TAILIEUCHUNG - Báo cáo khoa học: Anti-amyloid precursor protein immunoglobulins inhibit amyloid-b production by steric hindrance

The cleavage of amyloid precursor protein (APP) byb- and c-secretases results in the production of amyloid-b(Ab) in Alzheimer’s disease. We raised two monoclonal antibodies, 2B3 and 2B12, that recognize the b-secretase cleavage site on APP but not Ab. | IFEBS Journal Anti-amyloid precursor protein immunoglobulins inhibit amyloid-b production by steric hindrance Rhian S. Thomas1 J. Eryl Liddell2 and Emma J. Kidd1 1 Welsh Schoolof Pharmacy Cardiff University UK 2 MonoclonalAntibody Unit Schoolof Biosciences Cardiff University UK Keywords Alzheimer s disease amyloid precursor protein amyloid-p monoclonalantibodies p-secretase cleavage site Correspondence E. J. Kidd Welsh Schoolof Pharmacy Cardiff University Redwood Building King Edward VII Avenue Cardiff CF10 3NB UK Fax 44 29 20874149 Tel 44 29 20875803 E-mail KiddEJ@ Website http phrmy contactsandpeople fulltimeacademicstaff Received 15 July 2010 revised 30 September 2010 accepted 27 October 2010 doi The cleavage of amyloid precursor protein APP by p- and y-secretases results in the production of amyloid-b Ab in Alzheimer s disease. We raised two monoclonal antibodies 2B3 and 2B12 that recognize the b-secretase cleavage site on APP but not Ab. We hypothesized that these antibodies would reduce Ab levels via steric hindrance of b-secretase. Both antibodies decreased extracellular Ab levels from astrocytoma cells but 2B3 was more potent than 2B12. Levels of soluble sAPPa from the non-amyloidogenic a-secretase pathway and intracellular APP were not affected by either antibody nor were there any effects on cell viability. 2B3 exhibited a higher affinity for APP than 2B12 and its epitope appeared to span the cleavage site whereas 2B12 bound slightly upstream. Both of these factors probably contribute to its greater effect on Ap levels. After 60 min incubation at pH most 2B3 and 2B12 remained bound to their antigen suggesting that the antibodies will remain bound to APP in the acidic endosomes where b-secretase cleavage probably occurs. Only 2B3 and 2B12 but not control antibodies inhibited the cleavage of sAPPa by b-sec-retase in a cell-free assay where the effects of antibody .

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