Amyloid-beta precursor protein

Last updated

APP
PBB Protein APP image.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases APP , AAA, ABETA, ABPP, AD1, APPI, CTFgamma, CVAP, PN-II, PN2, amyloid beta precursor protein, preA4, alpha-sAPP
External IDs OMIM: 104760; MGI: 88059; HomoloGene: 56379; GeneCards: APP; OMA:APP - orthologs
Orthologs
SpeciesHumanMouse
Entrez

351

11820

Ensembl

ENSG00000142192

ENSMUSG00000022892

UniProt

P05067

P12023

RefSeq (mRNA)

NM_001198823
NM_001198824
NM_001198825
NM_001198826
NM_007471

RefSeq (protein)

NP_001185752
NP_001185753
NP_001185754
NP_001185755
NP_031497

Location (UCSC) Chr 21: 25.88 – 26.17 Mb Chr 16: 84.75 – 84.97 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
(a) A low magnification image immediately after co-injection of red negatively charged and green glycine-conjugated beads showing the injection site, marked with an oil droplet, appearing as a round yellow sphere. Overlap of red and green fluorescence produces a yellow image. (b) At 50 min after injection, the red carboxylated beads have progressed in the anterograde direction (to the right) while the green glycine-conjugated beads have made no progress. (c)-(e) An axon co-injected with red APP-C beads and green glycine beads and imaged for 100 frames at 4 s intervals at 40x magnification. (c) Red channel (left) first frame; (center) 50 frames superimposed; (right) all 100 frames superimposed. Note the progression of individual beads towards the right, anterograde, side of the injection site heading towards the presynaptic terminal. (d) Two images of the green channel from the same video sequence; (left) first frame; (center) 100 frames superimposed. Note the lack of significant movement of the green glycine beads. (e) Both red and green channels from 100 frames superimposed of the same video as in (c) and (d). (f) Single bead trajectories at high magnification from a set of superimposed frames showing movements of beads. Relative transport of negatively charged, APP-C and glycine beads in the squid giant axon.jpg
(a) A low magnification image immediately after co-injection of red negatively charged and green glycine-conjugated beads showing the injection site, marked with an oil droplet, appearing as a round yellow sphere. Overlap of red and green fluorescence produces a yellow image. (b) At 50 min after injection, the red carboxylated beads have progressed in the anterograde direction (to the right) while the green glycine-conjugated beads have made no progress. (c)–(e) An axon co-injected with red APP-C beads and green glycine beads and imaged for 100 frames at 4 s intervals at 40× magnification. (c) Red channel (left) first frame; (center) 50 frames superimposed; (right) all 100 frames superimposed. Note the progression of individual beads towards the right, anterograde, side of the injection site heading towards the presynaptic terminal. (d) Two images of the green channel from the same video sequence; (left) first frame; (center) 100 frames superimposed. Note the lack of significant movement of the green glycine beads. (e) Both red and green channels from 100 frames superimposed of the same video as in (c) and (d). (f) Single bead trajectories at high magnification from a set of superimposed frames showing movements of beads.

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 [5] and has been implicated as a regulator of synapse formation, [6] neural plasticity, [7] antimicrobial activity, [8] and iron export. [9] It is coded for by the gene APP and regulated by substrate presentation. [10] 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.

Genetics

Amyloid-beta precursor protein is an ancient and highly conserved protein. [11] In humans, the gene APP is located on chromosome 21 and contains 18 exons spanning 290 kilobases. [12] [13] Several alternative splicing isoforms of APP have been observed in humans, ranging in length from 639 to 770 amino acids, with certain isoforms preferentially expressed in neurons; changes in the neuronal ratio of these isoforms have been associated with Alzheimer's disease. [14] Homologous proteins have been identified in other organisms such as Drosophila (fruit flies), C. elegans (roundworms), [15] and all mammals. [16] The amyloid beta region of the protein, located in the membrane-spanning domain, is not well conserved across species and has no obvious connection with APP's native-state biological functions. [16]

Mutations in critical regions of amyloid precursor protein, including the region that generates amyloid beta (Aβ), cause familial susceptibility to Alzheimer's disease. [17] [18] [19] [20] For example, several mutations outside the Aβ region associated with familial Alzheimer's have been found to dramatically increase production of Aβ. [21]

A mutation (A673T) in the APP gene protects against Alzheimer's disease. This substitution is adjacent to the beta secretase cleavage site and results in a 40% reduction in the formation of amyloid beta in vitro. [22]

Structure

The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the Cu(I) bound, Cu(II) bound, and unbound conformations, which differ by only small changes in orientation. 2fjz app.png
The metal-binding domain of APP with a bound copper ion. The side chains of the two histidine and one tyrosine residues that play a role in metal coordination are shown in the Cu(I) bound, Cu(II) bound, and unbound conformations, which differ by only small changes in orientation.
The extracellular E2 domain, a dimeric coiled coil and one of the most highly conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans. 1rw6 e2 app.png
The extracellular E2 domain, a dimeric coiled coil and one of the most highly conserved regions of the protein from Drosophila to humans. This domain, which resembles the structure of spectrin, is thought to bind heparan sulfate proteoglycans.

