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Search results for: Amyloid Precursor Protein (APP) N terminal, Human

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#32921309   2020/09/14 To Up

Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1.

Alzheimer's disease (AD) is the most frequent and costly neurodegenerative disorder. Although diverse lines of evidence suggest that the amyloid precursor protein (APP) is involved in its causation, the precise mechanisms remain unknown and no treatments are available to prevent or halt the disease. A favorite hypothesis has been that APP contributes to AD pathogenesis through the cerebral accumulation of the amyloid-β peptide (Aβ), which is derived from APP through sequential proteolytic cleavage by BACE1 and γ-secretase. However, inhibitors of these enzymes have failed in clinical trials despite clear evidence for target engagement.
Erik C B Johnson, Kaitlyn Ho, Gui-Qiu Yu, Melanie Das, Pascal E Sanchez, Biljana Djukic, Isabel Lopez, Xinxing Yu, Michael Gill, Weiping Zhang, Jeanne T Paz, Jorge J Palop, Lennart Mucke

1708 related Products with: Behavioral and neural network abnormalities in human APP transgenic mice resemble those of App knock-in mice and are modulated by familial Alzheimer's disease mutations but not by inhibition of BACE1.

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#32787955   2020/08/12 To Up

Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer's disease.

The amyloid precursor protein (APP) is a transmembrane glycoprotein that undergoes alternative proteolytic processing. Its processing through the amyloidogenic pathway originates a large sAPPβ ectodomain fragment and the β-amyloid peptide, while non-amyloidogenic processing generates sAPPα and shorter non-fibrillar fragments. Hence, measuring sAPPα and sAPPβ has been proposed as a means to identify imbalances between the amyloidogenic/non-amyloidogenic pathways in the brain of Alzheimer's disease (AD) patients. However, to date, no consistent changes in these proteolytic fragments have been identified in either the brain or cerebrospinal fluid of AD individuals.
Claudia P Boix, Inmaculada Lopez-Font, Inmaculada Cuchillo-Ibañez, Javier Sáez-Valero

2004 related Products with: Amyloid precursor protein glycosylation is altered in the brain of patients with Alzheimer's disease.

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#32617536   // To Up

Alzheimer's Disease is Driven by Intraneuronally Retained Beta-Amyloid Produced in the AD-Specific, βAPP-Independent Pathway: Current Perspective and Experimental Models for Tomorrow.

