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

INTRODUCTIONExtracellular 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. METHODSEVs 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. RESULTSBoth 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. DISCUSSIONResults 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. HighlightsA beta 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.

Automated summary

The study found that extracellular vesicles (EVs) in Alzheimer's disease (AD) and frontotemporal dementia (FTD) not only contribute to the spread of neuropathology, but also have an impact on behavioral outcomes associated with AD. Memory tests were conducted by injecting EVs isolated from post mortem brain tissue from control, AD, or FTD donors, as well as from APP/PS1 mice, into the hippocampi of wild-type or a humanized Tau mouse model. The results showed that AD-EVs and FTD-EVs carry Tau protein, have altered protein composition related to synapse regulation and transmission, and induce memory impairment.