Aβ oligomer toxicity inhibitor protects memory in models of synaptic toxicity.
OBJECTIVE
Amyloid-β (Aβ) aggregation into synaptotoxic, prefibrillar oligomers is a major pathogenic event underlying the neuropathology of Alzheimer's disease (AD). The pharmacological and neuroprotective properties of a novel Aβ aggregation inhibitor, SEN1269, were investigated on aggregation and cell viability and in test systems relevant to synaptic function and memory, using both synthetic Aβ(1-42)  and cell-derived Aβ oligomers.


METHODS
Surface plasmon resonance studies measured binding of SEN1269 to Aβ(1-42) . Thioflavin-T fluorescence and MTT assays were used to measure its ability to block Aβ(1-42) -induced aggregation and reduction in cell viability. In vitro and in vivo long-term potentiation (LTP) experiments measured the effect of SEN1269 on deficits induced by synthetic Aβ(1-42)  and cell-derived Aβ oligomers. Following i.c.v. administration of the latter, a complex (alternating-lever cyclic ratio) schedule of operant responding measured effects on memory in freely moving rats.


RESULTS
SEN1269 demonstrated direct binding to monomeric Aβ(1-42) , produced a concentration-related blockade of Aβ(1-42)  aggregation and protected neuronal cell lines exposed to Aβ(1-42) . In vitro, SEN1269 alleviated deficits in hippocampal LTP induced by Aβ(1-42)  and cell-derived Aβ oligomers. In vivo, SEN1269 reduced the deficits in LTP and memory induced by i.c.v. administration of cell-derived Aβ oligomers.


CONCLUSIONS
SEN1269 protected cells exposed to Aβ(1-42) , displayed central activity with respect to reducing Aβ-induced neurotoxicity and was neuroprotective in electrophysiological and behavioural models of memory relevant to Aβ-induced neurodegeneration. It represents a promising lead for designing inhibitors of Aβ-mediated synaptic toxicity as potential neuroprotective agents for treating AD.
Senexis Limited, Babraham Research Campus, Cambridge, UK. david_scopes@senexis.com
D I C
DI
Scopes
E
E
O'Hare
R
R
Jeggo
A D
AD
Whyment
D
D
Spanswick
E-M
EM
Kim
J
J
Gannon
H
H
Amijee
J M
JM
Treherne
D000627:Aminophenols / Q000494:pharmacology*; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D002460:Cell Line; D003959:Diamines / Q000737:chemistry / Q000494:pharmacology*; D055767:Immobilized Proteins / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008568:Memory / Q000187:drug effects; D015394:Molecular Structure; D011485:Protein Binding; D011724:Pyridazines / Q000737:chemistry / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013569:Synapses / Q000187:drug effects*
D000627:Aminophenols; D016229:Amyloid beta-Peptides; D003959:Diamines; D055767:Immobilized Proteins; C472970:N,N'-bis(3-hydroxyphenyl)pyridazine-3,6-diamine; D011724:Pyridazines; D011743:Pyrimidines; C577081:SEN1269