Exploring Alzheimer molecular pathology in Down's syndrome cerebrospinal fluid.

BACKGROUND

Individuals with Down's syndrome (DS) develop early Alzheimer's disease (AD) with β-amyloid (Aβ) plaque pathology. The extra amyloid precursor protein (APP) gene copy in DS is believed to result in a 50% increase in Aβ production, but it is unclear how this relates to the development of other AD hallmarks, including axonal degeneration and microglia cell activation, and to other neurological problems in DS, including disturbed sleep regulation.

OBJECTIVE

To evaluate if cerebrospinal fluid (CSF) biomarkers for cerebral amyloidosis, axonal degeneration, microglial activation and sleep regulation were altered in young and old patients with DS, and if these biomarkers were related to altered Aβ and APP metabolism, reflected by CSF levels of different Aβ and APP peptides.

METHODS

CSF from DS patients (n=12) and healthy controls (n=20) were analyzed for Aβ peptides (Aβ1-42, AβX-38/40/42), secreted APP species (sAPPα/β), biomarkers for AD-like axonal degeneration [total tau (T-tau), phosphorylated tau], microglial activation (YKL-40, CC chemokine ligand 2) and orexin-A, which is a peptide involved in sleep regulation. We compared biomarker levels between groups and tested for relations between biomarkers, disease stage and age.

RESULTS

Several of the markers were specifically increased in DS, including AβX-40, sAPPα and sAPPβ. Οrexin-A was significantly decreased in DS and correlated with Aβ and sAPP. Orexin-A decreased with age in DS, while T-tau and YKL-40 increased with age.

CONCLUSION

Down's patients have increased APP and Aβ production and increased microglial activation with age. The orexin-A metabolism is disturbed in DS and may be linked to APP and Aβ production. Biomarker studies of DS may contribute to our understanding of the amyloidogenic and neurodegenerative process in AD.