Abstract：
:Presenilins (PSs) are catalytic components of the γ-secretase complex that produces Aβ peptides. Substrates of γ-secretase are membrane-bound protein fragments deriving from the cleavage of extracellular sequence of cell surface proteins. APP-derived γ-secretase substrates are cleaved at gamma (γ) sites to produce Aβ while cleavage at the epsilon (ε) site produces AICD proposed to function in transcription. In addition to APP, γ-secretase promotes the ε-cleavage of a large number of cell surface proteins producing cytosolic peptides shown to function in cell signaling. A common hypothesis suggests that Alzheimer's disease (AD) is caused by Aβ peptides or their products. Treatment of patients with inhibitors of Aβ production however, showed no therapeutic benefits while inducing cytotoxicity. Similarly, treatments with anti-Aβ antibodies yielded disappointing results. Importantly, recent evidence shows that PS familial AD (FAD) mutations cause a loss of γ-secretase cleavage activity at ε site of substrates thus inhibiting production of biologically important cell signaling peptides while promoting accumulation of membrane-bound cytotoxic substrates. These data support a hypothesis that FAD mutations may increase neurotoxicity by inhibiting the γ-secretase-catalyzed ε cleavage of substrates thus interfering with cell signaling while also promoting accumulation of cytotoxic peptides. Similar mechanisms may explain γ-secretase inhibitor-associated toxicities observed in clinical trials. Here we discuss evidence that FAD neurodegeneration may be caused by loss of γ-secretase cleavage function at ε sites of substrates.
journal_name
Neurochem Resjournal_title
Neurochemical researchauthors
Robakis NKdoi
10.1007/s11064-013-1003-6subject
Has Abstractpub_date
2014-01-01 00:00:00pages
570-5issue
3eissn
0364-3190issn
1573-6903journal_volume
39pub_type
杂志文章,评审abstract：:The characteristics and properties of the increase in cytosolic [Ca2+] that occurs in bovine adrenal medullary chromaffin cells on exposure to angiotensin 11 have been investigated. In fura-2 loaded cells exposure to a maximally effective concentration of angiotensin II (100 nM) caused a rapid, but transient increase ...
journal_title：Neurochemical research
pub_type： 杂志文章
doi：10.1023/a:1024987128090
更新日期：2003-09-01 00:00:00
abstract：:The ability of Sendai virosomes or Lipofectin to introduce an AAV vector into primary rat brain astroglial cultures was characterized. The pJDT95npy vector was constructed by inserting rat NPY cDNA downstream from the indigenous AAV p5, p19 and p40 promoters in pJDT95. Lipofectin-mediated transfection with pJDT95npy (...
journal_title：Neurochemical research
pub_type： 杂志文章
doi：10.1007/BF00967701
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journal_title：Neurochemical research
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doi：10.1007/s11064-010-0351-8
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doi：10.1007/s11064-012-0903-1
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pub_type： 杂志文章
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更新日期：2002-10-01 00:00:00
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journal_title：Neurochemical research
pub_type： 杂志文章
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journal_title：Neurochemical research
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更新日期：1997-05-01 00:00:00
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journal_title：Neurochemical research
pub_type： 杂志文章
doi：10.1007/BF00978372
更新日期：1993-11-01 00:00:00
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journal_title：Neurochemical research
pub_type： 杂志文章
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更新日期：1983-09-01 00:00:00
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pub_type： 杂志文章
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更新日期：2015-07-01 00:00:00
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journal_title：Neurochemical research
pub_type： 杂志文章
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更新日期：1995-12-01 00:00:00
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journal_title：Neurochemical research
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pub_type： 杂志文章,评审
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journal_title：Neurochemical research
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journal_title：Neurochemical research
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journal_title：Neurochemical research
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journal_title：Neurochemical research
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journal_title：Neurochemical research
pub_type： 杂志文章
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更新日期：1978-02-01 00:00:00
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journal_title：Neurochemical research
pub_type： 杂志文章
doi：10.1007/s11064-010-0203-6
更新日期：2010-09-01 00:00:00
