APH-1

Last updated

anterior pharynx defective 1 homolog A (C. elegans)
Identifiers
SymbolAPH1A
NCBI gene 51107
HGNC 29509
OMIM 607629
RefSeq NM_016022
UniProt Q96BI3
Other data
Locus Chr. 1 p36.13-q31.3
Search for
Structures Swiss-model
Domains InterPro
anterior pharynx defective 1 homolog B (C. elegans)
Identifiers
SymbolAPH1B
NCBI gene 83464
HGNC 24080
OMIM 607630
RefSeq NM_031301
UniProt Q8WW43
Other data
Locus Chr. 15 q22.2
Search for
Structures Swiss-model
Domains InterPro

APH-1 (anterior pharynx-defective 1) is a protein originally identified in the round worm Caenorhabditis elegans as a regulator of the cell-surface localization of nicastrin in the Notch signaling pathway. [1]

Contents

APH-1 homologs in other organisms, including humans (APH1A and APH1B), have since been identified as components of the gamma secretase complex along with the catalytic subunit presenilin and the regulatory subunits nicastrin and PEN-2. The gamma-secretase complex is a multimeric protease responsible for the intramembrane proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). Gamma-secretase cleavage of APP is one of two proteolytic steps required to generate the peptide known as amyloid beta, whose misfolded form is implicated in the causation of Alzheimer's disease. [2] All of the components of the gamma-secretase complex undergo extensive post-translational modification, especially proteolytic activation; APH-1 and PEN-2 are regarded as regulators of the maturation process of the catalytic component presenilin. [3] APH-1 contains a conserved alpha helix interaction motif glycine-X-X-X-glycine (GXXXG) that is essential to both assembly of the gamma secretase complex and to the maturation of the components. [4]

Alternative splicing

In humans, the genes APH1A and APH1B encode the APH-1 proteins, which are integral components of the gamma-secretase complex, a multi-protein complex essential for the intramembrane cleavage of various substrates, including the amyloid precursor protein (APP) and Notch receptors. APH1A is located on chromosome 1q21.2, [5] while APH1B is found on chromosome 15q22.2. [6] Both genes exhibit alternative splicing, leading to the generation of multiple transcript variants that enhance the functional diversity of the gamma-secretase complex. [7] [8]

The alternative splicing of APH1A and APH1B contributes significantly to the regulation of gamma-secretase activity. Studies have shown that different isoforms of APH1 can modulate the cleavage of APP, influencing the production of amyloid-beta peptides, which are implicated in Alzheimer's disease. [9] [10] Moreover, the expression levels of these isoforms can vary in different tissues and under various pathological conditions, suggesting a complex regulatory mechanism that may have implications for diseases such as cancer and neurodegeneration. [11] [12] The involvement of APH1A and APH1B in the Notch signaling pathway further underscores their importance in developmental processes and cellular fate decisions, which can be disrupted in various cancers. [13] [14]

The functional versatility provided by the alternative splicing of APH1A and APH1B is crucial for the gamma-secretase complex's role in cellular signaling and proteolytic processing. For example, APH1A has been shown to be critical for the activity of the gamma-secretase complex, and its alternative splicing can influence the complex's substrate specificity and cleavage efficiency. [15] [16] Additionally, the interplay between APH1 isoforms and other components of the gamma-secretase complex, such as presenilins and nicastrin, is essential for maintaining the proper function of this protease. [17] [18]

Differences between APH1A and APH1B

Expression patterns

APH1A and APH1B, while homologous, exhibit distinct expression patterns across various tissues. APH1A is known for its ubiquitous expression, with significantly higher levels observed in the brain, heart, and skeletal muscle. [19] In contrast, APH1B displays a more restricted expression profile, being predominantly expressed in the brain and testis. [11] This differential expression suggests that APH1A may play a more generalized role in cellular processes, while APH1B could be more specialized, particularly in neural and reproductive tissues. Recent studies have highlighted the potential of APH1B as a peripheral biomarker for Alzheimer's disease (AD). Specifically, dysregulated expression levels of APH1B in peripheral blood have been associated with brain atrophy and amyloid-β deposition in AD patients. [20] This association indicates that APH1B could serve as a valuable indicator of disease progression, providing insights into the underlying pathological mechanisms of AD.

