Growth or No Growth: APP Weighs the Question
Angela Biggs Proposes a Biological Function for APP
First, consider the two forms of APP. The membrane AβPP form has a receptor-like protease(1) with a cytoplasmic region capable of binding small G-proteins.(2) In neurons, the membrane form is found at the synaptic zone at the tip of growth.(3,4) The secreted form of APP is an extracellular protease that has been shown to stimulate neurite extension.
Now consider that AβPP is also known as protease nexin II, a serine protease.(5,6,7) The serine protease inhibitor neuroserpin has been shown in PC12 cells not only to decrease the length of neural axon extensions, but also to stop axon growth altogether.(11)
I propose that the biological function of APP appears to be to act as a serine protease to "switch" neurons into the growth mode.
To weigh this idea, discoveries in other cell types should be considered: Maspins are serine protease inhibitors that insert into the membrane and control the cytoskeleton; without maspins, breast cancer cells metastasize.(8)
Next, consider that P53 turns on maspin expression by binding DNA.(9) Note that p53 binding is also required for bcl-2 expression. In neurons, AβPP seems to prevent p53 from binding to DNA.(10) So serpins and serine proteases have opposite relationships with P53. This makes sense because p53 binding protects quiescent neurons from apoptosis via bcl-2, while rapidly growing neurons could be easily eliminated if needed.(14)
Neuroserpins and α-1-antichymotrypsin (α-1-ACT) are serine protease inhibitors that could be acting as maspins. Interestingly, expression of APP and α-1-ACT have been shown to coexist together in the membrane of human skeletal muscle.(12)—a serine protease receptor with a serine protease inhibitor receptor.
Putting it all together, there seem to be two critical states of neurons: those that are growing and using serine proteases to do so, and those that are quiescent. Growing neurons would be using APP pathways, possibly through RhoG (a small G-protein) to extend microtubules, whereas quiescent neurons would use the membrane serpin. I speculate that serpins may act through RhoA to dictate a non-growth cytoskeletal structure.(13)
APP and Cholesterol
Another nice feature of this proposed APP function as a controller of "growth of non-growth" is that it explains the cholesterol relationship. The elongated membrane of the nerve growth cone would require more cholesterol in the membrane for structural stability. Simple membrane structures require less cholesterol, while complex membrane structures require more. The addition of cholesterol to membranes stabilizes the lipids, thus preventing them from floating away.(15) If the body wanted to get rid of cholesterol, it might attempt to use as much as possible in complex membranes like those of growing axons and growth cones.
For example, treating APP-transfected HEK cells with statin drugs reduced the processing of newly synthesized APP. Adding cholesterol to the HEK cells increased BACE cleavage of APP by fourfold.(16) The cells appear to choose the APP pathway in order to use cholesterol in the membrane!
What about the decrease of the α-secretase processing of APP? My understanding is that there are two main types of APP cleavage, α and β. Transgenic mice overexpressing APP when exposed to high cholesterol show an increase of the β-secretase cleavage of APP and a decrease of α-secretase cleavage.(17) Since α-secretase cleavage occurs at the membrane surface of neurons,(18) I suggest that this α cleavage might be an "off cleavage." Could it also be that neuroserpin inhibits APP, then the secretase cleaves it, turning the growth mode of the APP receptor off permanently, then stimulating the nerves nearby as if to take turns growing?
I reason that high cholesterol would push neurons into the APP cytoskeleton growing mode, which uses cholesterol in the membrane. Problems could occur once the neuron could no longer keep up the growing pace, or too much Aβ was made due to high cholesterol stimulating APP production. If the nerve became stuck in the growth mode, it makes sense that proteins used in growth could pile up; this includes APP, tau,(21) and α-synuclein as a plasma membrane omega fatty acid transporter.(22)
APP and Dementia
Another appealing feature of APP functioning as a serine protease and the neuron switching into a growth mode is that it might also help explain dementia and the neuron's mitochondria. Assuming that the mitochondria must be coordinated with neuron growth and division, it is interesting to note that the transmembrane protease called rhomboid responsible for the proteolysis of mitochondrial membranes is a serine protease.(19) So a serine protease in mitochondrial membranes appears to remodel the mitochondria from the mesh system into "portable, hotdog-like" organelles. I am suggesting that when APP, a plasma membrane serine protease receptor, switches the neuron to a growth mode, somehow a serine protease in the mitochondrial membrane is also switched on.