A number of different structural domains that fold mostly on their own have been found in the APP sequence. The extracellular region, much larger than the intracellular region, is divided into the E1 and E2 domains, linked by an acidic domain (AcD); E1 contains two subdomains including a growth factor-like domain (GFLD) and a copper-binding domain (CuBD) interacting tightly together. [24] A serine protease inhibitor domain, absent from the isoform differentially expressed in the brain, is found between acidic region and E2 domain. [25] The complete crystal structure of APP has not yet been solved; however, individual domains have been successfully crystallized, the growth factor-like domain, [26] the copper-binding domain, [27] the complete E1 domain [24] and the E2 domain. [23]

Isoform diversity

Amyloid-beta precursor protein is highly versatile with several isoforms generated through alternative splicing of its mRNA. The primary isoforms include APP695, APP751, and APP770, differing in their inclusion of certain exons, mainly exon 7 and 8. APP695 is predominantly expressed in neuronal cells and is crucial for normal neuronal function. APP751 and APP770 are more widely expressed in non-neuronal tissues but exhibit distinct expression patterns during neuron differentiation. [28] The differential expression of these isoforms plays a significant role in cellular processes such as neurodevelopment, synaptic plasticity, and the pathogenesis of Alzheimer's disease. Understanding the isoform diversity of APP is essential for deciphering its various physiological and pathological roles.

Amyloid-beta precursor protein exon 7 & 8 dependent transcript variant abundance (Transcript variant groups containing major transcript variant 1, 2, 3 and, 11) in the immature (proliferative) SH-SY5Y cells and SH-SY5Y derived post-mitotic neurons. 41598 2024 63005 Fig6 HTML.webp
Amyloid-beta precursor protein exon 7 & 8 dependent transcript variant abundance (Transcript variant groups containing major transcript variant 1, 2, 3 and, 11) in the immature (proliferative) SH-SY5Y cells and SH-SY5Y derived post-mitotic neurons.

Post-translational processing

APP undergoes extensive post-translational modification including glycosylation, phosphorylation, sialylation, and tyrosine sulfation, as well as many types of proteolytic processing to generate peptide fragments. [29] It is commonly cleaved by proteases in the secretase family; alpha secretase and beta secretase both remove nearly the entire extracellular domain to release membrane-anchored carboxy-terminal fragments that may be associated with apoptosis. [16] Cleavage by gamma secretase within the membrane-spanning domain after beta-secretase cleavage generates the amyloid-beta fragment; gamma secretase is a large multi-subunit complex whose components have not yet been fully characterized, but include presenilin, whose gene has been identified as a major genetic risk factor for Alzheimer's. [30]

The amyloidogenic processing of APP has been linked to its presence in lipid rafts. When APP molecules occupy a lipid raft region of membrane, they are more accessible to and differentially cleaved by beta secretase, whereas APP molecules outside a raft are differentially cleaved by the non-amyloidogenic alpha secretase. [31] Gamma secretase activity has also been associated with lipid rafts. [32] The role of cholesterol in lipid raft maintenance has been cited as a likely explanation for observations that high cholesterol and apolipoprotein E genotype are major risk factors for Alzheimer's disease. [33]

Biological function

Although the native biological role of APP is of obvious interest to Alzheimer's research, thorough understanding has remained elusive. Experimental models of Alzheimer's disease are commonly used by researchers to gain better understandings about the biological function of APP in disease pathology and progression.

Synaptic formation and repair

The most-substantiated role for APP is in synaptic formation and repair; [6] its expression is upregulated during neuronal differentiation and after neural injury. Roles in cell signaling, long-term potentiation, and cell adhesion have been proposed and supported by as-yet limited research. [16] In particular, similarities in post-translational processing have invited comparisons to the signaling role of the surface receptor protein Notch. [34]

APP knockout mice are viable and have relatively minor phenotypic effects including impaired long-term potentiation and memory loss without general neuron loss. [35] On the other hand, transgenic mice with upregulated APP expression have also been reported to show impaired long-term potentiation. [36]

The logical inference is that because Aβ accumulates excessively in Alzheimer's disease its precursor, APP, would be elevated as well. However, neuronal cell bodies contain less APP as a function of their proximity to amyloid plaques. [37] The data indicate that this deficit in APP results from a decline in production rather than an increase in catalysis. Loss of a neuron's APP may affect physiological deficits that contribute to dementia.

Somatic recombination

In neurons of the human brain, somatic recombination occurs frequently in the gene that encodes APP. [38] Neurons from individuals with sporadic Alzheimer's disease show greater APP gene diversity due to somatic recombination than neurons from healthy individuals. [38]

Anterograde neuronal transport

Molecules synthesized in the cell bodies of neurons must be conveyed outward to the distal synapses. This is accomplished via fast anterograde transport. It has been found that APP can mediate interaction between cargo and kinesin and thus facilitate this transport. Specifically, a short peptide 15-amino-acid sequence from the cytoplasmic carboxy-terminus is necessary for interaction with the motor protein. [39]

Additionally, it has been shown that the interaction between APP and kinesin is specific to the peptide sequence of APP. [40] In a recent experiment involving transport of peptide-conjugated colored beads, controls were conjugated to a single amino acid, glycine, such that they display the same terminal carboxylic acid group as APP without the intervening 15-amino-acid sequence mentioned above. The control beads were not motile, which demonstrated that the terminal COOH moiety of peptides is not sufficient to mediate transport.

