Prion protein expression in senile plaques in Alzheimer's disease

Abstract.

Prion protein (PrP^C) is a glycolipid-anchored cell membrane sialoglycoprotein that localises in presynaptic membranes. Since synapses are vulnerable to Alzheimer's disease (AD), the present study examines PrP^C expression in senile plaques, one of the major structural abnormalities in AD, by single- and double-labelling immunohistochemistry. Punctate PrP^C immunoreactivity is found in diffuse plaques, whereas isolated large coarse PrP^C-positive granules reminiscent of dystrophic neurites are observed in neuritic plaques. Finally, PrP^C deposition also occurs as dense filamentous and amorphous precipitates in amyloid cores of senile plaques, but not in the walls of blood vessels with amyloid angiopathy. In contrast to PrP^C, βA4-amyloid immunoreactivity is preserved and even enhanced following incubation of the tissue sections with proteinase K prior to immunohistochemistry, thus indicating no PrP^C and βA4-amyloid cross-reactivity in dense amyloid cores of senile plaques. Punctate PrP^C deposition in diffuse plaques is similar to that of synaptophysin, a synaptic vesicle-associated protein, as already reported in other studies. Immunoprecipitation, electrophoresis and Western blot studies have shown that synaptophysin, amyloid precursor protein (APP) and βA4 do not co-precipitate with PrP. These results suggest that synaptophysin, APP and βA4 are likely not bound to PrP. PrP^C accumulation in βA4-amyloid dense cores may be the consequence of the release of PrP into the extracellular space. Whether PrP^C accumulation in the extracellular space is the result of impaired endocytosis and subsequent hydrolysis in the endosomal compartment, in contrast to normal degradation of PrP^C, resulting from or occurring in parallel to abnormal APP degradation, deserves further study.