Where does this line of thought lead? Mitochondria have been called the "memory" of neurons, as they use their calcium stores to record stimulation and adjust neurotransmitter release based on stimulation.(20) Wouldn't it be interesting if the morphology of the mitochondria affected this calcium memory property? For instance, if the mitochondria are in the mesh form, the neuron can "remember," but when mitochondria are in the hot dog form during serine protease expression, the neuron cannot. This is, in effect, a speculation that sudden returnable memory relates to the state of the mitochondria. It is unknown whether the APP serine protease in the plasma membrane is coordinated with the mitochondrial serine protease, but the fact that they are both transmembrane serine proteases is suggestive. Could APP trigger dementia by causing the mitochondrial serine protease to be expressed?
Consider resveratrol, the polyphenolic compound of red wine, cranberries, and blueberries. Resveratrol has been found to slow the growth of prostate cancer cells.(23) Serine protease inhibitors—the serpins—use their phenol groups to inhibit the serine proteases. Could the return of memory that occurs with blueberries and other resveratrol-containing foods actually be due to resveratrol acting like a serpin, thus inhibiting the serine protease of the mitochondria and allowing the mitochondria to form back into a mesh?
There are a lot of possibilities with this growth model of APP as a serine protease. I hope enterprising scientists will take up testing it! —Angela Biggs, Independent Researcher.
Please note: Just in case it is not mentioned in the live discussion, I would like to note that clioquinol is an antifungal and it is not entirely understood how it is working in Alzheimer's patients.
References:
1. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. Abstract
2. Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o) Nature. 1993 Mar 4;362(6415):75-9. Abstract
3. Schubert D. The possible role of adhesion in synaptic modification. Trends Neurosci. 1991 Apr;14(4):127-30. Review. No abstract available. Abstract
4. Levitan and Kaczmarek. 1991. The Neuron. pp 343-344.
5. Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci. 1995 Mar;15(3 Pt 2):2157-67. Abstract
6. Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saitoh T. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci. 1994 Sep;14(9):5461-70. Abstract
7. Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood KL, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144-7. Abstract
8. Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11669-74. Abstract
9. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000 Mar 3;275(9):6051-4. Abstract
10. Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7547-52. Abstract
11. Parmar PK, Coates LC, Pearson JF, Hill RM, Birch NP. Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells. J Neurochem. 2002 Sep;82(6):1406-15. Abstract
12. Akaaboune M, Ma J, Festoff BW, Greenberg BD, Hantai D. Neurotrophic regulation of mouse muscle beta-amyloid protein precursor and alpha 1-antichymotrypsin as revealed by axotomy. J Neurobiol. 1994 May;25(5):503-14. Abstract and Akaaboune M, Verdiere-Sahuque M, Lachkar S, Festoff BW, Hantai D. Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro. J Cell Physiol. 1995 Dec;165(3):503-11. Abstract
13. Vignal E, Blangy A, Martin M, Gauthier-Rouviere C, Fort P. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Mol Cell Biol. 2001 Dec;21(23):8022-34. Abstract
14. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci. 2003 Oct 15;116(Pt 20):4077-85. Abstract
15. Alberts et al. 1989. Molecular Biology of the Cell, 2nd edition. pp 279.
16. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. Abstract
17. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. Erratum in: Neurobiol Dis 2000 Dec;7(6 Pt B):690. Abstract
18. Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM. Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. Biochemistry. 1999 Jul 27;38(30):9728-34. Abstract
19. McQuibban GA, Saurya S, Freeman M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature. 2003 May 29;423(6939):537-41. Abstract
20. Kaczmarek LK. Mitochondrial memory banks. Calcium stores keep a record of neuronal stimulation. J Gen Physiol. 2000 Mar;115(3):347-50. Review. No abstract available. Abstract
21. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem. 2001 Jan;76(2):391-400. Abstract
