title: Continuous production of prions after infectious particles are eliminated: implications for Alzheimer's disease.
abstract: Rat septal cells, induced to enter a terminal differentiation-like state by temperature shift, produce prion protein (PrP) levels 7x higher than their proliferative counterparts. Host PrP accumulates on the plasma membrane, newly elaborated nanotubes, and cell-to-cell junctions, important conduits for viral spread. To find if elevated PrP increased susceptibility to FU-CJD infection, we determined agent titers under both proliferating and arresting conditions. A short 5 day arrest and a prolonged 140 day arrest increased infectivity by 5x and 122x (>2 logs) respectively as compared to proliferating cells. Total PrP rapidly increased 7x and was even more elevated in proliferating cells that escaped chronic arrest conditions. Amyloid generating PrP (PrP-res), the "infectious prion" form, present at ~100,000 copies per infectious particle, also increased proportionately by 140 days. However, when these highly infectious cells were switched back to proliferative conditions for 60 days, abundant PrP-res continued to be generated even though 4 logs of titer was lost. An identical 4 log loss was found with maximal PrP and PrP-res production in parallel cells under arresting conditions. While host PrP is essential for TSE agent spread and replication, excessive production of all forms of PrP can be inappropriately perpetuated by living cells, even after the initiating infectious agent is eliminated. Host PrP changes can start as a protective innate immune response that ultimately escapes control. A subset of other neurodegenerative and amyloid diseases, including non-transmissible AD, may be initiated by environmental infectious agents that are no longer present.
authors.affiliation: Section of Neuropathology, Department of Surgery, Yale University Medical School, New Haven, Connecticut, United States of America.
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Miyazawa
authors.forename: Terry
authors.initials: T
authors.lastname: Kipkorir
authors.forename: Sarah
authors.initials: S
authors.lastname: Tittman
authors.forename: Laura
authors.initials: L
authors.lastname: Manuelidis
mesh_terms: D000199:Actins / Q000378:metabolism; D000544:Alzheimer Disease / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D007562:Creutzfeldt-Jakob Syndrome / Q000473:pathology; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D051379:Mice; D043942:Nanotubes / Q000737:chemistry; D018620:PrPSc Proteins / Q000096:biosynthesis* / Q000378:metabolism / Q000472:pathogenicity*; D011328:Prions / Q000096:biosynthesis* / Q000378:metabolism / Q000472:pathogenicity*; D051381:Rats; D020665:Septum of Brain / Q000166:cytology; D014404:Tubulin / Q000378:metabolism
chemical_list: D000199:Actins; D018620:PrPSc Proteins; D011328:Prions; D014404:Tubulin