Liu_2013_Eur.J.Neurosci_37_1714

Deposition of beta -amyloid (Abeta) peptides, cleavage products of beta-amyloid precursor protein (APP) by beta-secretase-1 (BACE1) and gamma-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). gamma-Secretase inhibition is a therapeutical anti-Abeta approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Abeta peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Abeta efficacy. The present study compared active gamma-secretase binding sites with Abeta deposition in aged and AD human cerebrum, and explored the possibility of Abeta production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity gamma-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and beta-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Abeta40 and Abeta42 into the medium. Overall, our results suggest that gamma-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Abeta, probably at reduced levels in AD.