A view of the origin and progression of Alzheimer's disease, AD, prevailing until now and formalized as the Amyloid Cascade Hypothesis theory, maintains that the disease is initiated by overproduction of beta-amyloid, Aβ, which is generated solely by the Aβ precursor protein, βAPP, proteolytic pathway and secreted from the cell. Consequent extracellular accumulation of Aβ triggers a cascade of molecular and cellular events leading to neurodegeneration that starts early in life, progresses as one prolonged process, builds up for decades, and culminates in symptomatic manifestations of the disease late in life. In this paradigm, a time window for commencement of therapeutic intervention is small and accessible only early in life. The outlook introduced in the present study is fundamentally different. It posits that the βAPP proteolytic/secretory pathway of Aβ production causes AD in humans no more than it does in either short- or long-lived non-human mammals that share this pathway with humans, accumulate beta-amyloid as they age, but do not develop the disease. Alzheimer's disease, according to this outlook, is driven by an additional powerful AD-specific pathway of Aβ production that operates in affected humans, is completely independent of the βAPP precursor, and is not available in non-human mammals. The role of the βAPP proteolytic pathway in the disease in humans is activation of this additional AD-specific Aβ production pathway. This occurs through accumulation of intracellular Aβ, primarily via ApoE-assisted cellular uptake of secreted beta-amyloid, but also through retention of a fraction of Aβ produced in the βAPP proteolytic pathway. With time, accumulated intracellular Aβ triggers mitochondrial dysfunction. In turn, cellular stresses associated with mitochondrial dysfunction, including ER stress, activate a second, AD-specific, Aβ production pathway: Asymmetric RNA-dependent βAPP mRNA amplification; animal βAPP mRNA is ineligible for this process. In this pathway, every conventionally produced βAPP mRNA molecule serves potentially as a template for production of severely 5'-truncated mRNA encoding not the βAPP but its C99 fragment (hence "asymmetric"), the immediate precursor of Aβ. Thus produced, N-terminal signal peptide-lacking C99 is processed not in the secretory pathway on the plasma membrane, but at the intracellular membrane sites, apparently in a neuron-specific manner. The resulting Aβ is, therefore, not secreted but is retained intraneuronally and accumulates rapidly within the cell. Increased levels of intracellular Aβ augment mitochondrial dysfunction, which, in turn, sustains the activity of the βAPP mRNA amplification pathway. These self-propagating mutual Aβ overproduction/mitochondrial dysfunction feedback cycles constitute a formidable two-stroke engine, an engine that drives Alzheimer's disease. The present outlook envisions Alzheimer's disorder as a two-stage disease. The first stage is a slow process of intracellular beta-amyloid accumulation. It results neither in significant neurodegenerative damage, nor in manifestation of the disease. The second stage commences with the activation of the βAPP mRNA amplification pathway shortly before symptomatic onset of the disease, sharply increases the rate of Aβ generation and the extent of its intraneuronal accumulation, produces significant damages, triggers AD symptoms, and is fast. In this paradigm, the time window of therapeutic intervention is wide open, and preventive treatment can be initiated any time, even late in life, prior to commencement of the second stage of the disease. Moreover, there are good reasons to believe that with a drug blocking the βAPP mRNA amplification pathway, it would be possible not only to preempt the disease but also to stop and to reverse it even when early AD symptoms have already manifested. There are numerous experimental models of AD, all based on a notion of the exceptionality of βAPP proteolytic/secretory pathway in Aβ production in the disease. However, with no drug even remotely effective in Alzheimer's disease, a long list of candidate drugs that succeeded remarkably in animal models, yet failed utterly in human clinical trials of potential AD drugs, attests to the inadequacy of currently employed AD models. The concept of a renewable supply of beta-amyloid, produced in the βAPP mRNA amplification pathway and retained intraneuronally in Alzheimer's disease, explains spectacular failures of both BACE inhibition and Aβ-immunotherapy in human clinical trials. This concept also forms the basis of a new generation of animal and cell-based experimental models of AD, described in the present study. These models incorporate Aβ- or C99-encoding mRNA amplification pathways of Aβ production, as well as intracellular retention of their product, and can support not only further investigation of molecular mechanisms of AD but also screening for and testing of candidate drugs aimed at therapeutic targets suggested by the present study.
Vladimir Volloch, Bjorn Olsen, Sophia Rits

1428 related Products with: Alzheimer's Disease is Driven by Intraneuronally Retained Beta-Amyloid Produced in the AD-Specific, βAPP-Independent Pathway: Current Perspective and Experimental Models for Tomorrow.

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#32399180   2019/07/29 To Up

Validation of a commercial antibody to detect endogenous human nicastrin by immunoblot.

Nicastrin (NCSTN) is a transmembrane glycoprotein that is part of the gamma-secretase complex. Gamma-secretase is a protease complex that cleaves type-I single-pass transmembrane proteins. There are many potential substrates for this complex, including NOTCH receptors and amyloid precursor proteins (APP). There are a number of commercial antibodies to nicastrin, but they do not agree on expected peptide size. We confirmed the specificity of a C-terminal binding rabbit anti-human antibody from Sigma-Aldrich (#N1660) using wildtype HEK293 cells and HEK293 cells deleted for nicastrin. The wildtype cells showed a prominent band at approximately 110 kDa. We confirmed this larger than expected sized was due to glycosylation by treating the lysate with peptide-N-glycosidase F (PNGase F), which reduced the band to less than 75 kDa. These data suggest that this polyclonal is specific for nicastrin and can detect endogenous levels of protein.
Rosana A Mesa, Elisha D O Roberson

1446 related Products with: Validation of a commercial antibody to detect endogenous human nicastrin by immunoblot.

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#32296844   // To Up

Elevated Cerebrospinal Fluid and Plasma N-Cadherin in Alzheimer Disease.

