title: α-Syn suppression reverses synaptic and memory defects in a mouse model of dementia with Lewy bodies.
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.
authors: Department of Pathology and Laboratory Medicine, Institute on Aging and Center for Neurodegenerative Disease Research, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
authors: Youngshin
authors: Y
authors: Lim
authors: Victoria M
authors: VM
authors: Kehm
authors: Edward B
authors: EB
authors: Lee
authors: James H
authors: JH
authors: Soper
authors: Chi
authors: C
authors: Li
authors: John Q
authors: JQ
authors: Trojanowski
authors: Virginia M-Y
authors: VM
authors: Lee
mesh_terms: D000161:Acoustic Stimulation / Q000009:adverse effects; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000473:pathology*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000172:deficiency; D003214:Conditioning, Classical; D003463:Cues; D004195:Disease Models, Animal; D018450:Disease Progression; D004622:Embryo, Mammalian; D005239:Fear / Q000523:psychology; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D005911:Gliosis / Q000209:etiology; D006801:Humans; D066298:In Vitro Techniques; D007211:Indoles; D020961:Lewy Body Disease / Q000150:complications* / Q000235:genetics / Q000473:pathology*; D008297:Male; D008569:Memory Disorders / Q000209:etiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000209:etiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D012694:Serine / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000378:metabolism / Q000473:pathology / Q000502:physiology; D051844:alpha-Synuclein / Q000172:deficiency / Q000378:metabolism*
chemical_list: D005904:Glial Fibrillary Acidic Protein; D007211:Indoles; D009419:Nerve Tissue Proteins; D051844:alpha-Synuclein; D012694:Serine; C007293:DAPI; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2