Gamma-secretase activity

Functional studies have demonstrated that APH1A- and APH1B-containing gamma-secretase complexes exhibit distinct effects on enzyme activity and substrate processing. Notably, complexes containing APH1B have been shown to produce higher amounts of amyloid-beta 42 (Aβ42), a peptide closely linked to the pathology of Alzheimer's disease, compared to those containing APH1A. [9] [21] This difference in Aβ42 production is significant, as elevated levels of this peptide are associated with the formation of amyloid plaques, a hallmark of AD. The variations in substrate specificity and activity between the two isoforms could influence critical biological processes, including the processing of amyloid precursor protein (APP) and Notch signaling pathways. For instance, studies suggest that the presence of APH1B may lead to a shift in the cleavage patterns of APP, potentially favoring the production of longer and more pathogenic Aβ species. [9] This altered processing could have profound implications for neuronal health and the progression of neurodegenerative diseases.

Structure

APH-1 proteins, which include APH1A and APH1B, are classified as polytopic membrane proteins characterized by the presence of seven transmembrane domains (TMDs). This structural feature is crucial for their integration into cellular membranes and their interaction with other components of the gamma-secretase complex. [14] [15] The topology of APH-1 enables it to span the lipid bilayer multiple times, effectively creating a scaffold that supports the assembly and stability of the gamma-secretase complex.

The seven TMDs of APH-1 facilitate its proper localization within the membrane, allowing it to interact with other integral membrane proteins, such as presenilin and nicastrin, which are also essential components of the gamma-secretase complex. The arrangement of these transmembrane domains is vital for the functional integrity of the complex, as it influences the accessibility of substrates and the catalytic activity of the gamma-secretase. [17] In addition to the transmembrane domains, APH-1 proteins contain a conserved GXXXG motif within their transmembrane regions. This motif is critical for mediating helix-helix interactions that are essential for the assembly of the gamma-secretase complex. [22] The GXXXG motif facilitates the dimerization of transmembrane helices, promoting the stability and functionality of the protein complex. Furthermore, APH-1 contains other conserved sequences that play significant roles in maintaining the protein's stability and facilitating interactions with nicastrin and presenilin. [18] These structural motifs and domains are not only important for the assembly of the gamma-secretase complex but also for its enzymatic activity. The interactions between APH-1 and other components are crucial for the proper processing of substrates, including amyloid precursor protein (APP) and Notch receptors, which are involved in critical cellular signaling pathways. [19] [11]

Regulation of expression

Transcriptional

The expression of APH-1 genes, which include APH1A and APH1B, is regulated by several transcription factors and signaling pathways. One significant pathway involved in this regulation is the Notch signaling pathway, which can modulate the expression of APH-1, creating a feedback loop that adjusts gamma-secretase activity according to cellular needs. [7] This interaction underscores the importance of APH-1 in cellular signaling and its potential role in maintaining homeostasis within the gamma-secretase complex.

Additionally, factors such as hypoxia-inducible factor (HIF) have been shown to influence APH-1 expression under specific physiological conditions, particularly in response to low oxygen levels. [8] This suggests that APH-1 may play a role in cellular adaptation to hypoxic environments, further emphasizing its regulatory complexity.

Post-translational modifications

Post-translational modifications (PTMs) of APH-1, including glycosylation and phosphorylation, significantly affect the protein's stability, localization, and interactions within the gamma-secretase complex. Glycosylation, for instance, is a major PTM that can influence protein folding, stability, and interactions with other proteins. [9] The addition of carbohydrate moieties can affect how APH-1 interacts with other components of the gamma-secretase complex, thereby impacting its overall function.

