Lack of cellular prion protein causes Amyloid ß accumulation, increased extracellular vesicle abundance, and changes to exosome biogenesis proteins

• Alzheimer's disease (AD) progression is closely linked to the propagation of pathological Amyloid beta (A beta), a process increasingly understood to involve extracellular vesicles (EVs), namely exosomes. The specifics of A beta packaging into exosomes remain elusive, although evidence suggests an ESCRT (Endosomal Sorting Complex Required for Transport)-independent origin to be responsible in spreading of AD pathogenesis. Intriguingly, PrPC, known to influence exosome abundance and bind oligomeric A beta (oA beta), can be released in exosomes via both ESCRT-dependent and ESCRT-independent pathways, raising questions about its role in oA beta trafficking. Thus, we quantified A beta levels within EVs, cell medium, and intracellularly, alongside exosome biogenesis-related proteins, following deletion or overexpression of PrPC. The same parameters were also evaluated in the presence of specific exosome inhibitors, namely Manumycin A and GW4869. Our results revealed that deletion of PrPC increases intracellular A beta accumulation and amplifies EV abundance, alongside significant changes in cellular levels of exosome biogenesis-related proteins Vps25, Chmp2a, and Rab31. In contrast, cellular expression of PrPC did not alter exosomal A beta levels. This highlights PrPC's influence on exosome biogenesis, albeit not in direct A beta packaging. Additionally, our data confirm the ESCRT-independent exosome release of A beta and we show a direct reduction in Chmp2a levels upon oA beta challenge. Furthermore, inhibition of opposite exosome biogenesis pathway resulted in opposite cellular PrPC levels. In conclusion, our findings highlight the intricate relationship between PrPC, exosome biogenesis, and A beta release. Specifically, they underscore PrPC's critical role in modulating exosome-associated proteins, EV abundance, and cellular A beta levels, thereby reinforcing its involvement in AD pathogenesis.Graphical abstractThere are two main exosome biogenesis pathways: ESCRT dependent and ESCRT independent. In this study, we explored the effect of the cellular prion protein (PrPC) on the release of Amyloid beta via exosomes. Our findings demonstrate that Amyloid beta mainly is released via an ESCRT-independent pathway, independent of PrPC. However, lack of PrPC resulted in upregulation of the ESCRT-dependent proteins Tsg101 and VPS25, a decrease in Chmp2a, and an overall increase in extracellular vesicles. Lack of PrPC also caused an accumulation of cellular, but not exosomal, Amyloid beta.

Subject headings

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

Keyword

Alzheimer's disease; Amyloid beta; Extracellular vesicles; Exosome; Prion; ESCRT

Publication and Content Type

ref (subject category)

art (subject category)