期刊
ALZHEIMERS RESEARCH & THERAPY
卷 12, 期 1, 页码 -出版社
BMC
DOI: 10.1186/s13195-020-00623-4
关键词
Alzheimer's disease; Vascular dementia; Extracellular vesicles; Braak staging; Neurodegeneration; Autophagy; Neuroinflammation
资金
- National Medical Research Council of Singapore [NMRC-OF-IRG-0003-2016]
- Ministry of Education of Singapore [MOE2016-T2-2-018]
- Consejeria de Ciencia, Universidades e Innovacion of the Comunidad de Madrid, Spain [2018-T1/BIO-10633]
- Talento Program call 2018 Comunidad de Madrid
- Sara Borrell Program of the Instituto de Salud Carlos III, Ministry of Economy and Competitiveness (Spain) [European Union ERDF Funds (European Regional Development Fund)] [CD19/00243]
- PHS contract
- [HHSN-271-2013-00030C]
Background The contributions of brain intercellular communication mechanisms, specifically extracellular vesicles (EV), to the progression of Alzheimer's disease (AD) remain poorly understood. Methods Here, we investigated the role(s) of brain EV in the progressive course of AD through unbiased proteome-wide analyses of temporal lobe-derived EV and proteome-label quantitation of complementary remaining brain portions. Furthermore, relevant proteins identified were further screened by multiple reaction monitoring. Results Our data indicate that EV biogenesis was altered during preclinical AD with the genesis of a specific population of EV containing MHC class-type markers. The significant presence of the prion protein PrP was also manifested in these brain vesicles during preclinical AD. Similarly, sequestration of amyloid protein APP in brain EV coincided with the observed PrP patterns. In contrast, active incorporation of the mitophagy protein GABARAP in these brain vesicles was disrupted as AD progressed. Likewise, disrupted incorporation of LAMP1 in brain EV was evident from the initial manifestation of AD clinical symptoms, although the levels of the protein remained significantly upregulated in the temporal lobe of diseased brains. Conclusions Our findings indicate that impaired autophagy in preclinical AD coincides with the appearance of proinflammatory and neuropathological features in brain extracellular vesicles, facts that moderately remain throughout the entire AD progression. Thus, these data highlight the significance of brain EV in the establishment of AD neuropathology and represent a further leap toward therapeutic interventions with these vesicles in human dementias.
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