Alzheimer’s disease progression characterized by alterations in the molecular profiles and biogenesis of brain extracellular vesicles

Abstract

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.

Relationships of Alzheimer’s disease and apolipoprotein E genotypes with small RNA and protein cargo of brain tissue extracellular vesicles

“…Consistent with previous studies on bdEVs from human cortex (91, 92), we observed a similar bdEV recovery for AD and control. However, since bdEVs are released as a mixture of various subtypes and from diverse cells, this finding does not exclude the possibility that biogenesis of specific EV subtypes may be affected by AD.…”

“…However, since bdEVs are released as a mixture of various subtypes and from diverse cells, this finding does not exclude the possibility that biogenesis of specific EV subtypes may be affected by AD. For example, MHC class I bdEVs were reportedly enhanced in preclinical AD patients compared with controls and late-stage AD (92). Also, the APOE ε4 allele was reported to be involved in neuronal, endosomal, and lysosomal system dysfunction (93).…”

The future of Extracellular Vesicles as Theranostics – an ISEV meeting report

“…cell disruption [10,13,14]. Although biofluids are the preferred source due to their accessibility and high abundance, tissue derived EVs harbour cell type specific information which can be utilized as valuable tools to report on the physiological and pathological conditions of organs [15][16][17][18][19].…”

System-wide molecular dynamics of endothelial dysfunction in Gram-negative sepsis

“…Dysfunction of the endothelium is associated with the appearance and progression of the most severe human diseases, including sepsis, diabetes, stroke, dementia, and cancer [5][6][7][8][9][10]. Although these diseases are characterized by specific alterations of the endothelium, some of which have yet to be fully elucidated, inflammation has been defined as a core pathological mechanism affecting vascular beds in all these pathologies [11,12].…”