Increased CSF-decorin predicts brain pathological changes driven by Alzheimer's Aβ amyloidosis

Area of Science:

• Neuroscience
• Biochemistry
• Proteomics

Background:

• Alzheimer's disease (AD) diagnosis relies on cerebrospinal fluid (CSF) biomarkers, particularly those reflecting amyloid-β (Aβ) pathology.
• Understanding how brain pathologies translate to CSF proteomes is crucial for early AD detection.

Purpose of the Study:

• To investigate the relationship between AD-like brain pathologies and CSF proteome changes using mouse models.
• To identify novel CSF biomarkers for early stages of AD and specific AD subtypes.

Main Methods:

• Utilized App knock-in mouse models (App^NL-F/NL-F and App^{NL-G-F/NL-G-F}) exhibiting Aβ pathology.
• Employed label-free mass spectrometry (MS) to analyze CSF proteomes in mice and compared with human CSF MS data.
• Performed receiver operating characteristic (ROC) analysis to assess biomarker predictive capabilities.

Main Results:

• Identified significantly altered extracellular matrix (ECM) proteins in the CSF of App knock-in mice.
• Found decorin, an ECM protein, significantly increased in both mouse models and human preclinical AD subjects with abnormal CSF-Aβ42.
• Demonstrated that CSF decorin levels correlate with CSF-Aβ42, Aβ plaque load, and choroid plexus decorin levels, and can predict an AD subtype with innate immune activation.

Conclusions:

• Elevated CSF decorin is associated with early-stage Aβ amyloidosis and may reflect choroid plexus dysfunction in a subset of AD patients.
• Decorin's role in activating neuronal autophagy suggests a potential therapeutic target.
• CSF decorin shows promise as an early diagnostic biomarker for specific Alzheimer's disease subtypes.