γ-Secretase binding sites in aged and Alzheimer's disease human cerebrum: The choroid plexus as a putative origin of CSF Aβ

Fei Liu, Zhi Qin Xue, Si Hao Deng, Xiong Kun, Xue Gang Luo, Peter R. Patrylo, Gregory M. Rose, Huaibin Cai, Robert G. Struble, Yan Cai, Xiao Xin Yan

Research output: Contribution to journalArticle

Abstract

Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [3H]-L-685,458, a radiolabeled high-affinity γ-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 [3H]-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 β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-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 Aβ, probably at reduced levels in AD.

Original languageEnglish (US)
Pages (from-to)1714-1725
Number of pages12
JournalEuropean Journal of Neuroscience
Volume37
Issue number10
DOIs
Publication statusPublished - May 2013
Externally publishedYes

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Keywords

  • β-amyloid
  • γ-secretase
  • AD biomarker
  • Anti-Aβ therapy
  • BACE1

ASJC Scopus subject areas

  • Neuroscience(all)

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