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J. Biol. Chem., Vol. 276, Issue 46, 42645-42657, November 16, 2001

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Elevation of -Amyloid Peptide 2-42 in Sporadic and Familial Alzheimer's Disease and Its Generation in PS1 Knockout Cells^*

From the ^a Department of Psychiatry, Molecular Neurobiology, and ^k Department of Biochemistry II, University of Göttingen, D-37073 Göttingen, Germany, ^e Center for Human Genetics, Neuronal Cell Biology Group, Flanders Interuniversity Institute for Biotechnology and Catholic University of Leuven, B-3000 Leuven, Belgium, ^f Institute for Neuropathology, Ludwig-Maximilians-Universität, D-81377 Munich, Germany, ^g Research Institute of Molecular Pharmacology, D-13125 Berlin, Germany, ^h Institute for Medical Physics and Biophysics, University of Münster, D-48129 Münster, Germany, ⁱ Department of Psychiatry, University of Hamburg, D-20246 Hamburg, Germany, and ^j Department of Psychiatry, University of Erlangen, D-91054 Erlangen, Germany

Urea-based -amyloid (A) SDS-polyacrylamide gel electrophoresis and immunoblots were used to analyze the generation of A peptides in conditioned medium from primary mouse neurons and a neuroglioma cell line, as well as in human cerebrospinal fluid. A comparable and highly conserved pattern of A peptides, namely, 1-40/42 and carboxyl-terminal-truncated 1-37, 1-38, and 1-39, was found. Besides A1-42, we also observed a consistent elevation of amino-terminal-truncated A2-42 in a detergent-soluble pool in brains of subjects with Alzheimer's disease. A2-42 was also specifically elevated in cerebrospinal fluid samples of Alzheimer's disease patients. To decipher the contribution of potential different -secretases (presenilins (PSs)) in generating the amino-terminal- and carboxyl-terminal-truncated A peptides, we overexpressed -amyloid precursor protein (APP)-trafficking mutants in PS1+/+ and PS1/ neurons. As compared with APP-WT (primary neurons from control or PS1-deficient mice infected with Semliki Forest virus), PS1/ neurons and PS1+/+ neurons overexpressing APP-ct (a slow-internalizing mutant) show a decrease of all secreted A peptide species, as expected, because this mutant is processed mainly by -secretase. This drop is even more pronounced for the APP-KK construct (APP mutant carrying an endoplasmic reticulum retention motif). Surprisingly, A2-42 is significantly less affected in PS1/ neurons and in neurons transfected with the endocytosis-deficient APP-ct construct. Our data confirm that PS1 is closely involved in the production of A1-40/42 and the carboxyl-terminal-truncated A1-37, A1-38, and A1-39, but the amino-terminal-truncated and carboxyl-terminal-elongated A2-42 seems to be less affected by PS1 deficiency. Moreover, our results indicate that the latter A peptide species could be generated by a _Asp/Ala-secretase activity.

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