Transgenic Expression of the Amyloid-β Precursor Protein-Intracellular Domain Does Not Induce Alzheimer's Disease–Like Traits In Vivo

Amyloid-β (Aβ) deposition is a major pathological hallmark of Alzheimer's disease. Gleevec, a known tyrosine kinase inhibitor, has been shown to lower Aβ secretion, and it is considered a potential basis for novel therapies for Alzheimer's disease. Here, we show that Gleevec decreases Aβ levels without the inhibition of Notch cleavage by a mechanism distinct from γ-secretase inhibition. Gleevec does not influence γ-secretase activity in vitro; however, treatment of cell lines leads to a dose-dependent increase in the amyloid precursor protein intracellular domain (AICD), whereas secreted Aβ is decreased. This effect is observed even in presence of a potent γ-secretase inhibitor, suggesting that Gleevec does not activate AICD generation but instead may slow down AICD turnover. Concomitant with the increase in AICD, Gleevec leads to elevated mRNA and protein levels of the Aβ-degrading enzyme neprilysin, a potential target gene of AICD-regulated transcription. Thus, the Gleevec mediated-increase in neprilysin expression may involve enhanced AICD signaling. The finding that Gleevec elevates neprilysin levels suggests that its Aβ-lowering effect may be caused by increased Aβ-degradation.

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Potential Natural Products for Alzheimer’s Disease: Targeted Search Using the Internal Ribosome Entry Site of Tau and Amyloid-β Precursor Protein

International Journal of Molecular Sciences ◽

10.3390/ijms16048789 ◽

2015 ◽

Vol 16 (12) ◽

pp. 8789-8810 ◽

Cited By ~ 4

Author(s):

Yun-Chieh Tasi ◽

Ting-Yu Chin ◽

Ying-Ju Chen ◽

Chun-Chih Huang ◽

Shou-Lun Lee ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Natural Products ◽

Internal Ribosome Entry Site ◽

Amyloid Β ◽

Precursor Protein ◽

Entry Site ◽

Internal Ribosome Entry

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Effects of Huanglian-Jie-Du-Tang and Its Modified Formula on the Modulation of Amyloid-β Precursor Protein Processing in Alzheimer's Disease Models

PLoS ONE ◽

10.1371/journal.pone.0092954 ◽

2014 ◽

Vol 9 (3) ◽

pp. e92954 ◽

Cited By ~ 19

Author(s):

Siva Sundara Kumar Durairajan ◽

Ying-Yu Huang ◽

Pui-Yee Yuen ◽

Lei-Lei Chen ◽

Ka-Yan Kwok ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Protein Processing ◽

Precursor Protein ◽

Disease Models ◽

Modified Formula

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A Numerical Study of Sensitivity Coefficients for a Model of Amyloid Precursor Protein and Tubulin-Associated Unit Protein Transport and Agglomeration in Neurons at the Onset of Alzheimer's Disease

Journal of Biomechanical Engineering ◽

10.1115/1.4041905 ◽

2019 ◽

Vol 141 (3) ◽

Cited By ~ 2

Author(s):

I. A. Kuznetsov ◽

A. V. Kuznetsov

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Tau Protein ◽

Protein Transport ◽

Numerical Study ◽

Amyloid Β ◽

Precursor Protein ◽

Model Parameters ◽

In The Beginning

Modeling of intracellular processes occurring during the development of Alzheimer's disease (AD) can be instrumental in understanding the disease and can potentially contribute to finding treatments for the disease. The model of intracellular processes in AD, which we previously developed, contains a large number of parameters. To distinguish between more important and less important parameters, we performed a local sensitivity analysis of this model around the values of parameters that give the best fit with published experimental results. We show that the influence of model parameters on the total concentrations of amyloid precursor protein (APP) and tubulin-associated unit (tau) protein in the axon is reciprocal to the influence of the same parameters on the average velocities of the same proteins during their transport in the axon. The results of our analysis also suggest that in the beginning of AD the aggregation of amyloid-β and misfolded tau protein have little effect on transport of APP and tau in the axon, which suggests that early damage in AD may be reversible.

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

International Journal of Alzheimer s Disease ◽

10.1155/2012/353145 ◽

2012 ◽

Vol 2012 ◽

pp. 1-10 ◽

Cited By ~ 7

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.

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Application of optogenetic Amyloid-β distinguishes between metabolic and physical damages in neurodegeneration

eLife ◽

10.7554/elife.52589 ◽

2020 ◽

Vol 9 ◽

Cited By ~ 3

Author(s):

Chu Hsien Lim ◽

Prameet Kaur ◽

Emelyne Teo ◽

Vanessa Yuk Man Lam ◽

Fangchen Zhu ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Disease Progression ◽

