scholarly journals Apolipoprotein E forms stable complexes with recombinant Alzheimer's disease β-amyloid precursor protein

1997 ◽  
Vol 325 (1) ◽  
pp. 169-175 ◽  
Author(s):  
Cristina HAAS ◽  
Pilar CAZORLA ◽  
Carlos DE MIGUEL ◽  
Fernando VALDIVIESO ◽  
Jesús VÁZQUEZ
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Senile Plaques ◽  
Precursor Protein ◽  
Amyloid Peptide ◽  
Reducing Conditions ◽  
Β Amyloid

Apolipoprotein E (apoE), a protein genetically linked to the incidence of Alzheimer's disease, forms SDS-stable complexes in vitro with β-amyloid peptide (Aβ), the primary component of senile plaques. In the present study, we investigated whether apoE was able to bind full-length Aβ precursor protein (APP). Using a maltose-binding-protein–APP fusion protein and human very-low-density lipoprotein (VLDL), we detected an interaction of apoE with APP that was inhibited by Aβ or anti-apoE antibody. Saturation-binding experiments indicated a single binding equilibrium with an apparent 1:1 stoichiometry and a dissociation constant of 15 nM. An interaction was also observed using apoE from cerebrospinal fluid or delipidated VLDL, as well as recombinant apoE. APP·apoE complexes were SDS-stable, and their formation was not inhibited by reducing conditions; however, they were dissociated by SDS under reducing conditions. ApoE·APP complexes formed high-molecular-mass aggregates, and competition experiments suggested that amino acids 14–23 of Aβ are responsible for complex-formation. Finally, no differences were found when studying the interaction of APP with apoE3 or apoE4. Taken together, our results demonstrate that apoE may form stable complexes with the Aβ moiety of APP with characteristics similar to those of complexes formed with isolated Aβ, and suggest the intriguing possibility that apoE–APP interactions may be pathologically relevant in vivo.

A spiropyran-based fluorescent probe for the specific detection of β-amyloid peptide oligomers in Alzheimer's disease

2016 ◽  
Vol 52 (57) ◽  
pp. 8865-8868 ◽  
Author(s):  
Guanglei Lv ◽  
Anyang Sun ◽  
Peng Wei ◽  
Ning Zhang ◽  
Haichuang Lan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fluorescent Probe ◽  
Amyloid Peptide ◽  
Specific Detection ◽  
Aβ Oligomers ◽  
Β Amyloid ◽  
Β Amyloid Peptide

A fluorescent probe for the specific detection of Aβ oligomers in Alzheimer's disease both in vitro and in vivo was developed.

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.

scholarly journals SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1275
Author(s):  
Soo Yong Park ◽  
Joo Yeong Kang ◽  
Taehee Lee ◽  
Donggyu Nam ◽  
Chang-Jin Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Physiological Activity ◽  
Precursor Protein ◽  
Age Related

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

scholarly journals Olive-Oil-Derived Oleocanthal Enhances β-Amyloid Clearance as a Potential Neuroprotective Mechanism against Alzheimer’s Disease: In Vitro and in Vivo Studies

2013 ◽  
Vol 4 (6) ◽  
pp. 973-982 ◽  
Author(s):  
Alaa H. Abuznait ◽  
Hisham Qosa ◽  
Belnaser A. Busnena ◽  
Khalid A. El Sayed ◽  
Amal Kaddoumi
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Olive Oil ◽  
In Vivo Studies ◽  
Β Amyloid

scholarly journals Fibrillogenesis in Alzheimer's disease of amyloid β peptides and apolipoprotein E

1995 ◽  
Vol 306 (2) ◽  
pp. 599-604 ◽  
Author(s):  
E M Castano ◽  
F Prelli ◽  
T Wisniewski ◽  
A Golabek ◽  
R A Kumar ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Apolipoprotein E ◽  
Late Onset ◽  
Senile Plaques ◽  
Amyloid Β ◽  
Fibril Formation ◽  
Tau Proteins ◽  
Amyloid Formation

A central event in Alzheimer's disease is the conformational change from normally circulating soluble amyloid beta peptides (A beta) and tau proteins into amyloid fibrils, in the form of senile plaques and neurofibrillary tangles respectively. The apolipoprotein E (apoE) gene locus has recently been associated with late-onset Alzheimer's disease. It is not know whether apoE plays a direct role in the pathogenesis of the disease. In the present work we have investigated whether apoE can affect the known spontaneous in vitro formation of amyloid-like fibrils by synthetic A beta analogues using a thioflavine-T assay for fibril formation, electron microscopy and Congo Red staining. Our results show that, under the conditions used, apoE directly promotes amyloid fibril formation, increasing both the rate of fibrillogenesis and the total amount of amyloid formed. ApoE accelerated fibril formation of both wild-type A beta-(1-40) and A beta-(1-40A), an analogue created by the replacement of valine with alanine at residue 18, which alone produces few amyloid-like fibrils. However, apoE produced only a minimal effect on A beta-(1-40Q), found in the Dutch variant of Alzheimer's disease. When recombinant apoE isoforms were used, apoE4 was more efficient than apoE3 at enhancing amyloid formation. These in vitro observations support the hypothesis that apoE acts as a pathological chaperone, promoting the beta-pleated-sheet conformation of soluble A beta into amyloid fibres, and provide a possible explanation for the association of the apoE4 genetic isoform with Alzheimer's disease.

