Repository logo
 

The Identification and Development of Small Molecule Inhibitors of Amyloid β Aggregation


Type

Thesis

Change log

Authors

Collins, Súil 

Abstract

Amyloid β (1-42) (A$\beta42)isaseminalneuropathicagentinAlzheimersdisease(AD),amultifacetedneurodegenerativedisorderforwhichnopreventativemeasuresordiseasemodifyingtherapiescurrentlyexist.Aggregationofthispeptideplaysakeyroleinthesynapticdysfunctionandneuronaldeathassociatedwiththedisease.Perturbingtheaggregationprocess,therefore,representsakeystrategyforthedevelopmentofnewADtherapeutics.Avarietyofissueswithcurrentscreeningmethods,includinglackofreproducibility,highreagentconsumptionandspectralinterferencefromthetestmolecules,canlimiteffortstoidentifynewsmallmoleculeinhibitors.Furthermore,thelackofrobust,timeandcostefficientmethodsforscreeningcompoundsincellularorinvivomodelslimitsthethroughputwithwhichseeminglyactivesmallmoleculescanbevalidatedandprioritised.Herein,thisthesisdescribeseffortstoovercomesuchlimitationsthroughthedevelopmentofaunifiedinvitrotoinvivoassaysystem,inwhichhitsidentifiedinthenanoFLIMmicrofluidicbasedassaycanquicklybetestedincellularandwholeorganismdiseasemodels.Theassayplatformdesignedreliesontheuseofanamyloidaggregationfluorescencelifetimesensor.A\beta