22. Pro Natl. Acad Sci USA 98 (16):9110-5.
23. Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5. Abstract
Angela Biggs Proposes a Biological Function for APP
First, consider the two forms of APP. The membrane AβPP form has a receptor-like protease(1) with a cytoplasmic region capable of binding small G-proteins.(2) In neurons, the membrane form is found at the synaptic zone at the tip of growth.(3,4) The secreted form of APP is an extracellular protease that has been shown to stimulate neurite extension.
Now consider that AβPP is also known as protease nexin II, a serine protease.(5,6,7) The serine protease inhibitor neuroserpin has been shown in PC12 cells not only to decrease the length of neural axon extensions, but also to stop axon growth altogether.(11)
I propose that the biological function of APP appears to be to act as a serine protease to "switch" neurons into the growth mode.
To weigh this idea, discoveries in other cell types should be considered: Maspins are serine protease inhibitors that insert into the membrane and control the cytoskeleton; without maspins, breast cancer cells metastasize.(8)
Next, consider that P53 turns on maspin expression by binding DNA.(9) Note that p53 binding is also required for bcl-2 expression. In neurons, AβPP seems to prevent p53 from binding to DNA.(10) So serpins and serine proteases have opposite relationships with P53. This makes sense because p53 binding protects quiescent neurons from apoptosis via bcl-2, while rapidly growing neurons could be easily eliminated if needed.(14)
Neuroserpins and α-1-antichymotrypsin (α-1-ACT) are serine protease inhibitors that could be acting as maspins. Interestingly, expression of APP and α-1-ACT have been shown to coexist together in the membrane of human skeletal muscle.(12)—a serine protease receptor with a serine protease inhibitor receptor.
Putting it all together, there seem to be two critical states of neurons: those that are growing and using serine proteases to do so, and those that are quiescent. Growing neurons would be using APP pathways, possibly through RhoG (a small G-protein) to extend microtubules, whereas quiescent neurons would use the membrane serpin. I speculate that serpins may act through RhoA to dictate a non-growth cytoskeletal structure.(13)
APP and Cholesterol
Another nice feature of this proposed APP function as a controller of "growth of non-growth" is that it explains the cholesterol relationship. The elongated membrane of the nerve growth cone would require more cholesterol in the membrane for structural stability. Simple membrane structures require less cholesterol, while complex membrane structures require more. The addition of cholesterol to membranes stabilizes the lipids, thus preventing them from floating away.(15) If the body wanted to get rid of cholesterol, it might attempt to use as much as possible in complex membranes like those of growing axons and growth cones.
For example, treating APP-transfected HEK cells with statin drugs reduced the processing of newly synthesized APP. Adding cholesterol to the HEK cells increased BACE cleavage of APP by fourfold.(16) The cells appear to choose the APP pathway in order to use cholesterol in the membrane!
What about the decrease of the α-secretase processing of APP? My understanding is that there are two main types of APP cleavage, α and β. Transgenic mice overexpressing APP when exposed to high cholesterol show an increase of the β-secretase cleavage of APP and a decrease of α-secretase cleavage.(17) Since α-secretase cleavage occurs at the membrane surface of neurons,(18) I suggest that this α cleavage might be an "off cleavage." Could it also be that neuroserpin inhibits APP, then the secretase cleaves it, turning the growth mode of the APP receptor off permanently, then stimulating the nerves nearby as if to take turns growing?