scholarly journals Supplementation with Curcuma longa Reverses Neurotoxic and Behavioral Damage in Models of Alzheimer’s Disease: A Systematic Review

2019 ◽  
Vol 17 (5) ◽  
pp. 406-421 ◽  
Author(s):  
Ianara Mendonça da Costa ◽  
Marco Aurelio de Moura Freire ◽  
José Rodolfo Lopes de Paiva Cavalcanti ◽  
Dayane Pessoa de Araújo ◽  
Bianca Norrara ◽  
...  
Keyword(s):  
Systematic Review ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Clinical Symptoms ◽  
Curcuma Longa ◽  
Senile Plaques ◽  
Experimental Models ◽  
Cochrane Library

Background: The formation of senile plaques and neurofibrillary tangles of the tau protein are the main pathological mechanism of Alzheimer’s disease (AD). Current therapies for AD offer discrete benefits to the clinical symptoms and do not prevent the continuing degeneration of neuronal cells. Therefore, novel therapeutic strategies have long been investigated, where curcumin (Curcuma longa) has shown some properties that can prevent the deleterious processes involved in neurodegenerative diseases. Objective: The aim of the present work is to review studies that addressed the effects of curcumin in experimental models (in vivo and in vitro) for AD. Method: This study is a systematic review conducted between January and June 2017, in which a consultation of scientific articles from indexed periodicals was carried out in Science Direct, United States National Library of Medicine (PubMed), Cochrane Library and Scielo databases, using the following descriptors: “Curcuma longa”, “Curcumin” and “Alzheimer’s disease”. Results: A total of 32 studies were analyzed, which indicated that curcumin supplementation reverses neurotoxic and behavioral damages in both in vivo and in vitro models of AD. Conclusion: The administration of curcumin in experimental models seems to be a promising approach in AD, even though it is suggested that additional studies must be conducted using distinct doses and through other routes of administration.

To rectify Alzheimer's disease etiology, excessive mitochondrial division might be stopped or mitophagy might be promoted

2021 ◽  
Author(s):  
Moataz Dowaidar
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mitochondrial Dysfunction ◽  
Senile Plaques ◽  
Mitochondrial Division ◽  
Disease Etiology ◽  
Abnormal Mitochondria ◽  
Unifying Principles

In both in vitro and in vivo Alzheimer's disease (AD) models, mitochondrial dysfunction is a crucial feature that limits neuronal activity and results in A and phosphorylated Tau toxicity. To rectify AD etiology, excessive mitochondrial division might be stopped or mitophagy might be promoted. However, there are still unexplained mysteries surrounding the formation of senile plaques and NFTs, and the pathophysiology of Alzheimer's disease lacks fundamental unifying principles. Some scientists believe A toxicity and Tau toxicity are upstream processes in mitochondrial dysfunction, while others feel it is a downstream chain of events involving abnormal mitochondria. There are several mitophagy mechanisms for the clearance of dead mitochondria in PINK1 signaling; some are regulated by Parkin, while others are not. Drp1, Mfn1/2, PINK1, or Parkin, according to some researchers, have no role in mitophagy cleaning dysfunctional mitochondria; so, additional study is needed to solve the puzzle of mitophagy signaling pathways for clearing dead mitochondria and conserving high-quality mitochondria. Therapeutic techniques targeting mitophagy activity might be useful in reversing AD etiology.

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.

P1-174: Early detection of β-amyloid aggregation in in vivo and in vitro models of Alzheimer's disease

2010 ◽  
Vol 6 ◽  
pp. S224-S224 ◽  
Author(s):  
Louise A. Scrocchi ◽  
Elizabeth Karaskov ◽  
Vivian Lee ◽  
Hui Chen ◽  
Melissa Osborne ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Early Detection ◽  
In Vitro Models ◽  
Amyloid Aggregation ◽  
Β Amyloid

scholarly journals Apolipoprotein E Isoforms Differentially Regulate Alzheimer’s Disease and Amyloid-β-Induced Inflammatory Response in vivo and in vitro

2017 ◽  
Vol 57 (4) ◽  
pp. 1265-1279 ◽  
Author(s):  
Evan Dorey ◽  
Michelle Bamji-Mirza ◽  
Dema Najem ◽  
Yan Li ◽  
Hong Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Inflammatory Response ◽  
Apolipoprotein E ◽  
Amyloid Β
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