Dataset Information

Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.

ABSTRACT:

Introduction

Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline.

Methods

We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity and brain Aβ accumulation.

Results

We show that Aβ 37/42 can distinguish physiological and pathological status in (1) presenilin-1 mutant vs wild-type cultured cells, (2) AD vs control brain tissue, and (3) AD versus cognitively normal (CN) subjects in CSF, where 37/42 (AUC 0.9622) outperformed 42/40 (AUC 0.8651) in distinguishing CN from AD.

Discussion

We conclude that the Aβ 37/42 ratio sensitively detects presenilin/γ-secretase dysfunction and better distinguishes CN from AD than Aβ42/40 in CSF. Measuring this novel ratio alongside promising phospho-tau analytes may provide highly discriminatory fluid biomarkers for AD.

SUBMITTER: Liu L

PROVIDER: S-EPMC9464800 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Publications

Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.

Liu Lei L Lauro Bianca M BM He Amy A Lee Hyo H Bhattarai Sanjay S Wolfe Michael S MS Bennett David A DA Karch Celeste M CM Young-Pearse Tracy T Selkoe Dennis J DJ

Alzheimer's & dementia : the journal of the Alzheimer's Association 20220312 1

<h4>Introduction</h4>Identifying CSF-based biomarkers for the β-amyloidosis that initiates Alzheimer's disease (AD) could provide inexpensive and dynamic tests to distinguish AD from normal aging and predict future cognitive decline.<h4>Methods</h4>We developed immunoassays specifically detecting all C-terminal variants of secreted amyloid β-protein and identified a novel biomarker, the Aβ 37/42 ratio, that outperforms the canonical Aβ42/40 ratio as a means to evaluate the γ-secretase activity a ...[more]

PMID: 35278341

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Project description:Human mini-brains (MB) are cerebral organoids that recapitulate in part the complexity of the human brain in a unique three-dimensional in vitro model, yielding discrete brain regions reminiscent of the cerebral cortex. Specific proteins linked to neurodegenerative disorders are physiologically expressed in MBs, such as APP-derived amyloids (Aβ), whose physiological and pathological roles and interactions with other proteins are not well established in humans. Here, we demonstrate that neuroectodermal organoids can be used to study the Aβ accumulation implicated in Alzheimer's disease (AD). To enhance the process of protein secretion and accumulation, we adopted a chemical strategy of induction to modulate post-translational pathways of APP using an Amyloid-β Forty-Two Inducer named Aftin-5. Secreted, soluble Aβ fragment concentrations were analyzed in MB-conditioned media. An increase in the Aβ42 fragment secretion was observed as was an increased Aβ42/Aβ40 ratio after drug treatment, which is consistent with the pathological-like phenotypes described in vivo in transgenic animal models and in vitro in induced pluripotent stem cell-derived neural cultures obtained from AD patients. Notably in this context we observe time-dependent Aβ accumulation, which differs from protein accumulation occurring after treatment. We show that mini-brains obtained from a non-AD control cell line are responsive to chemical compound induction, producing a shift of physiological Aβ concentrations, suggesting that this model can be used to identify environmental agents that may initiate the cascade of events ultimately leading to sporadic AD. Increases in both Aβ oligomers and their target, the cellular prion protein (PrPC), support the possibility of using MBs to further understand the pathophysiological role that underlies their interaction in a human model. Finally, the potential application of MBs for modeling age-associated phenotypes and the study of neurological disorders is confirmed.

Project description:Currently, there are very limited pharmaceutical interventions for Alzheimer's disease (AD) to alleviate the amyloid burden implicated in the pathophysiology of the disease. Alzheimer's disease is characterized immunohistologically by the accumulation of senile plaques in the brain with afflicted patients progressively losing short-term memory and, ultimately, cognition. Although significant improvements in clinical diagnosis and care for AD patients have been made, effective treatments for this devastating disease remain elusive. A key component of the amyloid burden of AD comes from accumulation of the amyloid-beta (Aβ) peptide which comes from processing of the amyloid precursor protein (APP) by enzymes termed secretases, leading to production of these toxic Aβ peptides of 40-42 amino acids. New therapeutic approaches for reducing Aβ are warranted after the most logical avenues of inhibiting secretase activity appear less than optimal in ameliorating the progression of AD.Novel therapeutics may be gleaned from proteomics biomarker initiatives to yield detailed molecular interactions of enzymes and their potential substrates. Explicating the APPome by deciphering protein complexes forming in cells is a complementary approach to unveil novel molecular interactions with the amyloidogenic peptide precursor to both understand the biology and develop potential upstream drug targets. Utilizing these strategies we have identified EC 3.4.24.15 (EP24.15), a zinc metalloprotease related to neprilysin (NEP), with the ability to catabolize Aβ 1-42 by examining first potential in silico docking and then verification by mass spectrometry. In addition, a hormone carrier protein, transthyreitin (TTR), was identified and with its abundance in cerebrospinal fluid (CSF), found to clear Aβ by inhibiting formation of oligomeric forms of Aβ peptide. The confluence of complementary strategies may allow new therapeutic avenues as well as biomarkers for AD that will aid in diagnosis, prognosis and treatment.

Dataset Information

Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.

Introduction

Methods

Results

Discussion

Publications

Identification of the Aβ37/42 peptide ratio in CSF as an improved Aβ biomarker for Alzheimer's disease.

Similar Datasets

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