Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease

Sogorb‐Esteve, Aitana; García‐Ayllón, María‐Salud; Fortea, Juan; Sánchez‐Valle, Raquel; Lleó, Alberto; Molinuevo, José Luís; Sáez‐Valero, Javier

doi:10.1186/s13024-016-0131-2

Cited by 10 publications

(7 citation statements)

References 37 publications

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“…Here, we replicated the occurrence of the ~500 kDa reelin in AD CSF by treating the cells with amyloidogenic Aβ42. Interestingly, complexes of several CSF proteins, such as presenilins [ 57 , 58 ], cholinesterase [ 59 ], and apoE [ 60 , 61 ], formed under amyloidogenic conditions appear to be particularly stable. Reelin interacts with Aβ both in vitro [ 62 ] and in vivo [ 19 ], as it is recruited into amyloid fibrils; thus, we hypothesized that Aβ played a direct role in the formation of the 500 kDa reelin species detected in AD CSF.…”

Section: Discussionmentioning

confidence: 99%

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

López-Font

Lennol

Iborra-Lázaro

et al. 2022

IJMS

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Reelin binds to the apolipoprotein E receptor apoER2 to activate an intracellular signaling cascade. The proteolytic cleavage of reelin follows receptor binding but can also occur independently of its binding to receptors. This study assesses whether reelin proteolytic fragments are differentially affected in the cerebrospinal fluid (CSF) of Alzheimer’s disease (AD) subjects. CSF reelin species were analyzed by Western blotting, employing antibodies against the N- and C-terminal domains. In AD patients, we found a decrease in the 420 kDa full-length reelin compared with controls. In these patients, we also found an increase in the N-terminal 310 kDa fragment resulting from the cleavage at the so-called C-t site, whereas the 180 kDa fragment originated from the N-t site remained unchanged. Regarding the C-terminal proteolytic fragments, the 100 kDa fragment resulting from the cleavage at the C-t site also displayed increased levels, whilst the one resulting from the N-t site, the 250 kDa fragment, decreased. We also detected the presence of an aberrant reelin species with a molecular mass of around 500 kDa present in AD samples (34 of 43 cases), while it was absent in the 14 control cases analyzed. These 500 kDa species were only immunoreactive to N-terminal antibodies. We validated the occurrence of these aberrant reelin species in an Aβ42-treated reelin-overexpressing cell model. When we compared the AD samples from APOE genotype subgroups, we only found minor differences in the levels of reelin fragments associated to the APOE genotype, but interestingly, the levels of fragments of apoER2 were lower in APOE ε4 carriers with regards to APOE ε3/ε3. The altered proportion of reelin/apoER2 fragments and the occurrence of reelin aberrant species suggest a complex regulation of the reelin signaling pathway, which results impaired in AD subjects.

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Section: Discussionmentioning

confidence: 99%

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

López-Font

Lennol

Iborra-Lázaro

et al. 2022

IJMS

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“…Among the substrates of these proteases are, according to MEROPS, amyloid beta A4 protein in CSF, E‐cadherin in serum, and albumin in saliva (Table S1, Supporting Information). The presence of presenilin‐1 in CSF was already associated to AD . Presenilin‐1 appears to be also related to plasma and serum peptidomes; however, as far as we know, no previous assessment of its levels on these fluids was reported.…”

Section: Comparative Analysis Of Proteases Distribution Among Distincmentioning

confidence: 94%

Reviewing Mechanistic Peptidomics in Body Fluids Focusing on Proteases

et al. 2018

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The comprehension of how protease networks sculpt proteomes might help to disclose the functional annotation of the peptidome in health and disease. Envisioning to add new insights on the protease networks involved in the regulation of body fluid peptidomes, the authors apply Proteasix software to predict the proteases involved in the generation of the naturally occurring peptides present in six of the most studied human body fluids. Peptidome data is collected from the databases and from experimental studies. The analysis highlights 132 putative proteases from four families with the predominance of serine proteases and metalloproteases. From these, 49 proteases seem to be common to all fluids and are mostly associated to extracellular matrix organization as well as protein/peptide hormone processing. Data analysis also emphasizes: i) the similarity between plasma and CSF protease profiles; ii) that saliva and tears share proteases involved in the generation of peptides with antimicrobial activity; iii) that urine is the body fluid with the highest number of unique putative proteases, precluding an easy tracing of proteolytic events in this case. Taken together, the analysis emphasizes the intricate modus operandi of proteases, challenged by the interconnected pathways and amplification cascades in which they are involved.

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“…In contrast with BACE1, changes in APP, PSEN1, and PSEN2 protein levels have been considered unsuitable biomarkers in human fluids. Only two studies have shown that the levels of soluble PSEN1 complexes are increased in ventricular postmortem CSF from AD patients compared to control individuals [143] as well as in lumbar CSF samples obtained from genetically determined AD patients [144]. Regarding PSEN2, a transcript named PSV2 encoding a truncated form of PSEN2 is upregulated in AD postmortem brains [145].…”

Section: Role Of Genes For β-Secretases (Bace1 and Bace2mentioning

confidence: 99%

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

Santillán-Morales,

Rodriguez-Espinosa,

Muñoz-Estrada

et al. 2024

Brain Sciences

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Alzheimer’s disease (AD), as the main cause of dementia, affects millions of people around the world, whose diagnosis is based mainly on clinical criteria. Unfortunately, the diagnosis is obtained very late, when the neurodegenerative damage is significant for most patients. Therefore, the exhaustive study of biomarkers is indispensable for diagnostic, prognostic, and even follow-up support. AD is a multifactorial disease, and knowing its underlying pathological mechanisms is crucial to propose new and valuable biomarkers. In this review, we summarize some of the main biomarkers described in AD, which have been evaluated mainly by imaging studies in cerebrospinal fluid and blood samples. Furthermore, we describe and propose neuronal precursors derived from the olfactory neuroepithelium as a potential resource to evaluate some of the widely known biomarkers of AD and to gear toward searching for new biomarkers. These neuronal lineage cells, which can be obtained directly from patients through a non-invasive and outpatient procedure, display several characteristics that validate them as a surrogate model to study the central nervous system, allowing the analysis of AD pathophysiological processes. Moreover, the ease of obtaining and harvesting endows them as an accessible and powerful resource to evaluate biomarkers in clinical practice.

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Cerebrospinal fluid Presenilin-1 increases at asymptomatic stage in genetically determined Alzheimer’s disease

Cited by 10 publications

References 37 publications

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

Altered Balance of Reelin Proteolytic Fragments in the Cerebrospinal Fluid of Alzheimer’s Disease Patients

Reviewing Mechanistic Peptidomics in Body Fluids Focusing on Proteases

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

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