scholarly journals Enhanced β-secretase processing of amyloid precursor protein in the skeletal muscle of ALS animal models

2018 ◽  
Author(s):  
Huaqiang Yang
Keyword(s):  
Skeletal Muscle ◽  
Animal Models ◽  
Amyloid Precursor Protein ◽  
Neurodegenerative Disorder ◽  
Precursor Protein ◽  
Pathological Feature ◽  
App Processing ◽  
Regulated Expression ◽  
Selective Change ◽  
Lateral Sclerosis

ABSTRACTAmyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disorder primarily characterized by motor neuron degeneration and muscle paralysis. Several studies indicate that pathological changes in the skeletal muscle contribute to disease progression. We report a significant increase of β-secretase processing of amyloid precursor protein (APP) in the skeletal muscle but not the spinal cord or cerebral cortex of hSOD1 (G93A) transgenic ALS mouse models. Enhanced β-secretase processing of APP was manifested by up-regulated expression of βCTF, the 22-kd CTF of APP, and β-secretase processing enzyme, BACE1. Morphological analysis demonstrated that enhanced β-secretase processing of APP mainly occurred in the atrophic myofibers of ALS mice. We also observed a similar change in APP processing in an hSOD1 (G93A) transgenic ALS pig model, suggesting that enhanced β-secretase processing of APP in skeletal muscle may be a common pathological feature of ALS. These findings reveal a selective change in APP processing in skeletal muscle of ALS animal models, and highlight the involvement of aberrant APP processing in ALS pathogenesis.

The Absence of Myelin Basic Protein Reduces Non-Amyloidogenic Processing of Amyloid Precursor Protein

2021 ◽  
Vol 18 ◽  
Author(s):  
Chika Seiwa ◽  
Ichiro Sugiyama ◽  
Makoto Sugawa ◽  
Hiroaki Murase ◽  
Chiaki Kudoh ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Myelin Basic Protein ◽  
Basic Protein ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Amyloid Β Protein ◽  
Pathological Feature ◽  
Novel Therapy ◽  
App Processing ◽  
App Metabolism

Background: The accumulation of amyloid β-protein (Aβ) in the brain is a pathological feature of Alzheimer’s disease (AD). Aβ peptides originate from amyloid precursor protein (APP). APP can be proteolytically cleaved through amyloidogenic or non-amyloidogenic pathways. The molecular effects on APP metabolism / processing may be influenced by myelin and the breakdown of myelin basic protein (MBP) in AD patients and mouse models of AD pathology. Methods: We directly tested whether MBP can alter influence APP processing in MBP-/- mice, known as Shiverer (shi/shi) mice, in which no functional MBP is produced due to gene breakage from the middle of MBP exon II. Results: A significant reduction of the cerebral sAPPα level in Shiverer (shi/shi) mice was found, although the levels of both total APP and sAPPβ remain unchanged. The reduction of sAPPα was considered to be due to the changes in the expression levels of a disintegrin and metalloproteinase-9 (ADAM9) catalysis and non-amyloid genic processing of APP in the absence of MBP because it binds to ADAM9. MBP -/- mice exhibited increased Aβ oligomer production. Conclusion: Together, these findings suggest that in the absence of MBP, there is a marked reduction of non-amyloidogenic APP processing to sAPPα, and targeting myelin of oligodendrocytes may be a novel therapy for the prevention and treatment of AD.

scholarly journals Secretases Related to Amyloid Precursor Protein Processing

Membranes ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 983
Author(s):  
Xiaoling Liu ◽  
Yan Liu ◽  
Shangrong Ji
Keyword(s):  
Amyloid Precursor Protein ◽  
Drug Targets ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
Pathological Feature ◽  
App Processing ◽  
New Directions ◽  
Processing Pathways ◽  
Potential Drug Targets

Alzheimer’s disease (AD) is a common neurodegenerative disease whose prevalence increases with age. An increasing number of findings suggest that abnormalities in the metabolism of amyloid precursor protein (APP), a single transmembrane aspartic protein that is cleaved by β- and γ-secretases to produce β-amyloid protein (Aβ), are a major pathological feature of AD. In recent years, a large number of studies have been conducted on the APP processing pathways and the role of secretion. This paper provides a summary of the involvement of secretases in the processing of APP and the potential drug targets that could provide new directions for AD therapy.

scholarly journals Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1807
Author(s):  
Filomena Iannuzzi ◽  
Rossana Sirabella ◽  
Nadia Canu ◽  
Thorsten J. Maier ◽  
Lucio Annunziato ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Tyrosine Kinase ◽  
Amyloid Precursor Protein ◽  
Neurodegenerative Disorder ◽  
Amyloid Β ◽  
Adaptor Protein ◽  
Precursor Protein ◽  
App Processing ◽  
Fyn Tyrosine Kinase