Phosphorylation is another critical PTM that can modulate APH-1 activity. It has been shown that phosphorylation can alter protein conformation, localization, and interaction dynamics, which are essential for the proper functioning of the gamma-secretase complex. [10] The interplay between different types of PTMs can create a complex regulatory network that fine-tunes APH-1 activity in response to various cellular signals and conditions.

Clinical significance

Altered expression of APH-1 genes has been investigated in the context of Alzheimer's disease and other neurological disorders. Variations in these genes may modulate disease risk or progression by affecting gamma-secretase activity and amyloid-beta production. [23] [24] Elevated expression of APH1B in peripheral blood has been associated with brain atrophy and increased amyloid-β deposition in Alzheimer's patients, indicating its potential as a biomarker. [24]

As a drug target

Targeting APH-1 offers a potential therapeutic avenue for modulating gamma-secretase activity without completely inhibiting its function. Small molecules or peptides that specifically disrupt APH-1 interactions within the complex could reduce amyloid-beta production while minimizing side effects. [25] Modulating the composition of the gamma-secretase complex to favor APH1A over APH1B may reduce the production of neurotoxic Aβ42 species. [26] [27]

Related Research Articles

<span class="mw-page-title-main">Notch signaling pathway</span> Series of molecular signals

The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.

<span class="mw-page-title-main">Amyloid beta</span> Group of peptides

Amyloid beta denotes peptides of 36–43 amino acids that are the main component of the amyloid plaques found in the brains of people with Alzheimer's disease. The peptides derive from the amyloid-beta precursor protein (APP), which is cleaved by beta secretase and gamma secretase to yield Aβ in a cholesterol-dependent process and substrate presentation. Both neurons and oligodendrocytes produce and release Aβ in the brain, contributing to formation of amyloid plaques. Aβ molecules can aggregate to form flexible soluble oligomers which may exist in several forms. It is now believed that certain misfolded oligomers can induce other Aβ molecules to also take the misfolded oligomeric form, leading to a chain reaction akin to a prion infection. The oligomers are toxic to nerve cells. The other protein implicated in Alzheimer's disease, tau protein, also forms such prion-like misfolded oligomers, and there is some evidence that misfolded Aβ can induce tau to misfold.

<span class="mw-page-title-main">Amyloid-beta precursor protein</span> Mammalian protein found in humans

Amyloid-beta precursor protein (APP) is an integral membrane protein expressed in many tissues and concentrated in the synapses of neurons. It functions as a cell surface receptor and has been implicated as a regulator of synapse formation, neural plasticity, antimicrobial activity, and iron export. It is coded for by the gene APP and regulated by substrate presentation. APP is best known as the precursor molecule whose proteolysis generates amyloid beta (Aβ), a polypeptide containing 37 to 49 amino acid residues, whose amyloid fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients.

<span class="mw-page-title-main">Amyloid-beta precursor protein secretase</span> Type of enzyme

Secretases are enzymes that "snip" pieces off a longer protein that is embedded in the cell membrane.

<span class="mw-page-title-main">Beta-secretase 1</span> Enzyme

Beta-secretase 1, also known as beta-site amyloid precursor protein cleaving enzyme 1, beta-site APP cleaving enzyme 1 (BACE1), membrane-associated aspartic protease 2, memapsin-2, aspartyl protease 2, and ASP2, is an enzyme that in humans is encoded by the BACE1 gene. Expression of BACE1 is observed mainly in neurons and oligodendrocytes.

