Amyloid β oligomer selective antibodies for Alzheimers therapeutics and diagnostics

Abstract

Improvements have been made in the diagnosis of Alzheimers disease (AD), manifesting mostly in the development of in vivo imaging methods that allow for the detection of pathological changes in AD by MRI and PET scans. Many of these imaging methods, however, use agents that probe amyloid fibrils and plaques - species that do not correlate well with disease progression and are not present at the earliest stages of the disease. Amyloid {beta} oligomers (A{beta}Os), rather, are now widely accepted as the A{beta} species most germane to AD onset and progression. Here we report evidence further supporting the role of A{beta}Os as pathological instigators of AD and introduce promising anti-A{beta}O diagnostic probes capable of distinguishing the 5xFAD mouse model from wild type mice by PET and MRI. In a developmental study, A{beta} oligomers in 5xFAD mice were found to appear at 3 months of age, just prior to the onset of memory dysfunction, and spread as memory worsened. The increase of A{beta}Os is prominent in the subiculum and correlates with concomitant development of reactive astrocytosis. The impact of these A{beta}Os on memory is in harmony with findings that intraventricular injection of synthetic A{beta}Os into wild type mice induced hippocampal dependent memory dysfunction within 24 hours. Compelling support for the conclusion that endogenous A{beta}Os cause memory loss was found in experiments showing that intranasal inoculation of A{beta}O-selective antibodies into 5xFAD mice completely restored memory function, measured 30-40 days post-inoculation. These antibodies, which were modified to give MRI and PET imaging probes, were able to distinguish 5xFAD mice from wild type littermates. These results provide strong support for the role of A{beta}Os in instigating memory loss and salient AD neuropathology, and they demonstrate that A{beta}O selective antibodies have potential both for therapeutics and for diagnostics.