Biomedical subjects

Adriano Aguzzi

Publications and source records attributed to Adriano Aguzzi.

78 records · Page 5Linked to original sources

PubMed2002

Chronic subclinical prion disease induced by low-dose inoculum.

We have compared the transmission characteristics of the two mouse-adapted scrapie isolates, ME7 and Rocky Mountain Laboratory (RML), in tga20 mice. These mice express elevated levels of PrP protein compared to wild-type mice and display a relatively short disease incubation period following intracerebral prion inoculation. Terminal prion disease in tga20 mice induced by ME7 or RML was characterized by a distinct pattern of clinical signs and different incubation times. High-dose RML inoculated intracerebrally into tga20 mice induced the most rapid onset of clinical signs, with mice succumbing to terminal disease after only 58 +/- 3 days. In contrast, high-dose ME7 gave a mean time to terminal disease of 74 +/- 0 days. Histological examination of brain sections from prion-inoculated tga20 mice at terminal disease showed that ME7 gave rise to a more general and extensive pattern of vacuolation than RML. Low-dose inoculum failed to induce terminal disease but did cause preclinical symptoms, including the appearance of reversible clinical signs. Some mice oscillated between showing no clinical signs and early clinical signs for many months but never progressed to terminal disease. Brain tissue from these mice with chronic subclinical prion disease, sacrificed at >200 days postinoculation, contained high levels of infectivity and showed the presence of PrP(Sc). Parallel analysis of brain tissue from mice with terminal disease showed similar levels of infectivity and detectable PrP(Sc). These results show that high levels of infectivity and the presence of the abnormal isomer of PrP can be detected in mice with subclinical disease following low-dose prion inoculation.

Animals↗

PubMed2002

Analysis of the prion protein in primates reveals a new polymorphism in codon 226 (Y226F).

Bovine spongiform encephalopathy has been epizootic in cows for the last two decades, and most probably causes variant Creutzfeldt-Jakob disease in humans. A thorough understanding of prion pathogenesis relies on suitable animal models. Modeling the transmission of BSE to primates is a crucial public health priority, necessary for determining the tissue distribution of the agent and for devising therapies. Susceptibility of humans to BSE is partly determined by polymorphism within the gene encoding the cellular prion protein, Prnp, a fact that must be taken into account in primate studies. However, no information is available on Prnp polymorphisms in primates. We have sequenced the Prnp open reading frames of 30 non-consanguineous Rhesus macaques. All macaques were homozygous for methionine at codon 129, which is polymorphic in humans and seems to modulate prion susceptibility. However, we identified a novel polymorphism in macaque Prnp, localized on codon 226 (Y226F). A modulatory effect of this polymorphism on the development of prion disease is possible because codon 226 is close to the suggested binding side of the factor X, which has been invoked as a determinant of the prion species barrier.

Amyloid↗

PubMed2000

PrP(C) expression in the peripheral nervous system is a determinant of prion neuroinvasion.

Transmissible spongiform encephalopathies are often propagated by extracerebral inoculation. The mechanism of spread from peripheral portals of entry to the central nervous system (neuroinvasion) is complex: while lymphatic organs typically show early accumulation of prions, and B-cells and follicular dendritic cells are required for efficient neuroinvasion, actual entry into the central nervous system occurs probably via peripheral nerves and may utilize a PrP(C)-dependent mechanism. This study shows that transgenic mice overexpressing PrP(C) undergo rapid and efficient neuroinvasion upon intranerval and footpad inoculation of prions. These mice exhibited deposition of the pathological isoform of the prion protein (PrP(Sc)) and infectivity in specific portions of the central and peripheral sensory pathways, but almost no splenic PrP(Sc) accumulation. In contrast, wild-type mice always accumulated splenic PrP(Sc), and had widespread deposition of PrP(Sc) throughout the central nervous system even when prions were injected directly into the sciatic nerve. These results indicate that a lympho-neural sequence of spread occurs in wild-type mice even upon intranerval inoculation, while overexpression of PrP(C) leads to substantial predilection of intranerval over lymphoreticular spread. The rate of transport of infectivity in peripheral nerves was ca. 0.7 mm per day, and prion infectivity titres of sciatic nerves were much higher in tga20 than in wild-type mice, suggesting that overexpression of PrP(C) modulates the capacity for intranerval transport.

Animals↗

PubMed2000

The Neuroimmune Interface in Prion Diseases.

Prion diseases are fatal neurodegenerative disorders of animals and humans. Here we address the role of the immune system in the spread of prions from peripheral sites to the central nervous system and its potential relevance to iatrogenic prion disease.

Journal Article↗

PubMedDate not supplied

Alzheimer A beta vaccination of rhesus monkeys (Macaca mulatta).

Recent preliminary data suggest that vaccination with Alzheimer A beta might reduce senile plaque load and stabilize cognitive decline in human Alzheimer disease. To examine the mechanisms and consequences of anti-A beta-antibody formation in a species more closely related to humans, rhesus monkeys (Macaca mulatta) were vaccinated with aggregated A beta 1-42. Immunized monkeys developed anti-A beta titers exceeding 1:1000, and their plasma A beta levels were 5- to 10-fold higher than the plasma A beta levels observed in monkeys vaccinated with aggregated amylin. These data support the use of nonhuman primates to model certain phenomena associated with vaccination of humans with aggregated Alzheimer A beta.

Amyloid beta-Peptides↗

PubMedDate not supplied

[The prion hypothesis and the human prion diseases].

Our understanding of the pathogenesis of the transmissible spongiform encephalopathies (TSE) has made terrific headway over the past 40 years and some scientists are even of the opinion that this group of diseases belongs to the neurodegenerative syndromes best understood. On the other hand, the investigation of TSE has led to a multitude of unexpected and surprising results and consequently has initiated impassioned discussions among scientists. Although the human forms of TSE are very rare, the wildfire-like spread of the bovine spongiform encephalopathy (BSE) raises the pressing question as to whether BSE is communicable to humans. This overview summarizes some current hypotheses about the nature of the infectious agent and about the pathogenesis of the damage of the central nervous system.

Animals↗