The mechanism of γ-Secretase dysfunction in familial Alzheimer diseaseMutations in presenilin (PSEN) and amyloid precursor protein (APP) cause dominant early-onset Alzheimer's disease (AD), but the mechanism involved is debated. Here, such mutations are shown to alter γ-secretase activity, leading to changes in Aβ peptide cleavage patterns.

Mutations in the catalytic subunit of the γ-secretase complex, Presenilin, cause familial Alzheimer’s disease. Analysis of patients’ brains shows that these mutations do not result in loss of enzymatic function but in qualitative changes in Aβ product profiles.

ContentsI. General Introduction 443 II. Aldol Addition with Aldolases 443 1. Introduction 443 2. DHAP-Dependent Aldolases 447 2.1. General Background 447 2.2. Synthetic Applications 449 3. Pyruvate-and Phosphoenolpyruvate-Dependent Aldolases 453 3.1. N-Acetylneuraminic Acid Aldolase and NeuAc Synthetase 453 3.2. 3-Deoxy-D-manno-2-octulosonate (KDO) Aldolase and 3-Deoxy-D-manno-2-octulosonate 8-Phosphate (KDO-8-P) Synthetase 456 3.3. Other Pyruvate-and Phosphoenolpyruvate-Dependent Aldolases 457 4. 2-Deoxyribose-5-phosphate Aldolase 457 5. Glycine-Dependent Aldolases 459 III. Enzymatic Glycosidation 460 1. Glycosidases and Transglycosidases 460 2. Glycosyltransferases 462 2.1. Non-Leloir Glycosyltransferases 462 2.2. Leloir-type Glycosyltransferases 463 IV. Concluding Remarks 469 V. References 469

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