Abstract
BackgroundPresenilin-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.ResultsHere, 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.ConclusionsOur data suggest that fragments of the PS1 protein present in CSF as complexes may be useful as a biomarker for AD.
Highlights
Presenilin-1 (PS1) is the active component of the amyloid precursor protein cleaving γ-secretase complex
PS1 N-terminal fragment (NTF) and CTF are present in high molecular mass complexes in cerebrospinal fluid (CSF) and plasma PS1 is known to undergo endoproteolytic cleavage as part of its maturation, generating N- and C-terminal fragments (NTF and CTF) [8], with very little full-length PS1 detectable in brain or cultured cells [9]
Immunoblotting, using an antiPS1 NTF antibody (Calbiochem), revealed predominant bands of approximately 100 and 150 kDa and only a faint 29-kDa band corresponding to PS1-NTF (Figure 1B)
Summary
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. There is a continuing search for new cerebrospinal fluid (CSF) biomarkers for use in clinical diagnosis, especially for the early stages of AD, and for use in clinical trials. Other logical AD biomarker candidates are proteins involved in the pathological processing of the large transmembrane protein, the amyloid precursor protein (APP), To our knowledge, the presence of presenilins in CSF has not been reported to date. In this study we investigated if PS1 is detectable in CSF and if altered levels of this protein reflect the pathological condition
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