Phospholipase D (EC 3.1.4.4, lipophosphodiesterase II, lecithinase D, choline phosphatase, PLD; systematic name phosphatidylcholine phosphatidohydrolase) is an anesthetic sensitive and mechanosensitive enzyme of the phospholipase superfamily that catalyses the following reaction

<span class="mw-page-title-main">Gamma secretase</span> Type of protein

Gamma secretase is a multi-subunit protease complex, an integral membrane protein, that cleaves single-pass transmembrane proteins at residues within the transmembrane domain. Proteases of this type are known as intramembrane proteases. The most well-known substrate of gamma secretase is amyloid precursor protein, a large integral membrane protein that, when cleaved by both gamma and beta secretase, produces a short 37-43 amino acid peptide called amyloid beta whose abnormally folded fibrillar form is the primary component of amyloid plaques found in the brains of Alzheimer's disease patients. Gamma secretase is also critical in the related processing of several other type I integral membrane proteins, such as Notch, ErbB4, E-cadherin, N-cadherin, ephrin-B2, or CD44.

<span class="mw-page-title-main">Presenilin</span> Family of related multi class transmembrane proteins

Presenilins are a family of related multi-pass transmembrane proteins which constitute the catalytic subunits of the gamma-secretase intramembrane protease protein complex. They were first identified in screens for mutations causing early onset forms of familial Alzheimer's disease by Peter St George-Hyslop. Vertebrates have two presenilin genes, called PSEN1 that codes for presenilin 1 (PS-1) and PSEN2 that codes for presenilin 2 (PS-2). Both genes show conservation between species, with little difference between rat and human presenilins. The nematode worm C. elegans has two genes that resemble the presenilins and appear to be functionally similar, sel-12 and hop-1.

<span class="mw-page-title-main">Alpha secretase</span> Family of proteolytic enzymes

Alpha secretases are a family of proteolytic enzymes that cleave amyloid precursor protein (APP) in its transmembrane region. Specifically, alpha secretases cleave within the fragment that gives rise to the Alzheimer's disease-associated peptide amyloid beta when APP is instead processed by beta secretase and gamma secretase. The alpha-secretase pathway is the predominant APP processing pathway. Thus, alpha-secretase cleavage precludes amyloid beta formation and is considered to be part of the non-amyloidogenic pathway in APP processing. Alpha secretases are members of the ADAM family, which are expressed on the surfaces of cells and anchored in the cell membrane. Several such proteins, notably ADAM10, have been identified as possessing alpha-secretase activity. Upon cleavage by alpha secretases, APP releases its extracellular domain - a fragment known as APPsα - into the extracellular environment in a process known as ectodomain shedding.

<span class="mw-page-title-main">Nicastrin</span>

Nicastrin, also known as NCSTN, is a protein that in humans is encoded by the NCSTN gene.

<span class="mw-page-title-main">PEN-2</span> Protein-coding gene in the species Homo sapiens

PSENEN, formally PEN-2, is a protein that is a regulatory component of the gamma secretase complex, a protease complex responsible for proteolysis of transmembrane proteins such as the Notch protein and amyloid precursor protein (APP). The gamma secretase complex consists of PEN-2, APH-1, nicastrin, and the catalytic subunit presenilin. PEN-2 is a 101-amino acid integral membrane protein likely with a topology such that both the N-terminus and the C-terminus face first the lumen of the endoplasmic reticulum and later the extracellular environment. Biochemical studies have shown that a conserved sequence motif D-Y-L-S-F at the C-terminus, as well as the overall length of the C-terminal tail, is required for the formation of an active gamma secretase complex.

<span class="mw-page-title-main">Low-density lipoprotein receptor-related protein 8</span> Cell surface receptor, part of the low-density lipoprotein receptor family

Low-density lipoprotein receptor-related protein 8 (LRP8), also known as apolipoprotein E receptor 2 (ApoER2), is a protein that in humans is encoded by the LRP8 gene. ApoER2 is a cell surface receptor that is part of the low-density lipoprotein receptor family. These receptors function in signal transduction and endocytosis of specific ligands. Through interactions with one of its ligands, reelin, ApoER2 plays an important role in embryonic neuronal migration and postnatal long-term potentiation. Another LDL family receptor, VLDLR, also interacts with reelin, and together these two receptors influence brain development and function. Decreased expression of ApoER2 is associated with certain neurological diseases.

