MONOGENIC DETERMINANTS OF FAMILIAL ALZHEIMERS-DISEASE - PRESENILIN-1 MUTATIONS

Presenilin-1 (PSI) mutations account for the greatest portion of early onset familial Alzheimer's disease (FAD) cases. The exact cellular fu nction of PSI is not known. To date, PSI mutations have been shown to alter two potential biological roles of the protein, either of which c ould make neurons more susceptible to neurodegeneration. First, PSI mu tations result in elevated A beta 42/A beta 40 ratios in plasma of FAD patients, in transgenic mice and in transfected cell lines. A beta 42 is the more hydrophobic and most neurotoxic form of the peptide. A co mmon molecular event that has been associated with all of the known ea rly onset FAD genes is the excessive production or accumulation of the A beta peptide in the brain. PSI mutations have also been found to al ter the Notch signalling pathway, but the mechanism by which this may affect neurodegeneration remains to be determined. Future studies will be needed to elucidate whether PSI mutations lead directly to neurona l dysfunction and degeneration or cause cell death by increasing A bet a 42 generation and deposition.