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Orally bioavailable small molecule drug protects memory in Alzheimer's disease models
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O'Hare, Eugene, Scopes, David I.C., Kim, Eun-Mee, Palmer, Philip, Jones, Martyn, Whyment, Andrew D., Spanswick, David C., Amijee, Hozefa, Nerou, Edmund, McMahon, Bridgeen, Treherne, J. Mark and Jeggo, Ross (2013) Orally bioavailable small molecule drug protects memory in Alzheimer's disease models. Neurobiology of Aging, 34 (4). pp. 1116-1125. doi:10.1016/j.neurobiolaging.2012.10.016 ISSN 0197-4580.
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Official URL: http://dx.doi.org/10.1016/j.neurobiolaging.2012.10...
Abstract
Oligomers of beta-amyloid (Aβ) are implicated in the early memory impairment seen in Alzheimer's disease before to the onset of discernable neurodegeneration. Here, the capacity of a novel orally bioavailable, central nervous system-penetrating small molecule 5-aryloxypyrimidine, SEN1500, to prevent cell-derived (7PA2 [conditioned medium] CM) Aβ-induced deficits in synaptic plasticity and learned behavior was assessed. Biochemically, SEN1500 bound to Aβ monomer and oligomers, produced a reduction in thioflavin-T fluorescence, and protected a neuronal cell line and primary cortical neurons exposed to synthetic soluble oligomeric Aβ1–42. Electrophysiologically, SEN1500 alleviated the in vitro depression of long-term potentiation induced by both synthetic Aβ1–42 and 7PA2 CM, and alleviated the in vivo depression of long-term potentiation induced by 7PA2 CM, after systemic administration. Behaviorally, oral administration of SEN1500 significantly reduced memory-related deficits in operant responding induced after intracerebroventricular injection of 7PA2 CM. SEN1500 reduced cytotoxicity, acute synaptotoxicity, and behavioral deterioration after in vitro and in vivo exposure to synthetic Aβ and 7PA2 CM, and shows promise for development as a clinically viable disease-modifying Alzheimer's disease treatment.
| Item Type: | Journal Article | ||||||
|---|---|---|---|---|---|---|---|
| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Biomedical Sciences > Translational & Experimental Medicine > Metabolic and Vascular Health (- until July 2016) Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| Journal or Publication Title: | Neurobiology of Aging | ||||||
| Publisher: | Elsevier Inc. | ||||||
| ISSN: | 0197-4580 | ||||||
| Official Date: | April 2013 | ||||||
| Dates: |
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| Volume: | 34 | ||||||
| Number: | 4 | ||||||
| Page Range: | pp. 1116-1125 | ||||||
| DOI: | 10.1016/j.neurobiolaging.2012.10.016 | ||||||
| Status: | Peer Reviewed | ||||||
| Publication Status: | Published | ||||||
| Access rights to Published version: | Restricted or Subscription Access | ||||||
| Description: | In press corrected proof |
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