, we found that the distribution of α-syn pathology in an inducible α-syn transgenic mouse model recapitulates that in human DLB. Abnormal accumulation of α-syn in the limbic system, particularly in the hippocampus, correlated with memory impairment and led to structural synaptic deficits. Furthermore, when α-syn expression was suppressed, we observed partial clearing of pre-existing α-syn pathology and reversal of structural synaptic defects, resulting in an improvement in memory function.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acoustic Stimulation / adverse effects
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Age Factors
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Analysis of Variance
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Animals
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Animals, Newborn
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Brain / pathology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / deficiency
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Conditioning, Classical
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Cues
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Disease Models, Animal
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Disease Progression
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Embryo, Mammalian
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Fear / psychology
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Female
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Gene Expression Regulation / genetics
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Glial Fibrillary Acidic Protein / metabolism
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Gliosis / etiology
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Humans
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In Vitro Techniques
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Indoles
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Lewy Body Disease / complications*
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Lewy Body Disease / genetics
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Lewy Body Disease / pathology*
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Male
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Memory Disorders / etiology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Mutation / genetics
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Nerve Degeneration / etiology
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Nerve Tissue Proteins / metabolism
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Serine / genetics
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Serine / metabolism
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Synapses / metabolism
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Synapses / pathology
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Synapses / physiology
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alpha-Synuclein / deficiency
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alpha-Synuclein / metabolism*
Substances
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Glial Fibrillary Acidic Protein
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Indoles
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Nerve Tissue Proteins
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alpha-Synuclein
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Serine
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DAPI
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Calcium-Calmodulin-Dependent Protein Kinase Type 2