A Two-Year Study with Fibrillar β-Amyloid (Aβ) Immunization in Aged Canines: Effects on Cognitive Function and Brain Aβ

Abstract

Aged canines (dogs) accumulate human-type ␤-amyloid (A␤) in diffuse plaques in the brain with parallel declines in cognitive function. We hypothesized that reducing A␤ in a therapeutic treatment study of aged dogs with preexisting A␤ pathology and cognitive deficits would lead to cognitive improvements. To test this hypothesis, we immunized aged beagles (8.4 -12.4 years) with fibrillar A␤ 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 A␤ 1-40 and A␤ 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 〈␤ was correlated with frontal function and serum anti-A␤ antibody titers. Thus, reducing total A␤ 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 A␤ deposition and cognitive decline to prevent oligomeric or fibrillar A␤ formation may have a greater impact on cognition and also more directly evaluate the role of A␤ on cognition in canines. Alternatively, clearing preexisting A␤ from the brain in a treatment study may be more efficacious for cognition if combined with a second intervention that restores neuron health.

Rapid Improvement of Canine Cognitive Dysfunction with Immunotherapy designed for Alzheimer's Disease

“…Because of their many common hallmarks, CDS is presently considered a model of choice for Mild Cognitive Impairment (MCI) and AD research [15,20,21], and, in particular, for the development of anti-Aβ immunotherapy [13,22,23]. Diagnosed of graded cognitive dysfunctions by practicing neurology veterinarians, these animals are systematically and easily classified into wellcharacterized homogenous groups with no variation due to their breed (including sex, size and genetic background) or familiar life conditions [24][25][26].…”

Monoclonal Antibodies against Aβ42 Fibrils Distinguish Multiple Aggregation State Polymorphisms in Vitro and in Alzheimer Disease Brain

“…OC is a rabbit polyclonal antiserum that binds to fibrillar A␤, along with similar structures formed by other amyloid-forming peptides, but it does not bind to monomers or prefibrillar oligomers (10,11). The structural basis for the mutually exclusive aggregate specificities of A11 and OC is not entirely clear, but the structures that are known to react with A11 have been antiparallel ␤-sheets, ␤-barrels, and ␤-cylindrins (12)(13)(14), whereas the structures recognized by OC are known to be parallel, in-register ␤-sheets, whether they are associated with long fibrils or the smaller oligomers that may represent small segments of a fibril protofilament (15,16).…”

Aptamers

“…A last category of nanoparticles that will be considered consist of linear block copolymers and dendritic polymers which have been extensively used as encapsulating devices in drug delivery systems [188,189]. Aptamers have also been used to decorate the surface of these polymeric entities and to facilitate targeted delivery.…”

“…This aptamer's high affinity for the membrane receptors indicated its potential use as a diagnostic agent. Therefore, U2 was radiolabelled with 188 Re to investigate its ability to function as a molecular probe in EGFRvIII expressing glioblastoma xenografts in male BALB/c nude mice. This aptamer successfully accumulated in the target tumours, highlighting its potential to be used as an effective glioblastoma imaging tool.…”