Behavioral Assessment of Alzheimer's Transgenic Mice Following Long-Term A β Vaccination: Task Specificity and Correlations between A β Deposition and Spatial Memory

Abstract

Long-term vaccinations with human β-amyloid peptide 1-42 (Aβ1-42) have recently been shown to prevent or markedly reduce Aβ deposition in the PDAPP transgenic model of Alzheimer's disease (AD). Using a similar protocol to vaccinate 7.5-month-old APP (Tg2576) and APP+PS1 transgenic mice over an 8-month period, we previously reported modest reductions in brain Aβ deposition at 16 months. In these same mice, Aβ vaccinations had no deleterious behavioral effects and, in fact, benefited the mice by providing partial protection from age-related deficits in spatial working memory in the radial arm water maze task (RAWM) at 15.5 months. By contrast, control-vaccinated transgenic mice exhibited impaired performance throughout the entire RAWM test period at 15.5 months. The present study expands on our initial report by presenting additional behavioral results following long-term Aβ vaccination, as well as correlational analyses between cognitive performance and Aβ deposition in vaccinated animals. We report that 8 months of Aβ vaccinations did not reverse an early-onset balance beam impairment in transgenic mice. Additionally, in Y-maze testing at 16 months, all mice showed comparable spontaneous alternation irrespective of genotype or vaccination status. Strong correlations were nonetheless present between RAWM performance and extent of "compact" Aβ deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Aβ vaccinations is task specific, with preservation of hippocampal-associated working memory tasks most likely to occur. In view of the early short-term memory deficits exhibited by AD patients, Aβ vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.