Fibrillar prion peptide (106–126) and scrapie prion protein hamper phagocytosis in microglia

Abstract

The inflammatory response in prion diseases is dominated by microglial activation. As macrophages of the central nervous system, the phagocytic capacity of microglia is well recognized, and it is possible that microglia are involved in the removal and processing of amyloid fibrils, thus preventing their harmful effect. We have analyzed the effects of a synthetic peptide of the human prion protein, PrP(106-126), which can form fibrils, and the pathogenic form of prion protein, PrPsc, on phagocytosis in microglia isolated from neonatal rat brain cultures. To some extent, fibrillar PrP(106-126) is internalized and processed. However, both synthetic prion peptide PrP(106-126) in a fibrillar form and pathogenic prion protein PrPsc severely hamper the phagocytic activity as measured by the uptake of beads by microglia. At a concentration that does not induce microglial death, PrP(106-126) reduced the number of beads internalized and altered their cytoplasmic distribution. This effect was not due to decreased binding of beads to the cell surface, nor restricted to specific classes of receptors. Although the PrP(106-126) did not prevent F-actin and Rac1 accumulation at sites of particle engulfment, it appeared to interfere with a later step of the internalization process.

Comparison of Inflammatory and Acute-Phase Responses in the Brain and Peripheral Organs of the ME7 Model of Prion Disease

“…We have previously shown that the acute in vivo CNS responses to injected prion-infected and normal brain homogenates are indistinguishable (4), demonstrating that initial microglial activation is a nonspecific response to the injection of brain homogenate rather than to the PrP Sc contained in the homogenate. Consistent with the present data, it has now also been shown that the coating of inert latex beads with a fibrillar prion peptide (106-126) actually hampers their phagocytosis by cultured microglia (14). Taking these data together, it seems unlikely that PrP Sc is a stimulus for microglial activation in vivo.…”

Cellular pathogenesis in prion diseases

“…Misfolded monomers or oligomeric intermediates appear to be the more probable toxic species. This is consistent with recent data indicating that smaller subfibrillar particles with a mass equivalent to [14][15][16][17][18][19][20][21][22][23][24][25][26][27][28] PrP molecules are the most infectious moiety and may be much more toxic than larger amyloid fibrils or plaques [113].…”

“…Supporting this concept, recent data is demonstrating that 'pharmacogenetic' ablation of microglia from infected organotypic brain slices provoked an increase of PrP Sc levels, as well as an increase in susceptibility to infection [38]. However, fibrillar prion peptide (106-126) and scrapie prion protein were shown to hamper phagocytosis in microglia [21]. Altogether, this suggests that the extensive microglial activation accompanying prion diseases represents an efficient defensive reaction at least in a particular time frame.…”

Phagocytosis of apoptotic cells: a matter of balance

“…A similar control mechanism for phagocytosis may also be active within the nervous system. Interestingly, it was recently shown that the fibrillar prion peptide PrP and the scrapie form of the prion protein (PrP Sc ) also have negative effects on phagocytosis by microglial cells [173]. In summary, the Review Article 1541 cellular prion protein adds to a growing list of negative modulators, which may be essential in balancing the threshold of phagocytic responses ( fig.…”