THE AUTOPHAGOSOME MARKER LC3B IS ELEVATED IN THE CEREBROSPINAL FLUID OF ALZHEIMER’S DISEASE PATIENTS AND TAU-TRANSGENIC MICE
- David Holzinger, Germany
Abstract
Aims
Alzheimer’s disease (AD) is characterized by the accumulation of aggregated Tau and Amyloid beta in the brain. While autophagy is a crucial mechanism for the clearance of aggregated proteins in healthy cells, this process is impaired in AD. Therefore, pharmacological modulation of autophagy is of high interest as a potential disease-modifying therapy for AD. Due to its central role in autophagosome biogenesis, the protein LC3B is an excellent biomarker candidate to monitor autophagy.
Methods
The presence of different LC3B forms in human CSF was investigated by Western Blot. Quantification of total LC3B in CSF from an AD cohort with attached clinical and biomarker data and from Thy1-hTau.P301S mice was performed with an immunoassay developed and validated in house using the Singulex platform.
Results
We show that the cytoplasmic form LC3B-I is dominating in human CSF, whereas the membrane-bound form LC3B-II is likely present in low amounts. Quantification of total LC3B revealed significantly higher levels in the CSF of AD patients (n=18) compared to healthy controls (n=22) and Abeta-negative patients with cognitive impairment (n=30). Interestingly, LC3B strongly correlates with total tau in the CSF. Transgenic Thy1-hTau.P301S mice also showed an increase of LC3B in the CSF that is strongly correlating with pathological Tau inclusions in the brain.
Conclusions
Our data suggests a link between elevated levels of LC3B in the CSF and tau pathology. Due to the central role of LC3B in autophagosome biogenesis, its elevation in the CSF has the potential to indicate impaired autophagic processes in AD patients.