Iron export

A different perspective on Alzheimer's is revealed by a mouse study that has found that APP possesses ferroxidase activity similar to ceruloplasmin, facilitating iron export through interaction with ferroportin; it seems that this activity is blocked by zinc trapped by accumulated Aβ in Alzheimer's. [9] It has been shown that a single nucleotide polymorphism in the 5'UTR of APP mRNA can disrupt its translation. [41]

The hypothesis that APP has ferroxidase activity in its E2 domain and facilitates export of Fe(II) is possibly incorrect since the proposed ferroxidase site of APP located in the E2 domain does not have ferroxidase activity. [42] [43]

As APP does not possess ferroxidase activity within its E2 domain, the mechanism of APP-modulated iron efflux from ferroportin has come under scrutiny. One model suggests that APP acts to stabilize the iron efflux protein ferroportin in the plasma membrane of cells thereby increasing the total number of ferroportin molecules at the membrane. These iron-transporters can then be activated by known mammalian ferroxidases (i.e. ceruloplasmin or hephaestin). [44]

Hormonal regulation

The amyloid-β precursor protein (AβPP), and all associated secretases, are expressed early in development and play a key role in the endocrinology of reproduction – with the differential processing of AβPP by secretases regulating human embryonic stem cell (hESC) proliferation as well as their differentiation into neural precursor cells (NPC). The pregnancy hormone human chorionic gonadotropin (hCG) increases AβPP expression [45] and hESC proliferation while progesterone directs AβPP processing towards the non-amyloidogenic pathway, which promotes hESC differentiation into NPC. [46] [47] [48]

AβPP and its cleavage products do not promote the proliferation and differentiation of post-mitotic neurons; rather, the overexpression of either wild-type or mutant AβPP in post-mitotic neurons induces apoptotic death following their re-entry into the cell cycle. [49] It is postulated that the loss of sex steroids (including progesterone) but the elevation in luteinizing hormone, the adult equivalent of hCG, post-menopause and during andropause drives amyloid-β production [50] and re-entry of post-mitotic neurons into the cell cycle.

Interactions

Amyloid precursor protein has been shown to interact with:

APP interacts with reelin, a protein implicated in a number of brain disorders, including Alzheimer's disease. [71]

Related Research Articles

<span class="mw-page-title-main">Beta-secretase 2</span> Enzyme found in humans

Beta-secretase 2 is an enzyme that cleaves Glu-Val-Asn-Leu!Asp-Ala-Glu-Phe in the Swedish variant of Alzheimer's amyloid precursor protein. BACE2 is a close homolog of BACE1.

<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 plaques</span> Extracellular deposits of the amyloid beta protein

Amyloid plaques are extracellular deposits of amyloid beta (Aβ) protein that present mainly in the grey matter of the brain. Degenerative neuronal elements and an abundance of microglia and astrocytes can be associated with amyloid plaques. Some plaques occur in the brain as a result of aging, but large numbers of plaques and neurofibrillary tangles are characteristic features of Alzheimer's disease. The plaques are highly variable in shape and size; in tissue sections immunostained for Aβ, they comprise a log-normal size distribution curve, with an average plaque area of 400-450 square micrometers (μm2). The smallest plaques, which often consist of diffuse deposits of Aβ, are particularly numerous. Plaques form when Aβ misfolds and aggregates into oligomers and longer polymers, the latter of which are characteristic of amyloid.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<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.

The biochemistry of Alzheimer's disease, the most common cause of dementia, is not yet very well understood. Alzheimer's disease (AD) has been identified as a proteopathy: a protein misfolding disease due to the accumulation of abnormally folded amyloid beta (Aβ) protein in the brain. Amyloid beta is a short peptide that is an abnormal proteolytic byproduct of the transmembrane protein amyloid-beta precursor protein (APP), whose function is unclear but thought to be involved in neuronal development. The presenilins are components of proteolytic complex involved in APP processing and degradation.

<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">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">Insulin-degrading enzyme</span> Enzyme found in humans

Insulin-degrading enzyme, also known as IDE, is an enzyme.

<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">APBB1</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family B member 1 is a protein that in humans is encoded by the APBB1 gene.

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

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

<span class="mw-page-title-main">APBA2</span> Protein-coding gene in the species Homo sapiens

Amyloid beta A4 precursor protein-binding family A member 2 is a protein that in humans is encoded by the APBA2 gene.

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.

The biomarkers of Alzheimer's disease are neurochemical indicators used to assess the risk or presence of the disease. The biomarkers can be used to diagnose Alzheimer's disease (AD) in a very early stage, but they also provide objective and reliable measures of disease progress. It is imperative to diagnose AD disease as soon as possible, because neuropathologic changes of AD precede the symptoms by years. It is well known that amyloid beta (Aβ) is a good indicator of AD disease, which has facilitated doctors to accurately pre-diagnose cases of AD. When Aβ peptide is released by proteolytic cleavage of amyloid-beta precursor protein, some Aβ peptides that are solubilized are detected in CSF and blood plasma which makes AB peptides a promising candidate for biological markers. It has been shown that the amyloid beta biomarker shows 80% or above sensitivity and specificity, in distinguishing AD from dementia. It is believed that amyloid beta as a biomarker will provide a future for diagnosis of AD and eventually treatment of AD.