I reason that high cholesterol would push neurons into the APP cytoskeleton growing mode, which uses cholesterol in the membrane. Problems could occur once the neuron could no longer keep up the growing pace, or too much Aβ was made due to high cholesterol stimulating APP production. If the nerve became stuck in the growth mode, it makes sense that proteins used in growth could pile up; this includes APP, tau,(21) and α-synuclein as a plasma membrane omega fatty acid transporter.(22)
APP and Dementia
Another appealing feature of APP functioning as a serine protease and the neuron switching into a growth mode is that it might also help explain dementia and the neuron's mitochondria. Assuming that the mitochondria must be coordinated with neuron growth and division, it is interesting to note that the transmembrane protease called rhomboid responsible for the proteolysis of mitochondrial membranes is a serine protease.(19) So a serine protease in mitochondrial membranes appears to remodel the mitochondria from the mesh system into "portable, hotdog-like" organelles. I am suggesting that when APP, a plasma membrane serine protease receptor, switches the neuron to a growth mode, somehow a serine protease in the mitochondrial membrane is also switched on.
Where does this line of thought lead? Mitochondria have been called the "memory" of neurons, as they use their calcium stores to record stimulation and adjust neurotransmitter release based on stimulation.(20) Wouldn't it be interesting if the morphology of the mitochondria affected this calcium memory property? For instance, if the mitochondria are in the mesh form, the neuron can "remember," but when mitochondria are in the hot dog form during serine protease expression, the neuron cannot. This is, in effect, a speculation that sudden returnable memory relates to the state of the mitochondria. It is unknown whether the APP serine protease in the plasma membrane is coordinated with the mitochondrial serine protease, but the fact that they are both transmembrane serine proteases is suggestive. Could APP trigger dementia by causing the mitochondrial serine protease to be expressed?
Consider resveratrol, the polyphenolic compound of red wine, cranberries, and blueberries. Resveratrol has been found to slow the growth of prostate cancer cells.(23) Serine protease inhibitors—the serpins—use their phenol groups to inhibit the serine proteases. Could the return of memory that occurs with blueberries and other resveratrol-containing foods actually be due to resveratrol acting like a serpin, thus inhibiting the serine protease of the mitochondria and allowing the mitochondria to form back into a mesh?
There are a lot of possibilities with this growth model of APP as a serine protease. I hope enterprising scientists will take up testing it! —Angela Biggs, Independent Researcher.
Please note: Just in case it is not mentioned in the live discussion, I would like to note that clioquinol is an antifungal and it is not entirely understood how it is working in Alzheimer's patients.
References:
1. Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, Multhaup G, Beyreuther K, Muller-Hill B. The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature. 1987 Feb 19-25;325(6106):733-6. Abstract
2. Nishimoto I, Okamoto T, Matsuura Y, Takahashi S, Okamoto T, Murayama Y, Ogata E. Alzheimer amyloid protein precursor complexes with brain GTP-binding protein G(o) Nature. 1993 Mar 4;362(6415):75-9. Abstract
3. Schubert D. The possible role of adhesion in synaptic modification. Trends Neurosci. 1991 Apr;14(4):127-30. Review. No abstract available. Abstract