<span class="mw-page-title-main">Presenilin-1</span> Protein-coding gene in the species Homo sapiens

Presenilin-1(PS-1) is a presenilin protein that in humans is encoded by the PSEN1 gene. Presenilin-1 is one of the four core proteins in the gamma secretase complex, which is considered to play an important role in generation of amyloid beta (Aβ) from amyloid-beta precursor protein (APP). Accumulation of amyloid beta is associated with the onset of Alzheimer's disease.

<span class="mw-page-title-main">Presenilin-2</span> Protein-coding gene in the species Homo sapiens

Presenilin-2 is a protein that is encoded by the PSEN2 gene.

<span class="mw-page-title-main">ADAM10</span> Protein-coding gene in the species Homo sapiens

A Disintegrin and metalloproteinase domain-containing protein 10, also known as ADAM10 or CDw156 or CD156c is a protein that in humans is encoded by the ADAM10 gene.

<span class="mw-page-title-main">APLP1</span> Protein-coding gene in the species Homo sapiens

Amyloid precursor like protein 1, also known as APLP1, is a protein encoded by the APLP1 gene in humans. APLP1 along with APLP2 are important modulators of glucose and insulin homeostasis.

Early-onset Alzheimer's disease (EOAD), also called younger-onset Alzheimer's disease (YOAD), is Alzheimer's disease diagnosed before the age of 65. It is an uncommon form of Alzheimer's, accounting for only 5–10% of all Alzheimer's cases. About 60% have a positive family history of Alzheimer's and 13% of them are inherited in an autosomal dominant manner. Most cases of early-onset Alzheimer's share the same traits as the "late-onset" form and are not caused by known genetic mutations. Little is understood about how it starts.

<span class="mw-page-title-main">Protein pigeon homolog</span> Protein-coding gene in the species Homo sapiens

Protein pigeon homolog also known as gamma-secretase activating protein (GSAP) is a protein that in humans is encoded by the PION gene.

Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral membrane proteins with multiple transmembrane domains, and they have their active sites buried within the lipid bilayer of cellular membranes. Intramembrane proteases are responsible for proteolytic cleavage in the cell signaling process known as regulated intramembrane proteolysis (RIP).

<span class="mw-page-title-main">P3 peptide</span>

p3 peptide also known as amyloid β- peptide (Aβ)17–40/42 is the peptide resulting from the α- and γ-secretase cleavage from the amyloid precursor protein (APP). It is known to be the major constituent of diffuse plaques observed in Alzheimer's disease (AD) brains and pre-amyloid plaques in people affected by Down syndrome. However, p3 peptide's role in these diseases is not truly known yet.