<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. 1 2 3 GRCh38: Ensembl release 89: ENSG00000142192 – Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000022892 – Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ "Amyloid-beta precursor protein" . Retrieved 10 January 2021.
  6. 1 2 Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J (Jul 2006). "Synapse formation and function is modulated by the amyloid precursor protein". The Journal of Neuroscience. 26 (27): 7212–21. doi: 10.1523/JNEUROSCI.1450-06.2006 . PMC   6673945 . PMID   16822978.
  7. ↑ Turner PR, O'Connor K, Tate WP, Abraham WC (May 2003). "Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory". Progress in Neurobiology. 70 (1): 1–32. doi:10.1016/S0301-0082(03)00089-3. PMID   12927332. S2CID   25376584.
  8. ↑ Moir RD, Lathe R, Tanzi RE (2018). "The antimicrobial protection hypothesis of Alzheimer's disease". Alzheimer's & Dementia. 14 (12): 1602–1614. doi: 10.1016/j.jalz.2018.06.3040 . PMID   30314800.
  9. 1 2 Duce JA, Tsatsanis A, Cater MA, James SA, Robb E, Wikhe K, Leong SL, Perez K, Johanssen T, Greenough MA, Cho HH, Galatis D, Moir RD, Masters CL, McLean C, Tanzi RE, Cappai R, Barnham KJ, Ciccotosto GD, Rogers JT, Bush AI (Sep 2010). "Iron-export ferroxidase activity of β-amyloid precursor protein is inhibited by zinc in Alzheimer's disease". Cell. 142 (6): 857–67. doi:10.1016/j.cell.2010.08.014. PMC   2943017 . PMID   20817278.
  10. ↑ Wang H, Kulas JA, Wang C, Holtzman DM, Ferris HA, Hansen SB (17 August 2021). "Regulation of beta-amyloid production in neurons by astrocyte-derived cholesterol". Proceedings of the National Academy of Sciences. 118 (33): e2102191118. Bibcode:2021PNAS..11802191W. doi: 10.1073/pnas.2102191118 . PMC   8379952 . PMID   34385305.
  11. ↑ Tharp WG, Sarkar IN (April 2013). "Origins of amyloid-β". BMC Genomics. 14 (1): 290. doi: 10.1186/1471-2164-14-290 . PMC   3660159 . PMID   23627794.
  12. ↑ Yoshikai S, Sasaki H, Doh-ura K, Furuya H, Sakaki Y (Mar 1990). "Genomic organization of the human amyloid beta-protein precursor gene". Gene. 87 (2): 257–63. doi:10.1016/0378-1119(90)90310-N. PMID   2110105.
  13. ↑ Lamb BT, Sisodia SS, Lawler AM, Slunt HH, Kitt CA, Kearns WG, Pearson PL, Price DL, Gearhart JD (Sep 1993). "Introduction and expression of the 400 kilobase amyloid precursor protein gene in transgenic mice [corrected]". Nature Genetics. 5 (1): 22–30. doi:10.1038/ng0993-22. PMID   8220418. S2CID   42752531.
  14. ↑ Matsui T, Ingelsson M, Fukumoto H, Ramasamy K, Kowa H, Frosch MP, Irizarry MC, Hyman BT (Aug 2007). "Expression of APP pathway mRNAs and proteins in Alzheimer's disease". Brain Research. 1161: 116–23. doi:10.1016/j.brainres.2007.05.050. PMID   17586478. S2CID   26901380.
  15. ↑ Ewald CY, Li C (2012-04-01). "Caenorhabditis elegans as a model organism to study APP function". Experimental Brain Research. 217 (3–4): 397–411. doi:10.1007/s00221-011-2905-7. ISSN   0014-4819. PMC   3746071 . PMID   22038715.
  16. 1 2 3 4 Zheng H, Koo EH (2006). "The amyloid precursor protein: beyond amyloid". Molecular Neurodegeneration. 1 (1): 5. doi: 10.1186/1750-1326-1-5 . PMC   1538601 . PMID   16930452.
  17. ↑ Goate A, Chartier-Harlin MC, Mullan M, Brown J, Crawford F, Fidani L, Giuffra L, Haynes A, Irving N, James L (Feb 1991). "Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease". Nature. 349 (6311): 704–6. Bibcode:1991Natur.349..704G. doi:10.1038/349704a0. PMID   1671712. S2CID   4336069.
  18. ↑ Murrell J, Farlow M, Ghetti B, Benson MD (Oct 1991). "A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease". Science. 254 (5028): 97–9. Bibcode:1991Sci...254...97M. doi:10.1126/science.1925564. PMID   1925564.
  19. ↑ Chartier-Harlin MC, Crawford F, Houlden H, Warren A, Hughes D, Fidani L, Goate A, Rossor M, Roques P, Hardy J (Oct 1991). "Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene". Nature. 353 (6347): 844–6. Bibcode:1991Natur.353..844C. doi:10.1038/353844a0. PMID   1944558. S2CID   4345311.
