In prion and Alzheimer's diseases, the roles played by amyloid versus nonamyloid deposits in brain damage remain unresolved. In scrapie-infected transgenic mice expressing prion protein (PrP) lacking the glycosylphosphatidylinositol (GPI) membrane anchor, abnormal protease-resistant PrPres was deposited as amyloid plaques, rather than the usual nonamyloid form of PrPres. Although PrPres amyloid plaques induced brain damage reminiscent of Alzheimer's disease, clinical manifestations were minimal. In contrast, combined expression of anchorless and wild-type PrP produced accelerated clinical scrapie. Thus, the PrP GPI anchor may play a role in the pathogenesis of prion diseases.

https://science.sciencemag.org/content/sci/308/5727/1435.full.pdf

Anchorless prion protein results in infectious amyloid disease without clinical scrapie.

Alzheimer's disease (AD) and prion disease are characterized neuropathologically by extracellular deposits of Aβ and PrP amyloid fibrils, respectively. In both disorders, these cerebral amyloid deposits are co-localized with a broad variety of inflammation-related proteins (complement factors, acute-phase protein, pro-inflammatory cytokines) and clusters of activated microglia. The present data suggest that the cerebral Aβ and PrP deposits are closely associated with a locally induced, non-immune-mediated chronic inflammatory response. Epidemiological studies indicate that polymorphisms of certain cytokines and acute-phase proteins, which are associated with Aβ plaques, are genetic risk factors for AD. Transgenic mice studies have established the role of amyloid associated acute-phase proteins in Alzheimer amyloid formation. In contrast to AD, there is a lack of evidence that cytokines and acute-phase proteins can influence disease progression in prion disease. Clinicopathological and neuroradiological studies have shown that activation of microglia is a relatively early pathogenetic event that precedes the process of neuropil destruction in AD patients. It has also been found that the onset of microglial activation coincided in mouse models of prion disease with the earliest changes in neuronal morphology, many weeks before neuronal loss and subsequent clinical signs of disease. In the present work, we review the similarities and differences between the involvement of inflammatory mechanisms in AD and prion disease. We also discuss the concept that the demonstration of a chronic inflammatory-like process relatively early in the pathological cascade of both diseases suggests potential therapeutic strategies to prevent or to retard these chronic neurodegenerative disorders. GLIA 40:232–239, 2002. © 2002 Wiley-Liss, Inc.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/glia.10146

Neuroinflammation in Alzheimer's disease and prion disease.

The mode of internalization of glycosylphosphatidylinositol-anchored proteins, lacking any cytoplasmic domain by which to engage adaptors to recruit them into coated pits, is problematical; that of prion protein in particular is of interest since its cellular trafficking appears to play an essential role in its pathogenic conversion. Here we demonstrate, in primary cultured neurons and the N2a neural cell line, that prion protein is rapidly and constitutively endocytosed. While still on the cell surface, prion protein leaves lipid ‘raft’ domains to enter non-raft membrane, from which it enters coated pits. The N-terminal domain (residues 23–107) of prion protein is sufficient to direct internalization, an activity dependent upon its initial basic residues (NH2-KKRPKP). The effect of this changing membrane environment upon the susceptibility of prion protein to pathogenic conversion is discussed.

/pdf/the-mechanism-of-internalization-of-3cdkf0qug0.pdf

The mechanism of internalization of glycosylphosphatidylinositol-anchored prion protein

Prion protein (PrP) is usually attached to membranes by a glycosylphosphatidylinositol-anchor that associates with detergent-resistant membranes (DRMs), or rafts. To model the molecular processes that might occur during the initial infection of cells with exogenous transmissible spongiform encephalopathy (TSE) agents, we examined the effect of membrane association on the conversion of the normal protease-sensitive PrP isoform (PrP-sen) to the protease-resistant isoform (PrP-res). A cell-free conversion reaction approximating physiological conditions was used, which contained purified DRMs as a source of PrP-sen and brain microsomes from scrapie-infected mice as a source of PrP-res. Interestingly, DRM-associated PrP-sen was not converted to PrP-res until the PrP-sen was either released from DRMs by treatment with phosphatidylinositol-specific phospholipase C (PI-PLC), or the combined membrane fractions were treated with the membrane-fusing agent polyethylene glycol (PEG). PEG-assisted conversion was optimal at pH 6–7, and acid pre-treating the DRMs was not sufficient to permit conversion without PI-PLC or PEG, arguing against late endosomes/lysosomes as primary compartments for PrP conversion. These observations raise the possibility that generation of new PrP-res during TSE infection requires (i) removal of PrP-sen from target cells; (ii) an exchange of membranes between cells; or (iii) insertion of incoming PrP-res into the raft domains of recipient cells.

/pdf/conversion-of-raft-associated-prion-protein-to-the-protease-k4jl6kvpbk.pdf

Conversion of raft associated prion protein to the protease‐resistant state requires insertion of PrP‐res (PrPSc) into contiguous membranes

Prion diseases are transmissible, invariably fatal, neurodegenerative diseases which include Creutzfeldt-Jakob disease (CJD) in humans and bovine spongiform encephalopathy and scrapie in animals. A large number of putative treatments have been studied in experimental models over the past 30 years, with at best modest disease-modifying effects. The arrival of variant CJD in the UK in the 1990s has intensified the search for effective therapeutic agents, using an increasing number of animal, cellular and in vitro models with some recent promising proof of principle studies. Here, for the first time, we present a comprehensive systematic, rather than selective, review of published data on experimental approaches to prion therapeutics to provide a scientific resource for informing future therapeutics research, both in laboratory models and in clinical studies.

/pdf/a-systematic-review-of-prion-therapeutics-in-experimental-oiylpvbuep.pdf

A systematic review of prion therapeutics in experimental models

Heparan Sulfate Proteoglycan Is Associated with Amyloid Plaques and Neuroanatomically Targeted PrP Pathology throughout the Incubation Period of Scrapie-Infected Mice

M.I. Wilson

Papers

Heparan Sulfate Proteoglycan Is Associated with Amyloid Plaques and Neuroanatomically Targeted PrP Pathology throughout the Incubation Period of Scrapie-Infected Mice