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

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.

CSF beta‐amyloid 1–42 – what are we measuring in Alzheimer's disease?

“…We did not provide direct evidence that exogenous apoE or apoJ directly bound to CSF A β 42 to enhance its solubility, even though apolipoproteins are known to interact with A β and may prevent its aggregation 22 , 33 , 36 , 37 We also did not use gamma-secretase inhibitors to account for de novo production of A β 42 peptides, but gamma-secretase activity has not been reported in CSF and presenilin 1 and 2 fragments detected in CSF are felt to represent nonspecific aggregation rather than gamma-secretase complexes. 38 We propose that alterations in CSF % susA β are due to technical and biological factors, and susA β 42 levels, t-Tau/susA β 42 ratio, as well as their impact on other biological correlates of AD should be interpreted with care because these in vitro measures reflect amyloid protein's total abundance as well as its dynamic interactions with other AD-associated proteins and AD itself.…”

Transmembrane Amyloid-Related Proteins in CSF as Potential Biomarkers for Alzheimer’s Disease

“…Incubation of blots with antibodies for the different γ-secretase subunits confirmed that APH1 and PEN2, but not nicastrin, are present in CSF as complexes (see Ref. ( 25 ) to complete information). In all analyses performed on PS1, denaturation before electrophoresis was conducted at 50°C.…”

“…Accordingly, it has been assumed that the BACE1 present in CSF is a truncated soluble form of the originally membrane-bound BACE1 missing the transmembrane and intracellular domains ( 37 ). Indeed, some studies failed to demonstrate the presence of BACE1 containing the C-terminal domain in human CSF and plasma ( 38 , 39 ), but others detected immunoreactivity with BACE1 C-terminal antibodies ( 25 , 31 , 33 ), suggesting that full-length BACE1 exists in this fluid. The presence of full-length BACE1, together with its truncated form, has also been demonstrated in conditioned media from cultured neurons ( 40 ).…”

Heteromers of amyloid precursor protein in cerebrospinal fluid

“…A mechanism for sAPPf to appear in CSF has yet to be determined, but passive release from brain cells or neuronal cell death may be possible, as recently observed for BACE1 [ 21 ]. Full-length BACE1 and other membrane resident protein, such as presenilin-1, are present in CSF [ 22 ].…”