  20. ↑ Lloyd GM, Trejo-Lopez JA, Xia Y, McFarland KN, Lincoln SJ, Ertekin-Taner N, Giasson BI, Yachnis AT, Prokop S (12 March 2020). "Prominent amyloid plaque pathology and cerebral amyloid angiopathy in APP V717I (London) carrier - phenotypic variability in autosomal dominant Alzheimer's disease". Acta Neuropathologica Communications. 8 (1): 31. doi: 10.1186/s40478-020-0891-3 . PMC   7068954 . PMID   32164763.
  21. ↑ Citron M, Oltersdorf T, Haass C, McConlogue L, Hung AY, Seubert P, Vigo-Pelfrey C, Lieberburg I, Selkoe DJ (Dec 1992). "Mutation of the beta-amyloid precursor protein in familial Alzheimer's disease increases beta-protein production". Nature. 360 (6405): 672–4. Bibcode:1992Natur.360..672C. doi:10.1038/360672a0. PMID   1465129. S2CID   4341170.
  22. ↑ Jonsson T, Atwal JK, Steinberg S, Snaedal J, Jonsson PV, Bjornsson S, Stefansson H, Sulem P, Gudbjartsson D, Maloney J, Hoyte K, Gustafson A, Liu Y, Lu Y, Bhangale T, Graham RR, Huttenlocher J, Bjornsdottir G, Andreassen OA, Jönsson EG, Palotie A, Behrens TW, Magnusson OT, Kong A, Thorsteinsdottir U, Watts RJ, Stefansson K (Aug 2012). "A mutation in APP protects against Alzheimer's disease and age-related cognitive decline". Nature. 488 (7409): 96–9. Bibcode:2012Natur.488...96J. doi:10.1038/nature11283. PMID   22801501. S2CID   4333449.
  23. 1 2 PDB: 1RW6 ​; Wang Y, Ha Y (Aug 2004). "The X-ray structure of an antiparallel dimer of the human amyloid precursor protein E2 domain". Molecular Cell. 15 (3): 343–53. doi: 10.1016/j.molcel.2004.06.037 . PMID   15304215.
  24. 1 2 Dahms SO, Hoefgen S, Roeser D, Schlott B, Gührs KH, Than ME (Mar 2010). "Structure and biochemical analysis of the heparin-induced E1 dimer of the amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 107 (12): 5381–6. Bibcode:2010PNAS..107.5381D. doi: 10.1073/pnas.0911326107 . PMC   2851805 . PMID   20212142.; see also PDB ID 3KTM ​
  25. ↑ Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL (Jul 1993). "Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system". The Journal of Neuroscience. 13 (7): 3136–42. doi:10.1523/JNEUROSCI.13-07-03136.1993. PMC   6576678 . PMID   8331390.
  26. ↑ Rossjohn J, Cappai R, Feil SC, Henry A, McKinstry WJ, Galatis D, Hesse L, Multhaup G, Beyreuther K, Masters CL, Parker MW (Apr 1999). "Crystal structure of the N-terminal, growth factor-like domain of Alzheimer amyloid precursor protein". Nature Structural Biology. 6 (4): 327–31. doi:10.1038/7562. PMID   10201399. S2CID   30925432.; see also PDB ID 1MWP ​
  27. ↑ Kong GK, Adams JJ, Harris HH, Boas JF, Curtain CC, Galatis D, Masters CL, Barnham KJ, McKinstry WJ, Cappai R, Parker MW (Mar 2007). "Structural studies of the Alzheimer's amyloid precursor protein copper-binding domain reveal how it binds copper ions". Journal of Molecular Biology. 367 (1): 148–61. doi:10.1016/j.jmb.2006.12.041. PMID   17239395.; See also 2007 PDB IDs 2FJZ ​, 2FK2 ​, 2FKL ​.
  28. 1 2 Kulatunga DC, Ranaraja U, Kim EY, Kim RE, Kim DE, Ji KB, Kim MK (27 May 2024). "A novel APP splice variant-dependent marker system to precisely demarcate maturity in SH-SY5Y cell-derived neurons". Scientific Reports. 14 (1). doi:10.1038/s41598-024-63005-y. PMC   11130256 .
  29. ↑ De Strooper B, Annaert W (Jun 2000). "Proteolytic processing and cell biological functions of the amyloid precursor protein". Journal of Cell Science. 113 (11): 1857–70. doi:10.1242/jcs.113.11.1857. PMID   10806097.
  30. ↑ Chen F, Hasegawa H, Schmitt-Ulms G, Kawarai T, Bohm C, Katayama T, Gu Y, Sanjo N, Glista M, Rogaeva E, Wakutani Y, Pardossi-Piquard R, Ruan X, Tandon A, Checler F, Marambaud P, Hansen K, Westaway D, St George-Hyslop P, Fraser P (Apr 2006). "TMP21 is a presenilin complex component that modulates gamma-secretase but not epsilon-secretase activity". Nature. 440 (7088): 1208–12. doi:10.1038/nature04667. PMID   16641999. S2CID   4349251.
  31. ↑ Ehehalt R, Keller P, Haass C, Thiele C, Simons K (Jan 2003). "Amyloidogenic processing of the Alzheimer beta-amyloid precursor protein depends on lipid rafts". The Journal of Cell Biology. 160 (1): 113–23. doi:10.1083/jcb.200207113. PMC   2172747 . PMID   12515826.
  32. ↑ Vetrivel KS, Cheng H, Lin W, Sakurai T, Li T, Nukina N, Wong PC, Xu H, Thinakaran G (Oct 2004). "Association of gamma-secretase with lipid rafts in post-Golgi and endosome membranes". The Journal of Biological Chemistry. 279 (43): 44945–54. doi: 10.1074/jbc.M407986200 . PMC   1201506 . PMID   15322084.