Alzheimer’s disease (AD) is an incurable neurodegenerative disorder with a few early detection strategies. We previously proposed the amyloid precursor protein (APP) tyrosine 682 (Tyr682) residue as a valuable target for the development of new innovative pharmacologic or diagnostic interventions in AD. Indeed, when APP is phosphorylated at Tyr682, it is forced into acidic neuronal compartments where it is processed to generate neurotoxic amyloid β peptides. Of interest, Fyn tyrosine kinase (TK) interaction with APP Tyr682 residue increases in AD neurons. Here we proved that when Fyn TK was overexpressed it elicited APP Tyr682 phosphorylation in neurons from healthy donors and promoted the amyloidogenic APP processing with Aβ peptides accumulation and neuronal death. Phosphorylation of APP at Tyr (pAPP-Tyr) increased in neurons of AD patients and AD neurons that exhibited high pAPP-Tyr also had higher Fyn TK activity. Fyn TK inhibition abolished the pAPP-Tyr and reduced Aβ42 secretion in AD neurons. In addition, the multidomain adaptor protein Fe65 controlled the Fyn-mediated pAPP-Tyr, warranting the possibility of targeting the Fe65-APP-Fyn pathway to develop innovative strategies in AD. Altogether, these results strongly emphasize the relevance of focusing on pAPP Tyr682 either for diagnostic purposes, as an early biomarker of the disease, or for pharmacological targeting, using Fyn TKI.

scholarly journals The Skeletal Muscle Emerges as a New Disease Target in Amyotrophic Lateral Sclerosis

2021 ◽  
Vol 11 (7) ◽  
pp. 671
Author(s):  
Oihane Pikatza-Menoio ◽  
Amaia Elicegui ◽  
Xabier Bengoetxea ◽  
Neia Naldaiz-Gastesi ◽  
Adolfo López de Munain ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Amyotrophic Lateral Sclerosis ◽  
Muscle Tissue ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Disease Onset ◽  
Fine Tuning ◽  
Current State ◽  
The Central Nervous System ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder that leads to progressive degeneration of motor neurons (MNs) and severe muscle atrophy without effective treatment. Most research on ALS has been focused on the study of MNs and supporting cells of the central nervous system. Strikingly, the recent observations of pathological changes in muscle occurring before disease onset and independent from MN degeneration have bolstered the interest for the study of muscle tissue as a potential target for delivery of therapies for ALS. Skeletal muscle has just been described as a tissue with an important secretory function that is toxic to MNs in the context of ALS. Moreover, a fine-tuning balance between biosynthetic and atrophic pathways is necessary to induce myogenesis for muscle tissue repair. Compromising this response due to primary metabolic abnormalities in the muscle could trigger defective muscle regeneration and neuromuscular junction restoration, with deleterious consequences for MNs and thereby hastening the development of ALS. However, it remains puzzling how backward signaling from the muscle could impinge on MN death. This review provides a comprehensive analysis on the current state-of-the-art of the role of the skeletal muscle in ALS, highlighting its contribution to the neurodegeneration in ALS through backward-signaling processes as a newly uncovered mechanism for a peripheral etiopathogenesis of the disease.

Cell line construction and maintenance for Lyso-IP and Endo-IP analysis of amyloid precursor protein processing v1

2021 ◽  
Author(s):  
Hankum Park ◽  
Frances V Hundley ◽  
Harper JW
Keyword(s):  
Amyloid Precursor Protein ◽  
Cell Line ◽  
Quantitative Proteomics ◽  
Protein Processing ◽  
Precursor Protein ◽  
Amyloid Precursor Protein Processing ◽  
App Processing ◽  
293 Cells ◽  
Line Construction ◽  
App Gene

Lyso-IP is a method that allows for the isolation of lysosomes for proteomics and metabolomics (dx.doi.org/10.17504/protocols.io.bybjpskn; dx.doi.org/10.17504/protocols.io.bx9hpr36). We have developed an analogous approach for purification of early/sorting endosomes (Endo-IP). In addition, we have found that endolysosomal purification via Lyso-IP and Endo-IP can be coupled with a quantitative proteomics workflow to obtain snapshots of Amyloid Precursor Protein (APP) processing to its Aβ products (Park et al. in submission). Here, we describe methods for cell line construction and maintenance of 293 cells with TMEM192-3xHA and 3xFLAG-EEA1, which are used for lysosome and endosome purification, respectively, with the addition of patient mutations to APP promotes processing. Cells with endogenously tagged TMEM192 and stably expressing FLAG-EEA1 are referred to as 293EL cells, for Endo-IP and Lyso-IP. These cells were also prepared in a form that has a deletion of the APP gene (293EL;APP-/-) and the same cells reconstituted with a lentivirus stably expressing APPSw;T700N to allow functional analysis of APP processing.

The amyloid precursor protein (APP) processing as a biological link between Alzheimer’s disease and cancer

2019 ◽  
Vol 49 ◽  
pp. 83-91 ◽  
Author(s):  
Fernando Galvão ◽  
Kamila Castro Grokoski ◽  
Bruno Batista da Silva ◽  
Marcelo Lazzaron Lamers ◽  
Ionara Rodrigues Siqueira
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
App Processing

scholarly journals Distinct anterograde trafficking pathways of BACE1 and amyloid precursor protein from the TGN and the regulation of amyloid-β production

2020 ◽  
Vol 31 (1) ◽  
pp. 27-44 ◽  
Author(s):  
Jing Zhi A. Tan ◽  
Lou Fourriere ◽  
Jingqi Wang ◽  
Franck Perez ◽  
Gaelle Boncompain ◽  
...  
Keyword(s):  
Amyloid Precursor Protein ◽  
Secretory Pathway ◽  
Amyloid Β ◽  
Precursor Protein ◽  
Primary Neurons ◽  
App Processing

The anterograde trafficking of BACE1 and the potential processing of amyloid precursor protein along the secretory pathway remain poorly defined. Our findings reveal that Golgi exit of BACE1 and APP in primary neurons is tightly regulated, resulting in their segregation along different transport routes, which limits APP processing.

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.

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