A two-year study with fibrillar beta-amyloid (Abeta) immunization in aged canines: effects on cognitive function and brain Abeta.
Aged canines (dogs) accumulate human-type beta-amyloid (Abeta) in diffuse plaques in the brain with parallel declines in cognitive function. We hypothesized that reducing Abeta in a therapeutic treatment study of aged dogs with preexisting Abeta pathology and cognitive deficits would lead to cognitive improvements. To test this hypothesis, we immunized aged beagles (8.4-12.4 years) with fibrillar Abeta(1-42) formulated with aluminum salt (Alum) for 2.4 years (25 vaccinations). Cognitive testing during this time revealed no improvement in measures of learning, spatial attention, or spatial memory. After extended treatment (22 vaccinations), we observed maintenance of prefrontal-dependent reversal learning ability. In the brain, levels of soluble and insoluble Abeta(1-40) and Abeta(1-42) and the extent of diffuse plaque accumulation was significantly decreased in several cortical regions, with preferential reductions in the prefrontal cortex, which is associated with a maintenance of cognition. However, the amount of soluble oligomers remained unchanged. The extent of prefrontal Abeta was correlated with frontal function and serum anti-Abeta antibody titers. Thus, reducing total Abeta may be of limited therapeutic benefit to recovery of cognitive decline in a higher mammalian model of human brain aging and disease. Immunizing animals before extensive Abeta deposition and cognitive decline to prevent oligomeric or fibrillar Abeta formation may have a greater impact on cognition and also more directly evaluate the role of Abeta on cognition in canines. Alternatively, clearing preexisting Abeta from the brain in a treatment study may be more efficacious for cognition if combined with a second intervention that restores neuron health.
Head
Elizabeth
E
Institute for Brain Aging and Dementia, and Department of Neurology, University of California, Irvine, Irvine, California 92697, USA. ehead@uci.edu
Pop
Viorela
V
Vasilevko
Vitaly
V
Hill
MaryAnn
M
Saing
Tommy
T
Sarsoza
Floyd
F
Nistor
Michaela
M
Christie
Lori-Ann
LA
Milton
Saskia
S
Glabe
Charles
C
Barrett
Edward
E
Cribbs
David
D
D000375:Aging; D016229:Amyloid beta-Peptides / Q000276:immunology* / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002755:Choice Behavior / Q000502:physiology; D003071:Cognition / Q000502:physiology*; D004193:Discrimination Learning / Q000502:physiology; D004285:Dogs; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D005260:Female; D007114:Immunization; D007115:Immunization Schedule; D008137:Longitudinal Studies; D008297:Male; D008568:Memory / Q000502:physiology; D016874:Neurofibrillary Tangles / Q000473:pathology; D009483:Neuropsychological Tests; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism*
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)