  33. ↑ Riddell DR, Christie G, Hussain I, Dingwall C (Aug 2001). "Compartmentalization of beta-secretase (Asp2) into low-buoyant density, noncaveolar lipid rafts". Current Biology. 11 (16): 1288–93. Bibcode:2001CBio...11.1288R. doi: 10.1016/S0960-9822(01)00394-3 . PMID   11525745. S2CID   15502857.
  34. ↑ Selkoe D, Kopan R (2003). "Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration". Annual Review of Neuroscience. 26 (1): 565–97. doi:10.1146/annurev.neuro.26.041002.131334. PMID   12730322.
  35. ↑ Phinney AL, Calhoun ME, Wolfer DP, Lipp HP, Zheng H, Jucker M (1999). "No hippocampal neuron or synaptic bouton loss in learning-impaired aged beta-amyloid precursor protein-null mice". Neuroscience. 90 (4): 1207–16. doi:10.1016/S0306-4522(98)00645-9. PMID   10338291. S2CID   6001957.
  36. ↑ Matsuyama S, Teraoka R, Mori H, Tomiyama T (2007). "Inverse correlation between amyloid precursor protein and synaptic plasticity in transgenic mice". NeuroReport. 18 (10): 1083–7. doi:10.1097/WNR.0b013e3281e72b18. PMID   17558301. S2CID   34157306.
  37. ↑ Barger SW, DeWall KM, Liu L, Mrak RE, Griffin WS (Aug 2008). "Relationships between expression of apolipoprotein E and beta-amyloid precursor protein are altered in proximity to Alzheimer beta-amyloid plaques: potential explanations from cell culture studies". Journal of Neuropathology and Experimental Neurology. 67 (8): 773–83. doi:10.1097/NEN.0b013e318180ec47. PMC   3334532 . PMID   18648325.
  38. 1 2 Lee MH, Siddoway B, Kaeser GE, Segota I, Rivera R, Romanow WJ, Liu CS, Park C, Kennedy G, Long T, Chun J (November 2018). "Somatic APP gene recombination in Alzheimer's disease and normal neurons". Nature. 563 (7733): 639–645. Bibcode:2018Natur.563..639L. doi:10.1038/s41586-018-0718-6. PMC   6391999 . PMID   30464338.
  39. ↑ Satpute-Krishnan P, DeGiorgis JA, Conley MP, Jang M, Bearer EL (Oct 2006). "A peptide zipcode sufficient for anterograde transport within amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 103 (44): 16532–7. Bibcode:2006PNAS..10316532S. doi: 10.1073/pnas.0607527103 . PMC   1621108 . PMID   17062754.
  40. ↑ Seamster PE, Loewenberg M, Pascal J, Chauviere A, Gonzales A, Cristini V, Bearer EL (Oct 2012). "Quantitative measurements and modeling of cargo-motor interactions during fast transport in the living axon". Physical Biology. 9 (5): 055005. Bibcode:2012PhBio...9e5005S. doi:10.1088/1478-3975/9/5/055005. PMC   3625656 . PMID   23011729.
  41. ↑ Rogers JT, Bush AI, Cho HH, Smith DH, Thomson AM, Friedlich AL, Lahiri DK, Leedman PJ, Huang X, Cahill CM (Dec 2008). "Iron and the translation of the amyloid precursor protein (APP) and ferritin mRNAs: riboregulation against neural oxidative damage in Alzheimer's disease". Biochemical Society Transactions. 36 (Pt 6): 1282–7. doi:10.1042/BST0361282. PMC   2746665 . PMID   19021541.
  42. ↑ Ebrahimi KH, Hagedoorn PL, Hagen WR (2012). "A synthetic peptide with the putative iron binding motif of amyloid precursor protein (APP) does not catalytically oxidize iron". PLOS ONE. 7 (8): e40287. Bibcode:2012PLoSO...740287E. doi: 10.1371/journal.pone.0040287 . PMC   3419245 . PMID   22916096.
  43. ↑ Honarmand Ebrahimi K, Dienemann C, Hoefgen S, Than ME, Hagedoorn PL, Hagen WR (2013). "The amyloid precursor protein (APP) does not have a ferroxidase site in its E2 domain". PLOS ONE. 8 (8): e72177. Bibcode:2013PLoSO...872177H. doi: 10.1371/journal.pone.0072177 . PMC   3747053 . PMID   23977245.
  44. ↑ McCarthy RC, Park YH, Kosman DJ (Jul 2014). "sAPP modulates iron efflux from brain microvascular endothelial cells by stabilizing the ferrous iron exporter ferroportin". EMBO Reports. 15 (7): 809–15. doi:10.15252/embr.201338064. PMC   4196985 . PMID   24867889.
  45. ↑ Porayette P, Gallego MJ, Kaltcheva MM, Meethal SV, Atwood CS (Dec 2007). "Amyloid-beta precursor protein expression and modulation in human embryonic stem cells: a novel role for human chorionic gonadotropin". Biochemical and Biophysical Research Communications. 364 (3): 522–7. doi:10.1016/j.bbrc.2007.10.021. PMID   17959150.
