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

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

Victor Bodart-Santos  1   2 , Lisandra S Pinheiro  1 , Almir J da Silva-Junior  3 , Rudimar L Froza  4 , Rosemary Ahrens  2 , Rafaella A Gonçalves  5 , Mayara M Andrade  1 , Yan Chen  2 , Carolina de Lima Alcantara  3 , Lea T Grinberg  6   7 , Renata E P Leite  6 , Sergio T Ferreira  1   3 , Paul E Fraser  2   8 , Fernanda G De Felice  1   5   9
Affiliations

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

Victor Bodart-Santos et al. Alzheimers Dement. 2023 Dec.

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.

Keywords: Alzheimer's disease; brain-derived EVs; extracellular vesicles; proteomics; tauopathies.

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References

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