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EMBO Rep. 2007 Feb;8(2):141-6.

Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease.

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  • KULeuven and Flanders Interuniversitary Institute for Biotechnology (VIB), Centre for Human Genetics, Herestraat 49, 3000 Leuven, Belgium. bart.destrooper@med.kuleuven.be


Presenilin mutations are the main cause of familial Alzheimer disease. From a genetic point of view, these mutations seem to result in a gain of toxic function; however, biochemically, they result in a partial loss of function in the gamma-secretase complex, which affects several downstream signalling pathways. Consequently, the current genetic terminology is misleading. In fact, the available data indicate that several clinical presenilin mutations also lead to a decrease in amyloid precursor protein-derived amyloid beta-peptide generation, further implying that presenilin mutations are indeed loss-of-function mutations. The loss of function of presenilin causes incomplete digestion of the amyloid beta-peptide and might contribute to an increased vulnerability of the brain, thereby explaining the early onset of the inherited form of Alzheimer disease. In this review, I evaluate the implications of this model for the amyloid-cascade hypothesis and for the efficacy of presenilin/gamma-secretase as a drug target.

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