γ-Secretase Dependent Production of Intracellular Domains Is Reduced in Adult Compared to Embryonic Rat Brain Membranes

被引：10

作者：

Franberg, Jenny ^{[1
]}

Karlstrom, Helena ^{[1
]}

Winblad, Bengt ^{[1
]}

Tjernberg, Lars O. ^{[1
]}

Frykman, Susanne ^{[1
]}

机构：

[1] Karolinska Inst, Dept Neurobiol Care Sci & Soc NVS, Alzheimers Dis Res Ctr, Huddinge, Sweden

来源：

PLOS ONE | 2010年 / 5卷 / 03期

关键词：

AMYLOID PRECURSOR PROTEIN; P75 NEUROTROPHIN RECEPTOR; INSULIN-DEGRADING ENZYME; ALZHEIMERS-DISEASE; IN-VIVO; NOTCH; PRESENILIN; CLEAVAGE; MICE; DEFICIENCY;

D O I：

10.1371/journal.pone.0009772

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Background: gamma-Secretase is an intramembrane aspartyl protease whose cleavage of the amyloid precursor protein (APP) generates the amyloid beta-peptide (A beta) and the APP intracellular domain. A beta is widely believed to have a causative role in Alzheimer's disease pathogenesis, and therefore modulation of gamma-secretase activity has become a therapeutic goal. Besides APP, more than 50 substrates of gamma-secretase with different cellular functions during embryogenesis as well as adulthood have been revealed. Prior to gamma-secretase cleavage, substrates are ectodomain shedded, producing membrane bound C-terminal fragments (CTFs). Principal Findings: Here, we investigated gamma-secretase cleavage of five substrates; APP, Notch1, N-cadherin, ephrinB and p75 neurotrophin receptor (p75-NTR) in membranes isolated from embryonic, young or old adult rat brain by analyzing the release of the corresponding intracellular domains (ICDs) or A beta 40 by western blot analysis and ELISA respectively. The highest levels of all ICDs and A beta were produced by embryonic membranes. In adult rat brain only cleavage of APP and Notch1 could be detected and the A beta 40 and ICD production from these substrates was similar in young and old adult rat brain. The CTF levels of Notch1, N-cadherin, ephrinB and p75-NTR were also clearly decreased in the adult brain compared to embryonic brain, whereas the APP CTF levels were only slightly decreased. Conclusions: In summary our data suggests that gamma-secretase dependent ICD production is down-regulated in the adult brain compared to embryonic brain. In addition, the present approach may be useful for evaluating the specificity of gamma-secretase inhibitors.

引用

页数：9

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