Faculty Bibliography

Squirrel monkey is a valuable model to study pathogenesis of cerebrovascular amyloid angiopathy (CAA). Previous studies suggested that circulating amyloid-beta40 peptide (Abeta40) crosses the blood-brain barrier (BBB) and may therefore enhance cerebrovascular amyloidosis in aged squirrel monkeys. In the present study, we used single photon emission computed tomography (SPECT) to determine elimination of 123I-Abeta40 and 99mTc-DTPA, an extracellular marker, from the brain in squirrel monkeys at different age. Following intracerebral microinfusions, the time-activity brain clearance curves indicated bi-exponential removal of 123I-Abeta40 with an initial rapid washout (1.1 < or = t 1/2 < or = 2.7 h). This, plus the observed appearance of 123I-radioactivity in plasma suggest significant brain-to-blood transport. In contrast, 99mTc-DTPA was removed slowly by brain interstitial fluid bulk flow (monoexponential decay with 6.8 < or = t 1/2 < or = 16.8 h). A comparison of three middle aged (11-16 years old) vs. two old (22 yrs old) monkeys was consistent with an age-related decline in the BBB capacity to remove 123I-Abeta from the brain. This correlated with an age-dependent increase in A1beta40/42 cerebrovascular immunoreactivity and amyloid deposition. Thus, vascular clearance plays an important role in reducing Abeta levels in the squirrel monkey brain and impaired Abeta40 elimination across the BBB may contribute to the development of CAA

The prion diseases are a rapidly fatal group of neurodegenerative disorders, which currently have no effective therapy. Recently we have shown that active immunization with recombinant PrP protein increases the incubation period in mice exposed peripherally to the 139A strain of scrapie agent (Am.J.Pathol., in press). The antibody titers correlated with the increased incubation. We have extended these observations by using 6 different monoclonal anti-mouse PrP antibodies for passive immunization, with epitopes that span the murine PrP protein. Intraperitoneal antibody injections were performed weekly, starting immediately after and 1 month following peripheral exposure to scrapie strain 139A at two different dilutions. We found a statistically significant prolongation of the incubation period from scrapie exposure to the onset of clinical symptoms. These initial findings suggest that passive immunization can be used to prolong the incubation period among individuals with a known exposure to the prion agent

To date, transmissibility of amyloid diseases has not been thoroughly investigated. Although only some of these conformational disorders are considered infectious, all amyloid diseases could be infectious under certain conditions. For transmissibility, endogenous expression of an amyloidogenic peptide required, as well as the presence of an inoculum that is rich in amyloid fibrils and/or their precursors. Notably, administration of one type of amyloid might result in deposition of a different amyloid. Various cofactors could be essential for transmission - some might chaperone the amyloid peptides and/or fibrils, thereby directly facilitating their propagation; others might indirectly stabilize and/or increase levels of conformers with a high beta-sheet content. It is possible that these chaperones are induced by inflammation, which itself can lead to secondary amyloidosis. Thus, amyloid-related therapeutic approaches should not be based on administration of amyloidogenic peptides in conjunction with an inflammatory stimulus, such as in a recently halted clinical trial for Alzheimer's disease