Abstract
BackgroundThe contributions of brain intercellular communication mechanisms, specifically extracellular vesicles (EV), to the progression of Alzheimer’s disease (AD) remain poorly understood.MethodsHere, 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.ResultsOur 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.ConclusionsOur 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.
Highlights
Alzheimer’s disease (AD) is the largest global contributor to cognitive decline and dementia [1]
Ultrastructural characterization by cryo-electron microscopy of circulating extracellular vesicles (EV) isolated by PROSPR, as performed previously [25], confirmed the predominant presence of spherical vesicles in the EV preparations obtained by this method
Our systems biology approach revealed that EV biogenesis becomes altered during the we found by advanced proteome clustering that common patterns between mixed dementias and all analyzed AD stages could only be identified in brain EV from preclinical AD, a finding that reaffirms our recently suggested hypothesis indicating that the influence of the vascular component in brain EV may decay over the course of AD [17]
Summary
Alzheimer’s disease (AD) is the largest global contributor to cognitive decline and dementia [1]. Gallart-Palau et al Alzheimer's Research & Therapy (2020) 12:54 These can be considered the most evident neuropathological signs of the disease and are widely used to define the course of illness [3,4,5], recent findings indicate that subtler molecular mechanisms might be implicated in the progression of AD [6] and that their deciphering can notably help to guide the development of viable therapeutics for this fatal disease. The identification of subtle specific molecular alterations that can contribute to AD spreading inevitably drives our focus toward the scrutiny of abnormal brain intercellular communication [6, 10,11,12]. The contributions of brain intercellular communication mechanisms, extracellular vesicles (EV), to the progression of Alzheimer’s disease (AD) remain poorly understood
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
