The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein

2021 ◽  
Vol 18 ◽  
Author(s):  
Chika Seiwa ◽  
Ichiro Sugiyama ◽  
Makoto Sugawa ◽  
Hiroaki Murase ◽  
Chiaki Kudoh ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Pathological Feature ◽  
Novel Therapy ◽  
App Processing ◽  
App Metabolism

Background: The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer’s disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism / processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology. Methods: We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon II. Results: A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production. Conclusion: Together, these findings suggest that in the absence of MBP, there is a marked reduction of non-amyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

scholarly journals RNA Interference Silencing of the Adaptor Molecules ShcC and Fe65 Differentially Affect Amyloid Precursor Protein Processing and Aβ Generation

2006 ◽  
Vol 282 (7) ◽  
pp. 4318-4325 ◽  
Author(s):  
Zhongcong Xie ◽  
Yuanlin Dong ◽  
Uta Maeda ◽  
Weiming Xia ◽  
Rudolph E. Tanzi
Keyword(s):  
Rna Interference ◽  
Amyloid Precursor Protein ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Adaptor Proteins ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Amyloid Β Protein ◽  
App Processing ◽  
Rnai Silencing

The amyloid precursor protein (APP) and its pathogenic by-product amyloid-β protein (Aβ) play central roles in Alzheimer disease (AD) neuropathogenesis. APP can be cleaved by β-secretase (BACE) and α-secretase to produce APP-C99 and APP-C83. These C-terminal fragments can then be cleaved by γ-secretase to produce Aβ and p3, respectively. p3 has been reported to promote apoptosis, and Aβ is the key component of senile plaques in AD brain. APP adaptor proteins with phosphotyrosine-binding domains, including ShcA (SHC1), ShcC (SHC3), and Fe65 (APBB1), can bind to and interact with the conserved YENPTY motif in the APP-C terminus. Here we have described for the first time the effects of RNA interference (RNAi) silencing of ShcA, ShcC, and Fe65 expression on APP processing and Aβ production. RNAi silencing of ShcC led to reductions in the levels of APP-C-terminal fragments (APP-CTFs) and Aβ in H4 human neuroglioma cells stably overexpressing full-length APP (H4-FL-APP cells) but not in those expressing APP-C99 (H4-APP-C99 cells). RNAi silencing of ShcC also led to reductions in BACE levels in H4-FL-APP cells. In contrast, RNAi silencing of the homologue ShcA had no effect on APP processing or Aβ levels. RNAi silencing of Fe65 increased APP-CTF levels, although also decreasing Aβ levels in H4-FL-APP cells. These findings suggest that pharmacologically blocking interaction of APP with ShcC and Fe65 may provide novel therapeutic strategies against AD.

scholarly journals N-terminal Domain of Myelin Basic Protein Inhibits Amyloid β-Protein Fibril Assembly

2010 ◽  
Vol 285 (46) ◽  
pp. 35590-35598 ◽  
Author(s):  
Mei-Chen Liao ◽  
Michael D. Hoos ◽  
Darryl Aucoin ◽  
Mahiuddin Ahmed ◽  
Judianne Davis ◽  
...  
Keyword(s):  
Myelin Basic Protein ◽  
Basic Protein ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Terminal Domain ◽  
Β Protein ◽  
Protein Fibril

scholarly journals Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production

2020 ◽  
Vol 31 (1) ◽  
pp. 27-44 ◽  
Author(s):  
Jing Zhi A. Tan ◽  
Lou Fourriere ◽  
Jingqi Wang ◽  
Franck Perez ◽  
Gaelle Boncompain ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Secretory Pathway ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Primary Neurons ◽  
App Processing

The anterograde trafficking of BACE1 and the potential processing of amyloid precursor protein along the secretory pathway remain poorly defined. Our findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.

scholarly journals Potential Link between Amyloid β-Protein 42 and C-terminal Fragment γ 49–99 of β-Amyloid Precursor Protein

2003 ◽  
Vol 278 (27) ◽  
pp. 24294-24301 ◽  
Author(s):  
Toru Sato ◽  
Naoshi Dohmae ◽  
Yue Qi ◽  
Nobuto Kakuda ◽  
Hiroaki Misonou ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Terminal Fragment ◽  
Β Protein ◽  
Potential Link ◽  
Β Amyloid

scholarly journals Degradation of Amyloid β Protein by Purified Myelin Basic Protein

2009 ◽  
Vol 284 (42) ◽  
pp. 28917-28925 ◽  
Author(s):  
Mei-Chen Liao ◽  
Mahiuddin Ahmed ◽  
Steven O. Smith ◽  
William E. Van Nostrand
Keyword(s):  
Myelin Basic Protein ◽  
Basic Protein ◽  
Amyloid Β ◽  
Amyloid Β Protein ◽  
Β Protein

scholarly journals Enhanced β-secretase processing of amyloid precursor protein in the skeletal muscle of ALS animal models

2018 ◽  
Author(s):  
Huaqiang Yang
Keyword(s):  
Skeletal Muscle ◽  
Animal Models ◽  
Amyloid Precursor Protein ◽  
Neurodegenerative Disorder ◽  
Precursor Protein ◽  
Pathological Feature ◽  
App Processing ◽  
Regulated Expression ◽  
Selective Change ◽  
Lateral Sclerosis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder primarily characterized by motor neuron degeneration and muscle paralysis. Several studies indicate that pathological changes in the skeletal muscle contribute to disease progression. We report a significant increase of β-secretase processing of amyloid precursor protein (APP) in the skeletal muscle but not the spinal cord or cerebral cortex of hSOD1 (G93A) transgenic ALS mouse models. Enhanced β-secretase processing of APP was manifested by up-regulated expression of βCTF, the 22-kd CTF of APP, and β-secretase processing enzyme, BACE1. Morphological analysis demonstrated that enhanced β-secretase processing of APP mainly occurred in the atrophic myofibers of ALS mice. We also observed a similar change in APP processing in an hSOD1 (G93A) transgenic ALS pig model, suggesting that enhanced β-secretase processing of APP in skeletal muscle may be a common pathological feature of ALS. These findings reveal a selective change in APP processing in skeletal muscle of ALS animal models, and highlight the involvement of aberrant APP processing in ALS pathogenesis.

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