Recent evidence suggests that the deposition of beta-amyloid (Abeta) can be eliminated in a transgenic mouse model that overexpresses human mutant amyloid precursor protein (APP) by immunization with fibrillar Abeta. Further, memory decline appears to be reduced in immunized mice, suggesting a link between Abeta and cognition. We propose to replicate and extend these studies in mice to a higher mammalian model, the aged canine (dog). Over the past 10 years, we have demonstrated that aged canines show a decline in memory and learning and a corresponding increase in Abeta pathology. In addition, recent data support an association specifically between cognitive test scores and the location and extent of Abeta pathology. The questions we hope to answer specifically are: (1) will immunization with fibrillar Abeta reduce the development of cognitive dysfunction in aged canines? (2) will immunization reduce the more highly aggregated, insoluble and long-lived species of Abeta which are typical of both aged human and canine brain? (3) is the reduction of Abeta in the brain through immunization possible in immunologically intact animal models? and (4) are secondary pathologies related to Abeta also reduced (e.g., inflammation, neuritic dystrophy, gliosis, oxidative damage)? To address these issues we propose to study an aged group of dogs that have developed Abeta pathology. Dogs will be immunized with adjuvant-fibrillar Abeta, adjuvant-SAP (serum amyloid protein), adjuvant only, and an untreated control group which will be matched on the basis of cognitive ability. All dogs will undergo extensive baseline testing to evaluate learning (visual discrimination) and memory (object recognition and spatial) ability. After the start of intervention, learning will be evaluated at regular intervals using new visual discrimination tasks. Memory will be re-evaluated using the same object recognition and spatial memory tasks that are designed for repeated testing. At the conclusion of the study, evidence of an autoimmune or inflammatory response will be determined by necropsy. Secondly, the load or burden of several species of Abeta will be quantified using image analysis. Secondary pathological measures are expected to be reduced in parallel with reduced Abeta accumulation. The proposed studies will provide a test of the theory that Abeta causes cognitive dysfunction. Overall, this project should provide unique insight into the efficacy of immunization with fibrillar Abeta and have direct implications for the design of human clinical trials.
| Vasilevko, Vitaly; Pop, Viorela; Kim, Hyun Jin et al. (2010) Linear and conformation specific antibodies in aged beagles after prolonged vaccination with aggregated Abeta. Neurobiol Dis 39:301-10 |
| Vasilevko, Vitaly; Head, Elizabeth (2009) Immunotherapy in a natural model of Abeta pathogenesis: the aging beagle. CNS Neurol Disord Drug Targets 8:98-113 |
| Head, Elizabeth; Pop, Viorela; Vasilevko, Vitaly et al. (2008) A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta. J Neurosci 28:3555-66 |
| Cotman, Carl W; Head, Elizabeth (2008) The canine (dog) model of human aging and disease: dietary, environmental and immunotherapy approaches. J Alzheimers Dis 15:685-707 |
| Head, Elizabeth; Barrett, Edward G; Murphy, M Paul et al. (2006) Immunization with fibrillar Abeta(1-42) in young and aged canines: Antibody generation and characteristics, and effects on CSF and brain Abeta. Vaccine 24:2824-34 |
