Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for β-amyloid peptide over-production and localization in Alzheimer’s disease

2004 ◽  
Vol 36 (12) ◽  
pp. 2531-2540 ◽  
Author(s):  
W.H. Yu ◽  
A. Kumar ◽  
C. Peterhoff ◽  
L. Shapiro Kulnane ◽  
Y. Uchiyama ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Autophagic Vacuoles ◽  
Β Amyloid ◽  
Β Amyloid Peptide

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.

Pentapeptide Amides Interfere with the Aggregation of β-Amyloid Peptide of Alzheimer's Disease

2002 ◽  
Vol 292 (4) ◽  
pp. 931-936 ◽  
Author(s):  
Csaba Hetényi ◽  
Zoltán Szabó ◽  
Éva Klement ◽  
Zsolt Datki ◽  
Tamás Körtvélyesi ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Peptide ◽  
Β Amyloid ◽  
Β Amyloid Peptide

scholarly journals Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer's disease

2005 ◽  
Vol 171 (1) ◽  
pp. 87-98 ◽  
Author(s):  
W. Haung Yu ◽  
Ana Maria Cuervo ◽  
Asok Kumar ◽  
Corrinne M. Peterhoff ◽  
Stephen D. Schmidt ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cell Survival ◽  
Mammalian Target Of Rapamycin ◽  
Amyloid Peptide ◽  
Survival Pathways ◽  
Secretase Activity ◽  
Amyloid Aβ ◽  
Β Amyloid ◽  
Β Amyloid Peptide

Macroautophagy, which is a lysosomal pathway for the turnover of organelles and long-lived proteins, is a key determinant of cell survival and longevity. In this study, we show that neuronal macroautophagy is induced early in Alzheimer's disease (AD) and before β-amyloid (Aβ) deposits extracellularly in the presenilin (PS) 1/Aβ precursor protein (APP) mouse model of β-amyloidosis. Subsequently, autophagosomes and late autophagic vacuoles (AVs) accumulate markedly in dystrophic dendrites, implying an impaired maturation of AVs to lysosomes. Immunolabeling identifies AVs in the brain as a major reservoir of intracellular Aβ. Purified AVs contain APP and β-cleaved APP and are highly enriched in PS1, nicastrin, and PS-dependent γ-secretase activity. Inducing or inhibiting macroautophagy in neuronal and nonneuronal cells by modulating mammalian target of rapamycin kinase elicits parallel changes in AV proliferation and Aβ production. Our results, therefore, link β-amyloidogenic and cell survival pathways through macroautophagy, which is activated and is abnormal in AD.

scholarly journals The Amyloid Precursor Protein Intracellular Domain-Fe65 Multiprotein Complexes: A Challenge to the Amyloid Hypothesis for Alzheimer's Disease?

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Daniel A. Bórquez ◽  
Christian González-Billault
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Molecular Mechanisms ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Intracellular Domain ◽  
Multiprotein Complexes ◽  
Amyloid Cascade

Since its proposal in 1994, the amyloid cascade hypothesis has prevailed as the mainstream research subject on the molecular mechanisms leading to the Alzheimer's disease (AD). Most of the field had been historically based on the role of the different forms of aggregation ofβ-amyloid peptide (Aβ). However, a soluble intracellular fragment termed amyloid precursor protein (APP) intracellular domain (AICD) is produced in conjunction with Aβfragments. This peptide had been shown to be highly toxic in both culture neurons and transgenic mice models. With the advent of this new toxic fragment, the centerpiece for the ethiology of the disease may be changed. This paper discusses the potential role of multiprotein complexes between the AICD and its adapter protein Fe65 and how this could be a potentially important new agent in the neurodegeneration observed in the AD.

scholarly journals Neuronal aging potentiates beta-amyloid generation via amyloid precursor protein endocytosis

2019 ◽  
Author(s):  
Tatiana Burrinha ◽  
Ricardo Gomes ◽  
Ana Paula Terrasso ◽  
Cláudia Guimas Almeida
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
App Processing ◽  
Early Endosomes ◽  
Primary Mouse ◽  
Β Amyloid ◽  
Aβ Production

AbstractAging increases the risk of Alzheimer’s disease (AD). During normal aging synapses decline and β-Amyloid (Aβ) accumulates. An Aβ defective clearance with aging is postulated as responsible for Aβ accumulation, although a role for increased Aβ production with aging can also lead to Aβ accumulation. To test this hypothesis, we established a long-term culture of primary mouse neurons that mimics neuronal aging (lysosomal lipofuscin accumulation and synapse decline). Intracellular endogenous Aβ42 accumulated in aged neurites due to increased amyloid-precursor protein (APP) processing. We show that APP processing is up-regulated by a specific age-dependent increase in APP endocytosis. Endocytosed APP accumulated in early endosomes that, in turn were found augmented in aged neurites. APP processing and early endosomes up-regulation was recapitulated in vivo. Finally, we found that inhibition of Aβ production reduced the decline in synapses in aged neurons. We propose that potentiation of APP endocytosis by neuronal aging increases Aβ production, which contributes to aging-dependent decline in synapses.SummaryHow aging increases the risk of Alzheimer’s disease is not clear. We show that normal neuronal aging increases the intracellular production of β-amyloid, due to an upregulation of the amyloid precursor protein endocytosis. Importantly, increased Aβ production contributes to the aging-dependent synapse loss.

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