(2007) Prions and prion diseases. proteinase K-resistant conformer, termed scrapie PrP (PrPSc). Aggregates of PrPSc transferred around neurons lead to neuropathological alterations. Currently, there is no effective treatment for these fatal illnesses; thus, the development of an effective therapy is usually a priority. PrP peptide-based ELISA assay methods were developed for detection and immunoaffinity chromatography capture was developed for purification of naturally occurring PrP peptide autoantibodies present in human CSF, individual donor serum, and commercial preparations of pooled intravenous immunoglobulin (IVIg). The ratio of anti-PrP autoantibodies (PrP-AA) to total IgG was 1:1200. The binding epitope of purified PrP-AA was mapped to an N-terminal region comprising the PrP amino acid sequence KTNMK. Purified PrP-AA potently blocked fibril formation by a harmful 21-amino acid fragment of the PrP peptide made up of the amino acid alanine to valine substitution corresponding to position 117 of the full-length peptide (A117V). Furthermore, PrP-AA attenuated the neurotoxicity of PrP(A117V) and wild-type peptides in rat cerebellar granule neuron (CGN) cultures. In contrast, IgG preparations depleted of PrP-AA experienced little effect on PrP fibril formation or PrP neurotoxicity. The specificity of PrP-AA was exhibited by immunoprecipitating PrP protein in brain tissues of transgenic mice expressing the human PrP(A117V) epitope and Sc237 hamster. Based on these intriguing findings, it is suggested that human PrP-AA may be useful for interfering with the pathogenic effects of pathogenic prion proteins and, thereby has the potential to be an effective means for preventing or attenuating human prion disease progression. Keywords: Antibodies, Brain, Neurons, Neurotoxin, Peptides, IVIg, Prion, Autoantibody, Fibril Formation, Neurotoxicity Introduction Prion diseases, or transmissible spongiform encephalopathies (TSEs),2 are rapidly progressive neurodegenerative disorders with untreatable invariably fatal outcomes. Disease caused by altered forms of prion protein (PrP) include scrapie in sheep, bovine spongiform encephalopathy in cattle, as well as the human forms Kuru, Creutzfeldt-Jakob CPDA disease (CJD and CPDA vCJD), and the Gerstmann-Straussler-Scheinker (GSS) syndrome (1). These diseases are Rabbit polyclonal to ZC4H2 most likely caused by misfolding and CPDA aggregation of the normal host CPDA protein (PrPC) into a highly insoluble form PrPSc. In this process, a portion of the -helix and random coil structure of PrPC, which is usually ubiquitously expressed in neurons and leukocytes, adopts the PrPSc -pleated conformation, rendering the protein poorly soluble in water and resistant to protease digestion (1). Autopsy around the brains of prion disease patients has recognized amyloid plaques comprised of insoluble PrPSc aggregates deposited around neurons in affected brain regions, which is usually thought to induce neuronal dysfunction and death, thus generating the clinical symptoms of contamination (1C7). The primacy of a single protein causing disease across species by diverse mechanisms is unique in biology. To date, you will find no therapeutic treatments available for prion diseases. However, recent studies in cultured cells and mice indicate that immunotherapeutic strategies employing antibodies against the cellular form of PrPC can antagonize prion infectivity and disease development. Monoclonal antibodies (mAbs) or recombinant F(ab) fragments realizing PrP effectively prevented prion contamination of susceptible mouse neuroblastoma cells and abrogated PrPSc formation in chronically infected cells (8C9). In addition, passive transfer of a PrP mAb into scrapie-infected mice suppressed peripheral prion replication and infectivity, and significantly delayed onset of the disease (10C12). Notably, no obvious adverse effects were observed in these studies. These findings suggest that immunotherapeutic strategies for human prion diseases are worth pursuing. Recently, we as well as others (13C14) have suggested that an impaired or reduced ability to generate antibodies specific for beta amyloid (A) peptides may be one mechanism contributing to Alzheimer disease (AD) pathogenesis. Intravenous immunoglobulin (IVIg) preparations made up of natural levels of anti-A antibodies or purified autoantibodies against A have shown beneficial effects in trials with AD patients (13, 15C17). We have demonstrated that these autoantibodies prevent or disaggregate A fibril formation and block their harmful effects in main neurons (18). Since the CPDA pathogenic mechanisms of AD and prion diseases both involve harmful conformational changes and deposition of insoluble protein aggregates.