  46. ↑ Porayette P, Gallego MJ, Kaltcheva MM, Bowen RL, Vadakkadath Meethal S, Atwood CS (Aug 2009). "Differential processing of amyloid-beta precursor protein directs human embryonic stem cell proliferation and differentiation into neuronal precursor cells". The Journal of Biological Chemistry. 284 (35): 23806–17. doi: 10.1074/jbc.M109.026328 . PMC   2749153 . PMID   19542221.
  47. ↑ Gallego MJ, Porayette P, Kaltcheva MM, Meethal SV, Atwood CS (Jun 2009). "Opioid and progesterone signaling is obligatory for early human embryogenesis". Stem Cells and Development. 18 (5): 737–40. doi:10.1089/scd.2008.0190. PMC   2891507 . PMID   18803462.
  48. ↑ Gallego MJ, Porayette P, Kaltcheva MM, Bowen RL, Vadakkadath Meethal S, Atwood CS (2010). "The pregnancy hormones human chorionic gonadotropin and progesterone induce human embryonic stem cell proliferation and differentiation into neuroectodermal rosettes". Stem Cell Research & Therapy. 1 (4): 28. doi: 10.1186/scrt28 . PMC   2983441 . PMID   20836886.
  49. ↑ McPhie DL, Coopersmith R, Hines-Peralta A, Chen Y, Ivins KJ, Manly SP, Kozlowski MR, Neve KA, Neve RL (Jul 2003). "DNA synthesis and neuronal apoptosis caused by familial Alzheimer disease mutants of the amyloid precursor protein are mediated by the p21 activated kinase PAK3". The Journal of Neuroscience. 23 (17): 6914–27. doi:10.1523/JNEUROSCI.23-17-06914.2003. PMC   6740729 . PMID   12890786.
  50. ↑ Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS (May 2004). "Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition". The Journal of Biological Chemistry. 279 (19): 20539–45. doi: 10.1074/jbc.M311993200 . PMID   14871891.
  51. 1 2 3 Biederer T, Cao X, Südhof TC, Liu X (Sep 2002). "Regulation of APP-dependent transcription complexes by Mint/X11s: differential functions of Mint isoforms". The Journal of Neuroscience. 22 (17): 7340–51. doi: 10.1523/JNEUROSCI.22-17-07340.2002 . PMC   6757996 . PMID   12196555.
  52. 1 2 Borg JP, Ooi J, Levy E, Margolis B (Nov 1996). "The phosphotyrosine interaction domains of X11 and FE65 bind to distinct sites on the YENPTY motif of amyloid precursor protein". Molecular and Cellular Biology. 16 (11): 6229–41. doi:10.1128/mcb.16.11.6229. PMC   231626 . PMID   8887653.
  53. 1 2 Araki Y, Tomita S, Yamaguchi H, Miyagi N, Sumioka A, Kirino Y, Suzuki T (Dec 2003). "Novel cadherin-related membrane proteins, Alcadeins, enhance the X11-like protein-mediated stabilization of amyloid beta-protein precursor metabolism". The Journal of Biological Chemistry. 278 (49): 49448–58. doi: 10.1074/jbc.M306024200 . PMID   12972431.
  54. ↑ Tomita S, Ozaki T, Taru H, Oguchi S, Takeda S, Yagi Y, Sakiyama S, Kirino Y, Suzuki T (Jan 1999). "Interaction of a neuron-specific protein containing PDZ domains with Alzheimer's amyloid precursor protein". The Journal of Biological Chemistry. 274 (4): 2243–54. doi: 10.1074/jbc.274.4.2243 . PMID   9890987.
  55. ↑ Tanahashi H, Tabira T (Feb 1999). "X11L2, a new member of the X11 protein family, interacts with Alzheimer's beta-amyloid precursor protein". Biochemical and Biophysical Research Communications. 255 (3): 663–7. doi:10.1006/bbrc.1999.0265. PMID   10049767.
  56. ↑ Zambrano N, Buxbaum JD, Minopoli G, Fiore F, De Candia P, De Renzis S, Faraonio R, Sabo S, Cheetham J, Sudol M, Russo T (Mar 1997). "Interaction of the phosphotyrosine interaction/phosphotyrosine binding-related domains of Fe65 with wild-type and mutant Alzheimer's beta-amyloid precursor proteins". The Journal of Biological Chemistry. 272 (10): 6399–405. doi: 10.1074/jbc.272.10.6399 . PMID   9045663.
  57. ↑ Guénette SY, Chen J, Jondro PD, Tanzi RE (Oct 1996). "Association of a novel human FE65-like protein with the cytoplasmic domain of the beta-amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 93 (20): 10832–7. Bibcode:1996PNAS...9310832G. doi: 10.1073/pnas.93.20.10832 . PMC   38241 . PMID   8855266.
  58. ↑ Tanahashi H, Tabira T (Feb 1999). "Molecular cloning of human Fe65L2 and its interaction with the Alzheimer's beta-amyloid precursor protein". Neuroscience Letters. 261 (3): 143–6. doi:10.1016/S0304-3940(98)00995-1. PMID   10081969. S2CID   54307954.
