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EMBO reports 8, 2, 141–146 (2007)
doi:10.1038/sj.embor.7400897
Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease
Bart De Strooper
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KULeuven and Flanders Interuniversitary Institute for Biotechnology (VIB), Centre for Human Genetics, Herestraat 49, 3000 Leuven, Belgium
Tel: +3216346227; Fax: +3216347181;
e-mail: bart.destrooper@med.kuleuven.be
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Abstract
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  -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  -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 -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/-secretase as a drug target.
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