Faculty Bibliography

Prion diseases are of considerable importance because of the threat of a variant form of Creutzfeldt Jakob disease that has emerged in recent years. Pre-clinical diagnosis of prion diseases still remains poor and effective therapies also do not exist at present. This review examines research on possible therapeutic strategies that might have potential benefits if applied before neurodegeneration has occurred.

Alzheimer disease (AD) is the most common cause of dementia. Currently available therapies only provide symptomatic relief. A number of therapeutic approaches are under development that aim to increase the clearance of brain Abeta peptides. These include immune mediated clearance of Abeta and the inhibition of the interaction between Abeta and its pathological chaperones. Both active and passive immunization has been shown to have robust effects in transgenic mouse models of AD on amyloid reduction and behavioral improvements. However, a human trial of active immunization has been associated with significant toxicity in a minority of patients. New generation vaccines are being developed which likely will reduce the potential for cell-mediated toxicity. In addition, the recent development of anti-chaperone therapy opens a new therapeutic avenue which is unlikely to be associated with toxicity

Infection with any one of three strains of mouse scrapie prion (PrPSc), 139A, ME7, or 22L, results in the accumulation of two underglycosylated, full-length PrP species and an N-terminally truncated PrP species that are not detectable in uninfected animals. The levels of the N-terminally truncated PrP species vary depending on PrPSc strain. Furthermore, 22L-infected brains consistently have the highest levels of proteinase K (PK)-resistant PrP species, followed by ME7- and 139A-infected brains. The three strains of PrPSc are equally susceptible to PK and proteases papain and chymotrypsin. Their protease resistance patterns are also similar. In sucrose gradient velocity sedimentation, the aberrant PrP species partition with PrPSc aggregates, indicating that they are physically associated with PrPSc. In ME7-infected animals, one of the underglycosylated, full-length PrP species is detected much earlier than the other, before both the onset of clinical disease and the detection of PK-resistant PrP species. In contrast, the appearance of the N-terminally truncated PrP species coincides with the presence of PK-resistant species and the manifestation of clinical symptoms. Therefore, accumulation of the underglycosylated, full-length PrP species is an early biochemical fingerprint of PrPSc infection. Accumulation of the underglycosylated, full-length PrP species and the aberrant N-terminally truncated PrP species may be important in the pathogenesis of prion disease

Transgenic mice are used increasingly to model brain amyloidosis, mimicking the pathogenic processes involved in Alzheimer's disease (AD). In this chapter, a strategy is described that has been successfully used to map amyloid deposits in transgenic mouse models of AD with magnetic resonance imaging (MRI), utilizing molecular targeting vectors labeled with MRI contrast agents to enhance selectively the signal from amyloid plaques. To obtain sufficient spatial resolution for effective and sensitive mouse brain imaging, magnetic fields of 7-Tesla (T) or more are required. These are higher than the 1.5-T field strength routinely used for human brain imaging. The higher magnetic fields affect contrast agent efficiency, and determine the choice of pulse sequence parameters for in vivo MRI, all addressed in this chapter. Ex vivo imaging is also described as an important step to test and optimize protocols prior to in vivo studies. The experimental setup required for mouse brain imaging is explained in detail, including anesthesia, immobilization of the mouse head to reduce motion artifacts, and anatomical landmarks to use for the slice alignment procedure to improve image co-registration during longitudinal studies, and for subsequent matching of MRI with histology

In recent years major outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (prion protein cellular), to a toxic and infectious form, PrP(Sc) (prion protein scrapie). None of the prionoses currently have an effective treatment. A limited number of active immunization approaches have been shown to slightly prolong the incubation period of prion infection. Active immunization in wild-type animals is hampered by auto-tolerance to PrP and potential toxicity. Here we report that mucosal vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, is effective at overcoming tolerance to PrP and leads to a significant delay or prevention of prion disease in mice later exposed orally to the 139A scrapie strain. This mucosal vaccine induced gut anti-PrP immunoglobulin (Ig)A and systemic anti-PrP IgG. No toxicity was evident with this vaccination approach. This promising finding suggests that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk