ABSTRACT
Doubly transgenic mAPP+mPS1 mice (15-16 months) had impaired cognitive function in a spatial learning and memory task that combined features of a water maze and a radial arm maze. Nontransgenic mice learned a new platform location each day during 4 consecutive acquisition trials, and exhibited memory for this location in a retention trial administered 30 min later. In contrast, transgenic mice were, on average, unable to improve their performance in finding the hidden platform over trials. The cognitive performance of individual mice within the transgenic group were inversely related to the amount of Abeta deposited in the frontal cortex and hippocampus. These findings imply that mAPP+mPS1 transgenic mice develop deficits in cognitive ability as Abeta deposits increase. These data argue that radial arm water maze testing of doubly transgenic mice may be a useful behavioral endpoint in evaluating the functional consequences of potential AD therapies, especially those designed to reduce Abeta load.
Subject(s)
Amyloid beta-Peptides/metabolism , Amyloid beta-Protein Precursor/genetics , Membrane Proteins/genetics , Neurodegenerative Diseases/pathology , Neurodegenerative Diseases/physiopathology , Plaque, Amyloid/genetics , Plaque, Amyloid/metabolism , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Amino Acid Substitution/genetics , Amyloid beta-Peptides/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Female , Frontal Lobe/metabolism , Frontal Lobe/pathology , Frontal Lobe/physiopathology , Hippocampus/metabolism , Hippocampus/pathology , Hippocampus/physiopathology , Immunohistochemistry , Male , Maze Learning/physiology , Memory/physiology , Mice , Mice, Transgenic , Mutation/genetics , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/metabolism , Peptide Fragments/metabolism , Plaque, Amyloid/pathology , Presenilin-1 , Space Perception/physiologyABSTRACT
This study provides a comprehensive behavioral characterization during aging of transgenic mice bearing both presenilin-1 (PS1) and amyloid precursor protein (APP(670,671)) mutations. Doubly transgenic mice and non-transgenic controls were evaluated at ages wherein beta-amyloid (Abeta) neuropathology in APP+PS1 mice is low (5-7 months) or very extensive (15-17 months). Progressive cognitive impairment was observed in transgenic mice for both water maze acquisition and radial arm water maze working memory. However, transgenicity did not affect Y-maze alternations, circular platform performance, standard water maze retention, or visible platform recognition at either age, nor did transgenicity affect anxiety levels in elevated plus-maze testing. In sensorimotor tasks, transgenic mice showed a progressive increase in open field activity, a progressive impairment in string agility, and an early-onset impairment in balance beam. None of these sensorimotor changes appeared to be contributory to any cognitive impairments observed, however. Non-transgenic mice showed no progressive behavioral change in any measure evaluated. Given the age-related cognitive impairments presently observed in APP+PS1 transgenic mice and their progressive Abeta deposition/neuroinflammation, Abeta neuropathology could be involved in these progressive cognitive impairments. As such, the APP+PS1 transgenic mouse offers unique opportunities to develop therapeutics to treat or prevent Alzheimer's Disease through modulation of Abeta deposition/neuroinflammation.
Subject(s)
Aging/physiology , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Behavior, Animal/physiology , Cognition Disorders/physiopathology , Membrane Proteins/genetics , Mice, Transgenic/physiology , Aging/pathology , Alzheimer Disease/genetics , Amyloid beta-Protein Precursor/metabolism , Animals , Cognition Disorders/genetics , Female , Male , Maze Learning/physiology , Membrane Proteins/metabolism , Mice , Movement Disorders/genetics , Movement Disorders/physiopathology , Mutation/physiology , Postural Balance/physiology , Presenilin-1 , Psychomotor Performance/physiologyABSTRACT
Long-term vaccinations with human beta-amyloid peptide 1-42 (Abeta1-42) have recently been shown to prevent or markedly reduce Abeta 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 Abeta deposition at 16 months. In these same mice, Abeta 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 Abeta vaccination, as well as correlational analyses between cognitive performance and Abeta deposition in vaccinated animals. We report that 8 months of Abeta 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" Abeta deposition in both the hippocampus and the frontal cortex of vaccinated APP+PS1 mice. Our results suggest that the behavioral protection of long-term Abeta 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, Abeta vaccination of presymptomatic AD patients could be an effective therapeutic to protect against such cognitive impairments.
