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CSF Presenilin-1 complexes are increased in Alzheimer’s disease

María-Salud García-Ayllón123, María-Letizia Campanari12, Gunnar Brinkmalm4, Alberto Rábano25, Jordi Alom26, Carlos A Saura27, Niels Andreasen8, Kaj Blennow4 and Javier Sáez-Valero12*

Author Affiliations

1 Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-CSIC, Av. Ramón y Cajal s/n, Sant Joan d’Alacant E-03550, Spain

2 Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Barcelona, Spain

3 Unidad de Investigación, Hospital General Universitario de Elche, FISABIO, 03203 Elche, Spain

4 Department of Psychiatry and Neurochemistry, Institute of Neuroscience and Physiology, Sahlgrenska Academy at University of Gothenburg, 43 180 Mölndal, Sweden

5 Banco de Tejidos de la Fundación CIEN, CIEN Foundation, Carlos III Institute of Health, Alzheimer Center Reina Sofia Foundation, 28006 Madrid, Spain

6 Memory Clinic, Neurology Service, Hospital General Universitario de Elche, Elche, 03203, Spain

7 Institut de Neurociències, Departament Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain

8 Karolinska Institute-Alzheimer Disease Research center, 171 77 Stockholm, Sweden

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Acta Neuropathologica Communications 2013, 1:46  doi:10.1186/2051-5960-1-46

Published: 6 August 2013

Abstract

Background

Presenilin-1 (PS1) is the active component of the amyloid precursor protein cleaving γ-secretase complex. PS1 protein is a transmembrane protein containing multiple hydrophobic regions which presence in cerebrospinal fluid (CSF) has not been measured to date. This study assesses whether PS1 and other components of the γ-secretase complex are present in CSF.

Results

Here, we show that PS1 is present in ventricular post-mortem and lumbar ante-mortem CSF, and plasma as 100–150-kDa hetero-complexes containing both the N- and C-terminal fragments (NTF and CTF) of the protein. Immunoprecipitation and immunoblotting with different antibodies confirmed the identity of the PS1 species. The γ-secretase components, APH-1 (anterior pharynx-defective 1) and PEN-2 (presenilin enhancer 2), as well as presenilin-2 (PS2) fragments, co-exist within these CSF complexes, while nicastrin is not detected. These CSF-PS1 complexes differ from active γ-secretase membrane-complexes, and may represent nonspecific aggregation of the PS1 protein. Levels of PS1 complexes are increased in CSF samples from autopsy-confirmed Alzheimer’s disease (AD) cases and were found to be more stable than complexes in CSF from control subjects. Despite similar levels of total PS1 in CSF from probable AD patients and cognitively normal subjects, an increased proportion of highly stable PS1 complexes were observed in AD CSF.

Conclusions

Our data suggest that fragments of the PS1 protein present in CSF as complexes may be useful as a biomarker for AD.

Keywords:
Alzheimer’s disease; Cerebrospinal fluid; Diagnostic; Biomarker; Presenilin 1