Development of Alzheimer’s disease (AD) therapeutics is severely hampered by lack of methods for early diagnosis and for monitoring the efficacy of investigational new drugs (INDs). To address this need, we propose to create a molecular imaging strategy that can diagnose AD in its earliest stages, when newly emerging vaccines and other treatments can be truly effective. The strategy is designed to specifically follow changes in dementia-inducing AD toxins. To date, despite extraordinary investments, molecular imaging has been of limited use. PET probes for amyloid plaques have stimulated tremendous interest in AD brain imaging, but the plaques themselves are not diagnostic for early AD and are no longer regarded as the instigators of dementia. Our strategy is designed to target synaptotoxic Aβ oligomers (AβOs). Our hypothesis is that toxic AβOs, which appear early in the disease and are the putative instigators of dementia, offer an excellent molecular MRI target for AD diagnosis and for assessing efficacy of INDs. Our experimental strategy is to covalently attach high T2 contrast agents to high-affinity AβO antibodies and deliver the resultant probe to the brain by a non-invasive method that bypasses the blood brain barrier. Initial investigations have generated preliminary proof of concept. Small quantity syntheses have reliably yielded probes that retain the affinity and AβO-specificity of the parent antibody. In vitro cell experiments show the probes generate AβO-dependent MRI signals, and ex vivo experiments with human brain tissue show the probes generate an MRI signal that is AD-dependent. We have determined that a fluorescently-modified form of the parent antibody readily enters the brain when delivered intranasally, reaching AβOs attached to hippocampal neurons in the 5XFAD Tg mouse AD model. The new target, the new probe, and the new means of delivery provide an innovative solution to answer the need for diagnostic imaging of early AD. We propose to extend our successful pilot studies with three studies: (1) Carry out prototype assays for AβO-dependent MRI signals using brain sections from the 5X FAD mouse model; (2) Optimize intranasal delivery of probe to brain of AD and control mice; and (3) Obtain proof of concept that mice with AD pathology can be identified using the NU4MNS MRI probe, and that the probe can determine drug efficacy in lowering AβOs in treated animals. Our expectations are that the proposed research will demonstrate that toxins linked to early stages of AD can be detected in a live mouse model by MR imaging. Our work has the potential to provide the first imaging tool for early AD diagnosis, at a stage when intervention would theoretically maximize the effectiveness of therapy. Moreover, by providing the means to monitor levels of disease-causing oligomers, this new probe offers a potential breakthrough as a resource to identify INDs that are truly disease modifying.
|Effective start/end date||5/1/14 → 4/30/17|
- National Institute on Aging (1R21AG045637-01A1)