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P2‐318: Biological consequences of BACE1‐dependent processing of neuregulin
Author(s) -
Willem Michael,
Fleck Daniel,
Bettegazzi Barbara,
Volbracht Christiane,
Jacobsen Helmut,
Haass Christian
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.1196
Subject(s) - neuregulin 1 , neuregulin , amyloid precursor protein secretase , cleavage (geology) , amyloid precursor protein , gene isoform , chemistry , inhibitory postsynaptic potential , excitatory postsynaptic potential , neurotransmission , microbiology and biotechnology , neuroscience , biology , biochemistry , alzheimer's disease , receptor , medicine , gene , disease , paleontology , fracture (geology)
Background: The generation of amyloid b-peptide (Ab) from the amyloid precursor protein (APP) depends on sequential cleavage by band g-secretase. BACE1 (b-site APP cleaving enzyme-1), an as partylprotease, is known to be the major b-secretase in the brain, based on the complete absence of b-secretase cleavage products in BACE1 -/mice and reduced Ab levels in mouse brains upon treatment with a BACE1 inhibitor. We have shown previously that proteolytic processing of neuregulin 1 (NRG1) is dramatically reduced in BACE1 mice. Pharmacological treatment with BACE1 inhibitors is a promising therapeutic intervention to reduce Ab levels in AD patients. However, side effects of such a treatment could result in reduced activation of important physiological BACE1 substrates. Methods: We investigated in vitro whether BACE1 is participating in the release of the EGF-like domain, which is believed to be actively involved in NRG signalling. The cleavage sites were identified and verified by mutagenesis. Cleavage site specific antibodies were produced. BACE1 inhibitors were administered to neuronal cultures and living mice to investigate potential effects on NRG1 processing.Results: Biochemical analysis revealed preferential BACE1 cleavage of the major NRG isoform, type III NRG1-b1, expressed in the peripheral and central nervous system. In early postnatal development BACE1 is required for myelination and correct bundling of axons by Schwann cells most likely via processing of type III NRG1. Biological functions of NRG1 in the CNS of aged individuals are tightly associated with synaptic plasticity. NRG1 regulates both excitatory and inhibitory synaptic transmission in the adult brain. Specific BACE1 inhibitor treatment results in reduction of soluble Aß1-40 levels and of soluble sAPPß, the APP ectodomain liberated by BACE1, in brain. Moreover, we observed an accumulation of unprocessed full length APP and NRG1. Conclusions: These studies confirm genetically and pharmacologically, that BACE1 plays the predominant role in the ß-site cleavage of NRG and suggests that inhibition of ß-secretase activity could potentially interfere with NRG signaling in AD patients.