Biological Effects ◽

Amyloid Β ◽

Tissue Loss ◽

Amyloid Β Peptide ◽

Physical Damage ◽

Living Tissues

The brains of Alzheimer’s disease patients show a decrease in brain mass and a preponderance of extracellular Amyloid-β plaques. These plaques are formed by aggregation of polypeptides that are derived from the Amyloid Precursor Protein (APP). Amyloid-β plaques are thought to play either a direct or an indirect role in disease progression, however the exact role of aggregation and plaque formation in the aetiology of Alzheimer’s disease (AD) is subject to debate as the biological effects of soluble and aggregated Amyloid-β peptides are difficult to separate in vivo. To investigate the consequences of formation of Amyloid-β oligomers in living tissues, we developed a fluorescently tagged, optogenetic Amyloid-β peptide that oligomerizes rapidly in the presence of blue light. We applied this system to the crucial question of how intracellular Amyloid-β oligomers underlie the pathologies of A. We use Drosophila, C. elegans and D. rerio to show that, although both expression and induced oligomerization of Amyloid-β were detrimental to lifespan and healthspan, we were able to separate the metabolic and physical damage caused by light-induced Amyloid-β oligomerization from Amyloid-β expression alone. The physical damage caused by Amyloid-β oligomers also recapitulated the catastrophic tissue loss that is a hallmark of late AD. We show that the lifespan deficit induced by Amyloid-β oligomers was reduced with Li+ treatment. Our results present the first model to separate different aspects of disease progression.

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

10.1101/616540 ◽

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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Elevated Expression of MiR-17 in Microglia of Alzheimer’s Disease Patients Abrogates Autophagy-Mediated Amyloid-β Degradation

Frontiers in Immunology ◽

10.3389/fimmu.2021.705581 ◽

2021 ◽

Vol 12 ◽

Author(s):

Shady Estfanous ◽

Kylene P. Daily ◽

Mostafa Eltobgy ◽

Nicholas P. Deems ◽

Midhun N. K. Anne ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Β ◽

Therapeutic Interventions ◽

Tissue Sections ◽

Cargo Receptor ◽

5Xfad Mouse ◽

Aβ Degradation

Autophagy is a proposed route of amyloid-β (Aβ) clearance by microglia that is halted in Alzheimer’s Disease (AD), though mechanisms underlying this dysfunction remain elusive. Here, primary microglia from adult AD (5xFAD) mice were utilized to demonstrate that 5xFAD microglia fail to degrade Aβ and express low levels of autophagy cargo receptor NBR1. In 5xFAD mouse brains, we show for the first time that AD microglia express elevated levels of microRNA cluster Mirc1/Mir17-92a, which is known to downregulate autophagy proteins. By in situ hybridization in post-mortem AD human tissue sections, we observed that the Mirc1/Mir17-92a cluster member miR-17 is also elevated in human AD microglia, specifically in the vicinity of Aβ deposits, compared to non-disease controls. We show that NBR1 expression is negatively correlated with expression of miR-17 in human AD microglia via immunohistopathologic staining in human AD brain tissue sections. We demonstrate in healthy microglia that autophagy cargo receptor NBR1 is required for Aβ degradation. Inhibiting elevated miR-17 in 5xFAD mouse microglia improves Aβ degradation, autophagy, and NBR1 puncta formation in vitro and improves NBR1 expression in vivo. These findings offer a mechanism behind dysfunctional autophagy in AD microglia which may be useful for therapeutic interventions aiming to improve autophagy function in AD.

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MMP13 inhibition rescues cognitive decline in Alzheimer transgenic mice via BACE1 regulation

Brain ◽

10.1093/brain/awy305 ◽

2018 ◽

Vol 142 (1) ◽

pp. 176-192 ◽

Cited By ~ 13

Author(s):

Bing-Lin Zhu ◽

Yan Long ◽

Wei Luo ◽

Zhen Yan ◽

Yu-Jie Lai ◽

...

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Therapeutic Potential ◽

Amyloid Β ◽

Translation Initiation Factor ◽

Precursor Protein ◽

Initiation Factor ◽

Luciferase Reporter ◽

Protein Levels ◽

Model Of Alzheimer’S Disease

AbstractMMP13 (matrix metallopeptidase 13) plays a key role in bone metabolism and cancer development, but has no known functions in Alzheimer’s disease. In this study, we used high-throughput small molecule screening in SH-SY5Y cells that stably expressed a luciferase reporter gene driven by the BACE1 (β-site amyloid precursor protein cleaving enzyme 1) promoter, which included a portion of the 5′ untranslated region (5′UTR). We identified that CL82198, a selective inhibitor of MMP13, decreased BACE1 protein levels in cultured neuronal cells. This effect was dependent on PI3K (phosphatidylinositide 3-kinase) signalling, and was unrelated to BACE1 gene transcription and protein degradation. Further, we found that eukaryotic translation initiation factor 4B (eIF4B) played a key role, as the mutation of eIF4B at serine 422 (S422R) or deletion of the BACE1 5′UTR attenuated MMP13-mediated BACE1 regulation. In APPswe/PS1E9 mice, an animal model of Alzheimer’s disease, hippocampal Mmp13 knockdown or intraperitoneal CL82198 administration reduced BACE1 protein levels and the related amyloid-β precursor protein processing, amyloid-β load and eIF4B phosphorylation, whereas spatial and associative learning and memory performances were improved. Collectively, MMP13 inhibition/CL82198 treatment exhibited therapeutic potential for Alzheimer’s disease, via the translational regulation of BACE1.

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