N-cadherin is a synaptic adhesion molecule stabilizing synaptic cell structure and function. Cleavage of N-cadherin by γ-secretase produces a C-terminal fragment, which is increased in the brains of Alzheimer disease (AD) patients. Here, we investigated the relationship between fluid N-cadherin levels and AD pathology. We first showed that the cleaved levels of N-cadherin were increased in homogenates of postmortem brain from AD patients compared with that in non-AD patients. We found that cleaved N-cadherin levels in the cerebrospinal fluid were increased in AD dementia compared with that in healthy control. ELISA results revealed that plasma levels of N-cadherin in 76 patients with AD were higher than those in 133 healthy control subjects. The N-cadherin levels in the brains of an AD mouse model, APP Swedish/PS1delE9 Tg (APP Tg) were reduced compared with that in control. The N-terminal fragment of N-cadherin produced by cleavage at a plasma membrane was detected extravascularly, accumulated in senile plaques in the cortex of an APP Tg mouse. In addition, N-cadherin plasma levels were increased in APP Tg mice. Collectively, our study suggests that alteration of N-cadherin levels might be associated with AD pathology.
Ji-Young Choi, Sun-Jung Cho, Jung Hyun Park, Sang-Moon Yun, Chulman Jo, Eun-Joo Kim, Gi Yeong Huh, Moon Ho Park, Changsu Han, Young Ho Koh

1459 related Products with: Elevated Cerebrospinal Fluid and Plasma N-Cadherin in Alzheimer Disease.

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#32039447   // To Up

Proinflammatory cytokines induce accumulation of glypican-1-derived heparan sulfate and the C-terminal fragment of β-cleaved APP in autophagosomes of dividing neuronal cells.

Proinflammatory cytokines stimulate expression of β-secretase, which increases processing of amyloid precursor protein (APP), ultimately leading to the deposition of amyloid beta (Aβ). The N-terminal domain of β-cleaved APP supports Cu/NO-dependent release of heparan sulfate (HS) from the glypican-1 (Gpc-1) proteoglycan. HS is an inhibitor of β-secretase, thereby constituting a regulatory, negative feedback loop. Here, we have investigated the effect of the proinflammatory cytokines TNF-α, IL-1β and IL-6 on the interplay between APP processing and release of HS from Gpc-1 in neuronal cells. We have used deconvolution immunofluorescence microscopy and sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and a panel of monoclonal/polyclonal antibodies recognizing the released HS, the N-terminus of Aβ, Aβ, the C-terminus of APP and the autophagosome marker LC3 as well as the chemical lysosome marker LysoTrackerRed (LTR). We repeatedly found that N2a neuroblastoma cells and human neural stem cells grown in the presence of the cytokines developed large cytoplasmic clusters, which stained positive for HS, the N-terminus of Aβ, Aβ, the C-terminus of APP, LC3 and LTR, indicating accumulation of HS and APP/APP degradation products in enlarged autophagosomes/lysosomes. The SDS-PAGE of immunoisolates obtained from TNF-α-treated N2a cells by using anti-C-terminus of APP revealed the presence of SDS-stable complexes between HS and the C-terminal fragment of β-cleaved APP (βCTF) migrating in the range 10-18 kDa. Clustered accumulation of βCTF disappeared when HS release was prevented and slightly enhanced when HS release was increased. Hence, when proinflammatory cytokines induce increased processing of APP, inhibition of β-secretase by HS is insufficient, which may lead to the impaired autophagosomal degradation.
Fang Cheng, Lars-Åke Fransson, Katrin Mani

2340 related Products with: Proinflammatory cytokines induce accumulation of glypican-1-derived heparan sulfate and the C-terminal fragment of β-cleaved APP in autophagosomes of dividing neuronal cells.

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#31937505   2020/01/11 To Up

Different clinical and neuroimaging features of Japanese dementia siblings with a new N-terminal mutation (Val225Ala) of APP gene.

Autosomal dominant amyloid precursor protein (APP) mutations in familial Alzheimer's disease accelerate the amyloid beta (Aβ) pathology. Here we describe Japanese siblings with a new N-terminal mutation (a heterogeneous c.674T>C, p.Val225Ala) of the APP gene, developing a progressive dementia at 57 years and Aβ and tau pathologies in cerebrospinal fluid studies. However, the brother and sister showed different clinical and neuroimaging features, suggesting different Aβ pathologies for each sibling.
Yasuyuki Ohta, Nozomi Hishikawa, Ken Ikegami, Kota Sato, Yosuke Osakada, Mami Takemoto, Toru Yamashita, Yoshio Omote, Takeshi Ikeuchi, Koji Abe

1767 related Products with: Different clinical and neuroimaging features of Japanese dementia siblings with a new N-terminal mutation (Val225Ala) of APP gene.

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