References

  1. ↑ Goutte C, Tsunozaki M, Hale VA, Priess JR (January 2002). "APH-1 is a multipass membrane protein essential for the Notch signaling pathway in Caenorhabditis elegans embryos". Proceedings of the National Academy of Sciences of the United States of America. 99 (2): 775–9. Bibcode:2002PNAS...99..775G. doi: 10.1073/pnas.022523499 . PMC   117381 . PMID   11792846.
  2. ↑ Kaether C, Haass C, Steiner H (2006). "Assembly, trafficking and function of gamma-secretase" (PDF). Neuro-Degenerative Diseases. 3 (4–5): 275–83. doi:10.1159/000095267. PMID   17047368. S2CID   17324271.
  3. ↑ Luo WJ, Wang H, Li H, Kim BS, Shah S, Lee HJ, et al. (March 2003). "PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1". The Journal of Biological Chemistry. 278 (10): 7850–4. doi: 10.1074/jbc.C200648200 . PMID   12522139.
  4. ↑ Lee SF, Shah S, Yu C, Wigley WC, Li H, Lim M, et al. (February 2004). "A conserved GXXXG motif in APH-1 is critical for assembly and activity of the gamma-secretase complex". The Journal of Biological Chemistry. 279 (6): 4144–52. doi: 10.1074/jbc.M309745200 . PMID   14627705.
  5. ↑ "APH1A aph-1 homolog A, gamma-secretase subunit [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-12-05.
  6. ↑ "APH1B aph-1 homolog B, gamma-secretase subunit [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2024-12-05.
  7. 1 2 Todd NK, Huang Y, Lee JY, Doruker P, Krieger JM, Salisbury R, et al. (July 2022). "GPCR kinases generate an APH1A phosphorylation barcode to regulate amyloid-β generation". Cell Reports. 40 (3): 111110. doi:10.1016/j.celrep.2022.111110. PMC   9373432 . PMID   35858570.
  8. 1 2 Zhao G, Liu Z, Ilagan MX, Kopan R (February 2010). "Gamma-secretase composed of PS1/Pen2/Aph1a can cleave notch and amyloid precursor protein in the absence of nicastrin". The Journal of Neuroscience. 30 (5): 1648–1656. doi:10.1523/JNEUROSCI.3826-09.2010. PMC   2853942 . PMID   20130175.
  9. 1 2 3 4 Lessard CB, Cottrell BA, Maruyama H, Suresh S, Golde TE, Koo EH (2015-12-17). "γ-Secretase Modulators and APH1 Isoforms Modulate γ-Secretase Cleavage but Not Position of ε-Cleavage of the Amyloid Precursor Protein (APP)". PLOS ONE. 10 (12): e0144758. doi: 10.1371/journal.pone.0144758 . PMC   4683055 . PMID   26678856.
  10. 1 2 Lu P, Bai XC, Ma D, Xie T, Yan C, Sun L, et al. (August 2014). "Three-dimensional structure of human γ-secretase". Nature. 512 (7513): 166–170. Bibcode:2014Natur.512..166L. doi:10.1038/nature13567. PMC   4134323 . PMID   25043039.
  11. 1 2 3 Peltonen HM, Haapasalo A, Hiltunen M, Kataja V, Kosma VM, Mannermaa A (2013-11-01). "Γ-secretase components as predictors of breast cancer outcome". PLOS ONE. 8 (11): e79249. Bibcode:2013PLoSO...879249P. doi: 10.1371/journal.pone.0079249 . PMC   3815159 . PMID   24223915.
  12. ↑ Song C, Zhang J, Xu C, Gao M, Li N, Geng Q (2023-10-02). "The critical role of γ-secretase and its inhibitors in cancer and cancer therapeutics". International Journal of Biological Sciences. 19 (16): 5089–5103. doi:10.7150/ijbs.87334. PMC   10620818 . PMID   37928268.
  13. ↑ Wang S, Wu M, Ma S (August 2019). "Integrative Analysis of Cancer Omics Data for Prognosis Modeling". Genes. 10 (8): 604. doi: 10.3390/genes10080604 . PMC   6727084 . PMID   31405076.
  14. 1 2 Barbosa-Silva A, Magalhães M, Da Silva GF, Da Silva FA, Carneiro FR, Carels N (May 2022). "A Data Science Approach for the Identification of Molecular Signatures of Aggressive Cancers". Cancers. 14 (9): 2325. doi: 10.3390/cancers14092325 . PMC   9103663 . PMID   35565454.