4. Levitan and Kaczmarek. 1991. The Neuron. pp 343-344.
5. Qiu WQ, Ferreira A, Miller C, Koo EH, Selkoe DJ. Cell-surface beta-amyloid precursor protein stimulates neurite outgrowth of hippocampal neurons in an isoform-dependent manner. J Neurosci. 1995 Mar;15(3 Pt 2):2157-67. Abstract
6. Jin LW, Ninomiya H, Roch JM, Schubert D, Masliah E, Otero DA, Saitoh T. Peptides containing the RERMS sequence of amyloid beta/A4 protein precursor bind cell surface and promote neurite extension. J Neurosci. 1994 Sep;14(9):5461-70. Abstract
7. Oltersdorf T, Fritz LC, Schenk DB, Lieberburg I, Johnson-Wood KL, Beattie EC, Ward PJ, Blacher RW, Dovey HF, Sinha S. The secreted form of the Alzheimer's amyloid precursor protein with the Kunitz domain is protease nexin-II. Nature. 1989 Sep 14;341(6238):144-7. Abstract
8. Sheng S, Carey J, Seftor EA, Dias L, Hendrix MJ, Sager R. Maspin acts at the cell membrane to inhibit invasion and motility of mammary and prostatic cancer cells. Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11669-74. Abstract
9. Zou Z, Gao C, Nagaich AK, Connell T, Saito S, Moul JW, Seth P, Appella E, Srivastava S. p53 regulates the expression of the tumor suppressor gene maspin. J Biol Chem. 2000 Mar 3;275(9):6051-4. Abstract
10. Xu X, Yang D, Wyss-Coray T, Yan J, Gan L, Sun Y, Mucke L. Wild-type but not Alzheimer-mutant amyloid precursor protein confers resistance against p53-mediated apoptosis. Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7547-52. Abstract
11. Parmar PK, Coates LC, Pearson JF, Hill RM, Birch NP. Neuroserpin regulates neurite outgrowth in nerve growth factor-treated PC12 cells. J Neurochem. 2002 Sep;82(6):1406-15. Abstract
12. Akaaboune M, Ma J, Festoff BW, Greenberg BD, Hantai D. Neurotrophic regulation of mouse muscle beta-amyloid protein precursor and alpha 1-antichymotrypsin as revealed by axotomy. J Neurobiol. 1994 May;25(5):503-14. Abstract and Akaaboune M, Verdiere-Sahuque M, Lachkar S, Festoff BW, Hantai D. Serine proteinase inhibitors in human skeletal muscle: expression of beta-amyloid protein precursor and alpha 1-antichymotrypsin in vivo and during myogenesis in vitro. J Cell Physiol. 1995 Dec;165(3):503-11. Abstract
13. Vignal E, Blangy A, Martin M, Gauthier-Rouviere C, Fort P. Kinectin is a key effector of RhoG microtubule-dependent cellular activity. Mol Cell Biol. 2001 Dec;21(23):8022-34. Abstract
14. Haupt S, Berger M, Goldberg Z, Haupt Y. Apoptosis - the p53 network. J Cell Sci. 2003 Oct 15;116(Pt 20):4077-85. Abstract
15. Alberts et al. 1989. Molecular Biology of the Cell, 2nd edition. pp 279.
16. Frears ER, Stephens DJ, Walters CE, Davies H, Austen BM. The role of cholesterol in the biosynthesis of beta-amyloid. Neuroreport. 1999 Jun 3;10(8):1699-705. Abstract
17. Refolo LM, Malester B, LaFrancois J, Bryant-Thomas T, Wang R, Tint GS, Sambamurti K, Duff K, Pappolla MA. Hypercholesterolemia accelerates the Alzheimer's amyloid pathology in a transgenic mouse model. Neurobiol Dis. 2000 Aug;7(4):321-31. Erratum in: Neurobiol Dis 2000 Dec;7(6 Pt B):690. Abstract
18. Parvathy S, Hussain I, Karran EH, Turner AJ, Hooper NM. Cleavage of Alzheimer's amyloid precursor protein by alpha-secretase occurs at the surface of neuronal cells. Biochemistry. 1999 Jul 27;38(30):9728-34. Abstract
19. McQuibban GA, Saurya S, Freeman M. Mitochondrial membrane remodelling regulated by a conserved rhomboid protease. Nature. 2003 May 29;423(6939):537-41. Abstract
20. Kaczmarek LK. Mitochondrial memory banks. Calcium stores keep a record of neuronal stimulation. J Gen Physiol. 2000 Mar;115(3):347-50. Review. No abstract available. Abstract
21. Fan QW, Yu W, Senda T, Yanagisawa K, Michikawa M. Cholesterol-dependent modulation of tau phosphorylation in cultured neurons. J Neurochem. 2001 Jan;76(2):391-400. Abstract
22. Pro Natl. Acad Sci USA 98 (16):9110-5.
23. Mitchell SH, Zhu W, Young CY. Resveratrol inhibits the expression and function of the androgen receptor in LNCaP prostate cancer cells. Cancer Res. 1999 Dec 1;59(23):5892-5. Abstract
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