  59. ↑ Trommsdorff M, Borg JP, Margolis B, Herz J (Dec 1998). "Interaction of cytosolic adaptor proteins with neuronal apolipoprotein E receptors and the amyloid precursor protein". The Journal of Biological Chemistry. 273 (50): 33556–60. doi: 10.1074/jbc.273.50.33556 . PMID   9837937.
  60. ↑ Chow N, Korenberg JR, Chen XN, Neve RL (May 1996). "APP-BP1, a novel protein that binds to the carboxyl-terminal region of the amyloid precursor protein". The Journal of Biological Chemistry. 271 (19): 11339–46. doi: 10.1074/jbc.271.19.11339 . PMID   8626687.
  61. ↑ Zheng P, Eastman J, Vande Pol S, Pimplikar SW (Dec 1998). "PAT1, a microtubule-interacting protein, recognizes the basolateral sorting signal of amyloid precursor protein". Proceedings of the National Academy of Sciences of the United States of America. 95 (25): 14745–50. Bibcode:1998PNAS...9514745Z. doi: 10.1073/pnas.95.25.14745 . PMC   24520 . PMID   9843960.
  62. ↑ Wang B, Nguyen M, Breckenridge DG, Stojanovic M, Clemons PA, Kuppig S, Shore GC (Apr 2003). "Uncleaved BAP31 in association with A4 protein at the endoplasmic reticulum is an inhibitor of Fas-initiated release of cytochrome c from mitochondria". The Journal of Biological Chemistry. 278 (16): 14461–8. doi: 10.1074/jbc.M209684200 . PMID   12529377.
  63. ↑ Lefterov IM, Koldamova RP, Lazo JS (Sep 2000). "Human bleomycin hydrolase regulates the secretion of amyloid precursor protein". FASEB Journal. 14 (12): 1837–47. doi: 10.1096/fj.99-0938com . PMID   10973933. S2CID   44302063.
  64. ↑ Araki Y, Miyagi N, Kato N, Yoshida T, Wada S, Nishimura M, Komano H, Yamamoto T, De Strooper B, Yamamoto K, Suzuki T (Jun 2004). "Coordinated metabolism of Alcadein and amyloid beta-protein precursor regulates FE65-dependent gene transactivation". The Journal of Biological Chemistry. 279 (23): 24343–54. doi: 10.1074/jbc.M401925200 . PMID   15037614.
  65. ↑ Ikezu T, Trapp BD, Song KS, Schlegel A, Lisanti MP, Okamoto T (Apr 1998). "Caveolae, plasma membrane microdomains for alpha-secretase-mediated processing of the amyloid precursor protein". The Journal of Biological Chemistry. 273 (17): 10485–95. doi: 10.1074/jbc.273.17.10485 . PMID   9553108.
  66. ↑ Hashimoto T, Wakabayashi T, Watanabe A, Kowa H, Hosoda R, Nakamura A, Kanazawa I, Arai T, Takio K, Mann DM, Iwatsubo T (Apr 2002). "CLAC: a novel Alzheimer amyloid plaque component derived from a transmembrane precursor, CLAC-P/collagen type XXV". The EMBO Journal. 21 (7): 1524–34. doi:10.1093/emboj/21.7.1524. PMC   125364 . PMID   11927537.
  67. ↑ Ohsawa I, Takamura C, Kohsaka S (Mar 2001). "Fibulin-1 binds the amino-terminal head of beta-amyloid precursor protein and modulates its physiological function". Journal of Neurochemistry. 76 (5): 1411–20. doi: 10.1046/j.1471-4159.2001.00144.x . PMID   11238726. S2CID   83321033.
  68. ↑ Chauhan VP, Ray I, Chauhan A, Wisniewski HM (May 1999). "Binding of gelsolin, a secretory protein, to amyloid beta-protein". Biochemical and Biophysical Research Communications. 258 (2): 241–6. doi:10.1006/bbrc.1999.0623. PMID   10329371.
  69. ↑ Yan SD, Fu J, Soto C, Chen X, Zhu H, Al-Mohanna F, Collison K, Zhu A, Stern E, Saido T, Tohyama M, Ogawa S, Roher A, Stern D (Oct 1997). "An intracellular protein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer's disease". Nature. 389 (6652): 689–95. Bibcode:1997Natur.389..689D. doi:10.1038/39522. PMID   9338779. S2CID   4343238.
  70. ↑ Tarr PE, Roncarati R, Pelicci G, Pelicci PG, D'Adamio L (May 2002). "Tyrosine phosphorylation of the beta-amyloid precursor protein cytoplasmic tail promotes interaction with Shc". The Journal of Biological Chemistry. 277 (19): 16798–804. doi: 10.1074/jbc.M110286200 . PMID   11877420.
  71. ↑ Hoe HS, Lee KJ, Carney RS, Lee J, Markova A, Lee JY, Howell BW, Hyman BT, Pak DT, Bu G, Rebeck GW (Jun 2009). "Interaction of reelin with amyloid precursor protein promotes neurite outgrowth". The Journal of Neuroscience. 29 (23): 7459–73. doi:10.1523/JNEUROSCI.4872-08.2009. PMC   2759694 . PMID   19515914.

Further reading

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.