| First Author | Wang HY | Year | 2017 |
| Journal | Neurobiol Aging | Volume | 55 |
| Pages | 99-114 | PubMed ID | 28438486 |
| Mgi Jnum | J:244511 | Mgi Id | MGI:5913290 |
| Doi | 10.1016/j.neurobiolaging.2017.03.016 | Citation | Wang HY, et al. (2017) PTI-125 binds and reverses an altered conformation of filamin A to reduce Alzheimer's disease pathogenesis. Neurobiol Aging 55:99-114 |
| abstractText | We show that amyloid-beta1-42 (Abeta42) triggers a conformational change in the scaffolding protein filamin A (FLNA) to induce FLNA associations with alpha7-nicotinic acetylcholine receptor (alpha7nAChR) and toll-like receptor 4 (TLR4). These aberrant associations respectively enable Abeta42's toxic signaling via alpha7nAChR to hyperphosphorylate tau protein, and TLR4 activation to release inflammatory cytokines. PTI-125 is a small molecule that preferentially binds altered FLNA and restores its native conformation, restoring receptor and synaptic activities and reducing its alpha7nAChR/TLR4 associations and downstream pathologies. Two-month oral PTI-125 administration to triple-transgenic (3xTg) Alzheimer's disease (AD) mice before or after apparent neuropathology and to 8-month wildtypes with milder neuropathologies reduced receptor dysfunctions and improved synaptic plasticity, with some improvements in nesting behavior and spatial and working memory in 3xTg AD mice. PTI-125 also reduced tau hyperphosphorylation, aggregated Abeta42 deposition, neurofibrillary tangles, and neuroinflammation. Efficacy in postmortem AD and Abeta42-treated age-matched control hippocampal slices was concentration-dependent starting at 1 picomolar (pM) concentration. PTI-125 is the first therapeutic candidate to preferentially bind an altered protein conformation and reverse this proteopathy. |