  15. 1 2 Privitera AP, Barresi V, Condorelli DF (March 2021). "Aberrations of Chromosomes 1 and 16 in Breast Cancer: A Framework for Cooperation of Transcriptionally Dysregulated Genes". Cancers. 13 (7): 1585. doi: 10.3390/cancers13071585 . PMC   8037453 . PMID   33808143.
  16. ↑ Haapasalo A, Kovacs DM (2011-01-01). "The many substrates of presenilin/γ-secretase". Journal of Alzheimer's Disease. 25 (1): 3–28. doi:10.3233/JAD-2011-101065. PMC   3281584 . PMID   21335653.
  17. 1 2 Meckler X, Checler F (June 2016). "Presenilin 1 and Presenilin 2 Target γ-Secretase Complexes to Distinct Cellular Compartments". The Journal of Biological Chemistry. 291 (24): 12821–12837. doi: 10.1074/jbc.M115.708297 . PMC   4933450 . PMID   27059953.
  18. 1 2 Johnson DS, Li YM, Pettersson M, St George-Hyslop PH (December 2017). "Structural and Chemical Biology of Presenilin Complexes". Cold Spring Harbor Perspectives in Medicine. 7 (12): a024067. doi:10.1101/cshperspect.a024067. PMC   5710098 . PMID   28320827.
  19. 1 2 Ali A (2018). "Isoflurane Induces Neurodegenerative Changes in Retinal Pigment Epithelial Cells" (PDF). Open Access Journal of Ophthalmology. 3 (2). doi:10.23880/OAJO-16000146.
  20. ↑ Park YH, Pyun JM, Hodges A, Jang JW, Bice PJ, Kim S, et al. (November 2021). "Dysregulated expression levels of APH1B in peripheral blood are associated with brain atrophy and amyloid-β deposition in Alzheimer's disease". Alzheimer's Research & Therapy. 13 (1): 183. doi: 10.1186/s13195-021-00919-z . PMC   8567578 . PMID   34732252.
  21. ↑ Acx H, Chávez-Gutiérrez L, Serneels L, Lismont S, Benurwar M, Elad N, et al. (February 2014). "Signature amyloid β profiles are produced by different γ-secretase complexes". The Journal of Biological Chemistry. 289 (7): 4346–4355. doi: 10.1074/jbc.M113.530907 . PMC   3924297 . PMID   24338474.
  22. ↑ Haapasalo A, Kovacs DM (2011-01-01). "The many substrates of presenilin/γ-secretase". Journal of Alzheimer's Disease. 25 (1): 3–28. doi:10.3233/JAD-2011-101065. PMC   3281584 . PMID   21335653.
  23. ↑ Wang XN, Yang J, Xu PY, Chen J, Zhang D, Sun Y, et al. (2011-12-16), "Construction of Drug Screening Cell Model and Application to New Compounds Interfering Production and Accumulation of Beta-Amyloid by Inhibiting Gamma-Secretase", Advanced Understanding of Neurodegenerative Diseases, IntechOpen, doi:10.5772/27974, ISBN   978-953-307-529-7 , retrieved 2024-12-03
  24. 1 2 Qin W, Jia L, Zhou A, Zuo X, Cheng Z, Wang F, et al. (August 2011). "The -980C/G polymorphism in APH-1A promoter confers risk of Alzheimer's disease". Aging Cell. 10 (4): 711–719. doi: 10.1111/j.1474-9726.2011.00708.x . PMID   21443683.
  25. ↑ Wong E, Frost GR, Li YM (2020-12-02). "γ-Secretase Modulatory Proteins: The Guiding Hand Behind the Running Scissors". Frontiers in Aging Neuroscience. 12: 614690. doi: 10.3389/fnagi.2020.614690 . PMC   7738330 . PMID   33343338.
  26. ↑ Lee J, Song L, Terracina G, Bara T, Josien H, Asberom T, et al. (June 2011). "Identification of presenilin 1-selective γ-secretase inhibitors with reconstituted γ-secretase complexes". Biochemistry. 50 (22): 4973–4980. doi:10.1021/bi200026m. PMID   21528914.
  27. ↑ Sannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar AK, et al. (June 2016). "Restricted Location of PSEN2/γ-Secretase Determines Substrate Specificity and Generates an Intracellular Aβ Pool". Cell. 166 (1): 193–208. doi:10.1016/j.cell.2016.05.020. PMC   7439524 . PMID   27293189.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.