Pathological substrate of memory impairment in multiple system atrophy

Neuropathol Appl Neurobiol. 2022 Dec;48(7):e12844. doi: 10.1111/nan.12844. Epub 2022 Aug 12.

Abstract

Aims: Synaptic dysfunction in Parkinson's disease is caused by propagation of pathogenic α-synuclein between neurons. Previously, in multiple system atrophy (MSA), pathologically characterised by ectopic deposition of abnormal α-synuclein predominantly in oligodendrocytes, we demonstrated that the occurrence of memory impairment was associated with the number of α-synuclein-positive neuronal cytoplasmic inclusions (NCIs) in the hippocampus. In the present study, we aimed to investigate how abnormal α-synuclein in the hippocampus can lead to memory impairment.

Methods: We performed pathological and biochemical analyses using a mouse model of adult-onset MSA and human cases (MSA, N = 25; Parkinson's disease, N = 3; Alzheimer's disease, N = 2; normal controls, N = 11). In addition, the MSA model mice were examined behaviourally and physiologically.

Results: In the MSA model, inducible human α-synuclein was first expressed in oligodendrocytes and subsequently accumulated in the cytoplasm of excitatory hippocampal neurons (NCI-like structures) and their presynaptic nerve terminals with the development of memory impairment. α-Synuclein oligomers increased simultaneously in the hippocampus of the MSA model. Hippocampal dendritic spines also decreased in number, followed by suppression of long-term potentiation. Consistent with these findings obtained in the MSA model, post-mortem analysis of human MSA brain tissues showed that cases of MSA with memory impairment developed more NCIs in excitatory hippocampal neurons along with α-synuclein oligomers than those without.

Conclusions: Our results provide new insights into the role of α-synuclein oligomers as a possible pathological cause of memory impairment in MSA.

Keywords: memory impairment; multiple system atrophy; neuronal cytoplasmic inclusion; α-synuclein; α-synuclein oligomer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Brain / pathology
  • Humans
  • Inclusion Bodies / pathology
  • Multiple System Atrophy* / pathology
  • Neurons / pathology
  • Parkinson Disease* / pathology
  • alpha-Synuclein / metabolism

Substances

  • alpha-Synuclein