scholarly journals Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts

2003 ◽  
Vol 160 (1) ◽  
pp. 113-123 ◽  
Author(s):  
Robert Ehehalt ◽  
Patrick Keller ◽  
Christian Haass ◽  
Christoph Thiele ◽  
Kai Simons
Keyword(s):  
Amyloid Precursor Protein ◽  
Lipid Rafts ◽  
Senile Plaques ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Cross Linking ◽  
Dependent Manner ◽  
Dynamic Interactions ◽  
Β Amyloid ◽  
Aβ Generation

Formation of senile plaques containing the β-amyloid peptide (Aβ) derived from the amyloid precursor protein (APP) is an invariant feature of Alzheimer's disease (AD). APP is cleaved either by β-secretase or by α-secretase to initiate amyloidogenic (release of Aβ) or nonamyloidogenic processing of APP, respectively. A key to understanding AD is to unravel how access of these enzymes to APP is regulated. Here, we demonstrate that lipid rafts are critically involved in regulating Aβ generation. Reducing cholesterol levels in N2a cells decreased Aβ production. APP and the β-site APP cleavage enzyme (BACE1) could be induced to copatch at the plasma membrane upon cross-linking with antibodies and to segregate away from nonraft markers. Antibody cross-linking dramatically increased production of Aβ in a cholesterol-dependent manner. Aβ generation was dependent on endocytosis and was reduced after expression of the dynamin mutant K44A and the Rab5 GTPase-activating protein, RN-tre. This inhibition could be overcome by antibody cross-linking. These observations suggest the existence of two APP pools. Although APP inside raft clusters seems to be cleaved by β-secretase, APP outside rafts undergoes cleavage by α-secretase. Thus, access of α- and β-secretase to APP, and therefore Aβ generation, may be determined by dynamic interactions of APP with lipid rafts.

scholarly journals Filling the void: a role for exercise-induced BDNF and brain amyloid precursor protein processing

2017 ◽  
Vol 313 (5) ◽  
pp. R585-R593 ◽  
Author(s):  
Rebecca E. K. MacPherson
Keyword(s):  
Insulin Resistance ◽  
Amyloid Precursor Protein ◽  
Significant Risk ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Amyloid Precursor Protein Processing ◽  
Direct Effects ◽  
App Processing ◽  
Β Amyloid ◽  
Exercise Induced

Inactivity, obesity, and insulin resistance are significant risk factors for the development of Alzheimer’s disease (AD). Several studies have demonstrated that diet-induced obesity, inactivity, and insulin resistance exacerbate the neuropathological hallmarks of AD. The aggregation of β-amyloid peptides is one of these hallmarks. β-Site amyloid precursor protein-cleaving enzyme 1 (BACE1) is the rate-limiting enzyme in amyloid precursor protein (APP) processing, leading to β-amyloid peptide formation. Understanding how BACE1 content and activity are regulated is essential for establishing therapies aimed at reducing and/or slowing the progression of AD. Exercise training has been proven to reduce the risk of AD as well as decrease β-amyloid production and BACE1 content and/or activity. However, these long-term interventions also result in improvements in adiposity, circulating metabolites, glucose tolerance, and insulin sensitivity making it difficult to determine the direct effects of exercise on brain APP processing. This review highlights this large void in our knowledge and discusses our current understanding of the direct of effect of exercise on β-amyloid production. We have concentrated on the central role that brain-derived neurotrophic factor (BDNF) may play in mediating the direct effects of exercise on reducing brain BACE1 content and activity as well as β-amyloid production. Future studies should aim to generate a greater understanding of how obesity and exercise can directly alter APP processing and AD-related pathologies. This knowledge could provide evidence-based hypotheses for designing therapies to reduce the risk of AD and dementia.

scholarly journals Generation of the β-Amyloid Peptide and the Amyloid Precursor Protein C-terminal Fragment γ Are Potentiated by FE65L1

2003 ◽  
Vol 278 (51) ◽  
pp. 51100-51107 ◽  
Author(s):  
Yang Chang ◽  
Giuseppina Tesco ◽  
William J. Jeong ◽  
Loren Lindsley ◽  
Elizabeth A. Eckman ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Protein C ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Terminal Fragment ◽  
Β Amyloid ◽  
Β Amyloid Peptide

scholarly journals Cytotoxic Fragment of Amyloid Precursor Protein Accumulates in Hippocampus after Global Forebrain Ischemia

