Familial Alzheimer's disease presenilin 1 mutation M146V increases gamma secretase cutting of p75NTR in vitro.
The cholinergic neurons of the basal forebrain are amongst the first to degenerate in Alzheimer's disease. These neurons are unique in the brain, expressing the tyrosine kinase receptor TrkA, together with the common neurotrophin receptor p75NTR; both of which bind nerve growth factor. Activation of the TrkA receptor is important in the maintenance of cell viability, whereas the p75NTR receptor has been implicated in apoptosis. Mutations in the gene for presenilin 1, a multi-transmembrane aspartyl protease, are known to cause familial Alzheimer's disease. This is thought to be due to their effect on gamma-secretase-dependent processing of amyloid precursor protein and subsequent formation of amyloid. Since p75NTR was recently shown to undergo gamma-secretase regulated intramembrane proteolysis, this study examines the effect of familial Alzheimer mutations on processing of p75NTR. PC12 cells were stably transfected with familial mutations M146V, A246E and deltaE9 and wild-type presenilin 1 and were examined here for gamma-secretase-dependent proteolysis of p75NTR. Overexpression of wild-type presenilin 1 did not increase gamma-secretase-mediated cleavage of p75NTR. However, by contrast, the presence of the M146V mutation was shown to significantly increase cleavage of p75NTR compared with the other mutations. Survival of cholinergic neurons will depend on the balance between the receptors TrkA and p75NTR, and their respective signalling pathways. Thus alterations in p75NTR proteolysis may influence this equilibrium. The novel finding that a mutation may increase processing of p75NTR may have implications for the pathogenic outcome in Alzheimer's disease.
Hatchett
Caroline Sara
CS
Molecular Neurobiology Unit, University of Bristol, CSSB, Dorothy Hodgkin Building, Bristol BS1 3NY, UK.
Tyler
Sue
S
Armstrong
Dawn
D
Dawbarn
David
D
Allen
Shelley Jane
SJ
D000544:Alzheimer Disease / Q000235:genetics* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D000704:Analysis of Variance; D000818:Animals; D006868:Hydrolysis; D009154:Mutation; D016716:PC12 Cells; D053764:Presenilin-1 / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D020800:Receptor, Nerve Growth Factor / Q000378:metabolism*
D053764:Presenilin-1; D020800:Receptor, Nerve Growth Factor; D053829:Amyloid Precursor Protein Secretases