Faculty Bibliography

A significant percentage of Alzheimer's disease (AD) patients exhibit concomitant vascular pathology. Epidemiological evidence suggest that vascular disease may not only add to global cognitive impairment but also exacerbate the course of AD pathology. The goal of this study was to analyze the impact of global ischemia on the cellular and amyloid-beta pathology in AD murine transgenic (Tg) models. Seven month old double Tg mice, expressing Swedish amyloid precursor protein (APP) and M146L presenilin 1 (PS1) mutations and single Tg mice (PS1 mutation alone) were subjected to 45 minutes bilateral common carotid artery occlusion or sham surgery. Behavioral testing performed two weeks after the surgery showed impaired learning and memory retention on Morris water maze and Hebb-Williams tests in both single PS1 and double PS1/APP Tg mice which underwent ischemia comparing to sham operated animals (p<0.05). Double Tg mice scored worse than single Tg mice. Animals were sacrificed two months after ischemia. The total brain volume was decreased by 6.5% and 5% and the ventricular volume was increased by 33.7% and 46.4% in single and double operated Tg mice, respectively comparing to sham animals. Unbiased stereological analysis demonstrated a 23% neuronal dropout in the CA1 sector of the cornu Ammonis after ischemia. Increased Abetaburden and plaque density was also observed in APP/PS1 animals which underwent ischemia comparing to sham operated ones. Overall, this data indicate that global ischemia exacerbate both neuronal and Abetarelated pathology in AD Tg animal models

Abeta1-42 vaccination trials were recently terminated because of cerebral inflammation, which may be due to Abeta toxicity and/or autoimmunity. Abeta forms inflammatory/toxic fibrils, may seed fibril formation and crosses the blood brain barrier (BBB) in experimental animals. Because of attenuated immune response, the elderly may not clear injected Abeta1-42, which may then initiate and/or enhance amyloid angiopathy and plaque formation. Therefore, it is safer to use immunogenic Abeta derivatives, which are less likely to be toxic. Unlike Abeta1-42, K6Abeta1-30 is non-fibrillogenic and non-toxic in human cell culture but diminishes amyloid burden to a similar extent as reported for Abeta1-42. Additionally, ramified IL-1beta positive microglia, associated with the plaques, are absent in the immunized mice indicating reduced inflammation in these animals. We are currently comparing the therapeutic potential of these two compounds in alum adjuvants, which are approved for human use. Our behavioral findings in a year old Tg2576 mice show no difference between these groups and controls in various sensorimotor tasks, linear maze and water maze. However, in the radial arm maze, vaccinated Tg mice and their non-Tg littermates performed equally well and had fewer errors than Tg controls (p=0.008). These groups are being evaluated at a higher amyloid burden and subsequently their brain pathology will be assessed. Overall, the use of nontoxic Abeta derivatives and/or Abeta clearing compounds with very limited access into the CNS, such as IgM, may prove to have reduced side effects compared to Abeta and/or IgG-based immunization

The outbreak of new variant Creutzfeldt-Jakob disease has raised the specter of a potentially large population being at risk to develop this prionosis. None of the prionoses currently have an effective treatment. Recently, vaccination has shown therapeutic potential in mouse models of another neurodegenerative condition, namely Alzheimers disease. Here we report that immunization with recombinant mouse prion protein delays the onset of prion disease in mice (Am. J. Pathol., in press). Vaccination was performed both prior to and after peripheral exposure to the mouse-adapted scrapie strain 139A. A delay in disease onset was seen in both groups, but was more prolonged in animals immunized prior to exposure (p = 0.040-0.002). The increase in the incubation period closely correlated with the anti-prion antibody titer (p = 0.017-0.0001). Histological and Western blot evaluations of the brains of the treated-and control groups did not reveal any apparent differences in the degree of spongiform change or levels of scrapie prion. This was expected because the mice were killed when they scored positive for three consecutive weeks for behavioral signs of prion infection. Overall, the vaccination-mediated delay in prion disease onset is highly reproducible, correlates well with antibody titer and indicates that a similar approach may work in humans or other mammalian species at risk for prion disease

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

Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and can seed fibril formation. We report that immunization in transgenic APP mice (Tg2576) for 7 months with a soluble nonamyloidogenic, nontoxic Abeta homologous peptide reduced cortical and hippocampal brain amyloid burden by 89% (P = 0.0002) and 81% (P = 0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (P = 0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice indicating reduced inflammation in these animals. These promising findings suggest that immunization with nonamyloidogenic Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta fibrils

Transgenic mice with brain amyloid-beta (Abeta) plaques immunized with aggregated Abeta1-42 have reduced cerebral amyloid burden. However, the use of Abeta1-42 in humans may not be appropriate because it crosses the blood brain barrier, forms toxic fibrils, and it can seed fibril formation. We report that immunization in 11-12 months old Tg2576 APP mice for 7 months, with K6Abeta1-30, a highly soluble, non-amyloidogenic and non-toxic Abeta homologous peptide, reduced cortical and hippocampal brain amyloid burden by 89% (p=0.0002) and 81% (p=0.0001), respectively. Concurrently, brain levels of soluble Abeta1-42 were reduced by 57% (p=0.0019). Ramified microglia expressing interleukin-1beta associated with the Abeta plaques were absent in the immunized mice, indicating reduced inflammation in these animals. We are currently performing a long-term study on the histological, biochemical and behavioral effects of K6Abeta1-30 vaccination, where the mice received their first immunization at 2-4 months of age. Our preliminary results are that mice immunized with K6Abeta1-30 or Abeta1-42 in aluminum adjuvants have comparable titers although the former is much more soluble. Overall, our present findings suggest that immunization with soluble Abeta derivatives represents a potentially safer therapeutic approach to reduce amyloid burden in Alzheimer's disease, instead of using toxic Abeta aggregates