1996 ◽  
Vol 16 (6) ◽  
pp. 1219-1223 ◽  
Author(s):  
Masayuki Yokota ◽  
Takaomi C. Saido ◽  
Eiichi Tani ◽  
Ikuya Yamaura ◽  
Nobutaka Minami
Keyword(s):  
Amyloid Precursor Protein ◽  
Pyramidal Neurons ◽  
Granule Cells ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Forebrain Ischemia ◽  
Ischemic Insult ◽  
Dentate Granule Cells ◽  
Β Amyloid ◽  
Β Amyloid Peptide

We developed an antibody specific to β-amyloid precursor protein (βAPP) fragments possessing the exact amino terminus of the β-amyloid peptide and examined its induction in postischemic hippocampus. In control hippocampus, this APP fragment was lightly observed in pyramidal neurons of CA sectors and dentate granule cells. Transient forebrain ischemia enhanced accumulation of the APP fragment in CA1 pyramidal neurons. Seven days after the ischemia, while the APP fragment was still observed in dentate granule cells and CA3 neurons, it disappeared in dead CA1 neurons. While astrocytes did not show in any immunoreactivity throughout the experiment, those in the CA1 sector showed moderate immunoreactivity 7 days after the ischemia. The APP fragment has a cytotoxic effect on cultured neurons. These results suggest that the accumulation of the cytotoxic APP fragment in CA1 neurons may play a role in the development of delayed neuronal death after the ischemic insult.

scholarly journals β-Amyloid precursor protein-b is essential for Mauthner cell development in the zebrafish in a Notch-dependent manner

2016 ◽  
Vol 413 (1) ◽  
pp. 26-38 ◽  
Author(s):  
Rakesh Kumar Banote ◽  
Malin Edling ◽  
Fredrik Eliassen ◽  
Petronella Kettunen ◽  
Henrik Zetterberg ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Cell Development ◽  
Precursor Protein ◽  
Dependent Manner ◽  
Mauthner Cell ◽  
Β Amyloid ◽  
Protein B

scholarly journals Syntaxin 5 interacts with presenilin holoproteins, but not with their N- or C-terminal fragments, and affects β-amyloid peptide production

2004 ◽  
Vol 381 (3) ◽  
pp. 619-628 ◽  
Author(s):  
Kei SUGA ◽  
Takami TOMIYAMA ◽  
Hiroshi MORI ◽  
Kimio AKAGAWA
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Full Length ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Familial Alzheimer’S Disease ◽  
Aβ Amyloid ◽  
Β Amyloid ◽  
Familial Alzheimer's Disease

Mutations in presenilins 1 and 2 (PS1 and PS2) account for the majority of cases of early-onset familial Alzheimer's disease. However, the trafficking and interaction of PSs with other proteins in the early secretory pathways are poorly understood. Using co-immunoprecipitation, we found that PS bound to Syx5 (syntaxin 5), which is a target-soluble N-ethylmaleimide-sensitive fusion protein attachment protein receptor involved in endoplasmic reticulum (ER)–Golgi vesicular transport in vivo. Syx5 interacted only with the full-length PS holoproteins and not with the naturally occurring N- or C-terminal fragments. The PS holoproteins co-immunoprecipitated with the mutant Syx5, which localized to the ER and Golgi compartments, despite the substitution of the transmembrane region with that of syntaxin 1A. In contrast, the transmembrane deletion mutant that localized to the cytosol, but not to the ER or Golgi compartments, did not co-immunoprecipitate the PS holoproteins. The PS1 variant linked to familial Alzheimer's disease (PS1ΔE9), lacking the region that contains the endoproteolytic cleavage site in the cytoplasmic loop, showed markedly decreased binding to Syx5. Immunofluorescence and sucrose-density-gradient fractionation analyses showed that the full-length PS holoproteins co-localized with Syx5 to the ER and cis-Golgi compartments. Furthermore, Syx5 overexpression resulted in the accumulation of PS holoproteins and the β-amyloid precursor protein, and reduced the secretion of the Aβ (amyloid β) peptide in COS-7 cells. In summary, these results indicate that Syx5 binds to full-length PSs and affects the processing and trafficking of β-amyloid precursor protein in the early secretory compartments.

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