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J. Biol. Chem., Vol. 278, Issue 41, 39637-39643, October 10, 2003

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 278/41/39637    most recent M302295200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hol, E. M. Articles by van Leeuwen, F. W. Search for Related Content PubMed PubMed Citation Articles by Hol, E. M. Articles by van Leeuwen, F. W. Social Bookmarking                      What's this?

Frameshifted -Amyloid Precursor Protein (APP⁺¹) Is a Secretory Protein, and the Level of APP⁺¹ in Cerebrospinal Fluid Is Linked to Alzheimer Pathology^*,

Elly M. Hol  , Renske van Dijk , Lisya Gerez ¶, Jacqueline A. Sluijs , Barbara Hobo , Martijn T. Tonk , Annett de Haan ¶, Wouter Kamphorst ||, David F. Fischer , Rob Benne ¶ and Fred W. van Leeuwen 

From the Graduate School for Neurosciences, Netherlands Institute for Brain Research, 1105 AZ, Amsterdam, The Netherlands, the ^¶Department of Biochemistry, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands, and the ^||Department of Pathology, Free University Hospital, Amsterdam 1081 HV, The Netherlands

Molecular misreading of the -amyloid precursor protein (APP) gene generates mRNA with dinucleotide deletions in GAGAG motifs. The resulting truncated and partly frameshifted APP protein (APP⁺¹) accumulates in the dystrophic neurites and the neurofibrillary tangles in the cortex and hippocampus of Alzheimer patients. In contrast, we show here that neuronal cells transfected with APP⁺¹ proficiently secreted APP⁺¹. Because various secretory APP isoforms are present in cerebrospinal fluid (CSF), this study aimed to determine whether APP⁺¹ is also a secretory protein that can be detected in CSF. Post-mortem CSF was obtained at autopsy from 50 non-demented controls and 122 Alzheimer patients; all subjects were staged for neuropathology (Braak score). Unexpectedly, we found that the APP⁺¹ level in the CSF of non-demented controls was much higher (1.75 ng/ml) than in the CSF of Alzheimer patients (0.51 ng/ml) (p < 0.001), and the level of APP⁺¹ in CSF was inversely correlated with the severity of the neuropathology. Moreover the earliest neuropathological changes are already reflected in a significant decrease of the APP⁺¹ level in CSF. These data show that APP⁺¹ is normally secreted by neurons, preventing intra-neuronal accumulation of APP⁺¹ in brains of non-demented controls without neurofibrillary pathology.

Received for publication, March 5, 2003 , and in revised form, July 25, 2003.

^* This research was supported by Nederlandse Hersenstichting Grant H00.06, Platform Alternatieven voor Dierproeven Grant PAD98.19, European Union Grant QLRT-1999-02238, Jan Dekkerstichting en Dr. Ludgardine Bouwmanstiching Grant 99-17, Van Leersumfonds Koninklijke Nederlandse Akadamie van Wetenschappen, Netherlands Organization for Scientific Research (NWO) Program Grants 902-51-192 and 970-10-029 (Geheugenprocessen en Dementie), and Human Frontier Science Program Organization Grant RG0148/1999B. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains clinicopathological information on non-demented controls and Alzheimer patients in tabular form.

To whom correspondence should be addressed: Netherlands Inst. for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands. Tel.: 31-20-5665503; Fax: 31-20-6961006; E-mail: e.hol{at}nih.knaw.nl.

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