阿尔茨海默病脑源性细胞外囊泡揭示了改变的突触相关蛋白质组，并在小鼠中诱导认知障碍。

Alzheimer's disease brain-derived extracellular vesicles reveal altered synapse-related proteome and induce cognitive impairment in mice.

机构信息

Institute of Medical Biochemistry Leopoldo de Meis, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

Tanz Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, Canada.

出版信息

Alzheimers Dement. 2023 Dec;19(12):5418-5436. doi: 10.1002/alz.13134. Epub 2023 May 19.

DOI:10.1002/alz.13134

PMID:37204850

Abstract

INTRODUCTION

Extracellular vesicles (EVs) have been implicated in the spread of neuropathology in Alzheimer's disease (AD), but their involvement in behavioral outcomes linked to AD remains to be determined.

METHODS

EVs isolated from post mortem brain tissue from control, AD, or frontotemporal dementia (FTD) donors, as well as from APP/PS1 mice, were injected into the hippocampi of wild-type (WT) or a humanized Tau mouse model (hTau/mTauKO). Memory tests were carried out. Differentially expressed proteins in EVs were assessed by proteomics.

RESULTS

Both AD-EVs and APP/PS1-EVs trigger memory impairment in WT mice. We further demonstrate that AD-EVs and FTD-EVs carry Tau protein, present altered protein composition associated with synapse regulation and transmission, and trigger memory impairment in hTau/mTauKO mice.

DISCUSSION

Results demonstrate that AD-EVs and FTD-EVs have negative impacts on memory in mice and suggest that, in addition to spreading pathology, EVs may contribute to memory impairment in AD and FTD.

HIGHLIGHTS

Aβ was detected in EVs from post mortem AD brain tissue and APP/PS1 mice. Tau was enriched in EVs from post mortem AD, PSP and FTD brain tissue. AD-derived EVs and APP/PS1-EVs induce cognitive impairment in wild-type (WT) mice. AD- and FTD-derived EVs induce cognitive impairment in humanized Tau mice. Proteomics findings associate EVs with synapse dysregulation in tauopathies.

摘要

简介

细胞外囊泡（EVs）已被牵连到阿尔茨海默病（AD）的神经病理学传播中，但它们与 AD 相关的行为结果的关联仍有待确定。

方法

从对照、AD 或额颞叶痴呆（FTD）供体以及 APP/PS1 小鼠的死后脑组织中分离 EVs，并将其注入野生型（WT）或人源化 Tau 小鼠模型（hTau/mTauKO）的海马体中。进行记忆测试。通过蛋白质组学评估 EVs 中差异表达的蛋白质。

结果

AD-EVs 和 APP/PS1-EVs 均可引发 WT 小鼠的记忆障碍。我们进一步证明 AD-EVs 和 FTD-EVs 携带 Tau 蛋白，具有改变的与突触调节和传递相关的蛋白质组成，并引发 hTau/mTauKO 小鼠的记忆障碍。

讨论

结果表明 AD-EVs 和 FTD-EVs 对小鼠的记忆有负面影响，并表明除了传播病理学外，EVs 可能导致 AD 和 FTD 的记忆障碍。

要点

从 AD 死后脑组织和 APP/PS1 小鼠的 EVs 中检测到 Aβ。Tau 在 AD、PSP 和 FTD 死后脑组织的 EVs 中富集。AD 来源的 EVs 和 APP/PS1-EVs 诱导 WT 小鼠认知障碍。AD 和 FTD 来源的 EVs 诱导人源化 Tau 小鼠认知障碍。蛋白质组学发现将 EVs 与 Tau 病中的突触失调联系起来。