Gunawardena S, Yang G, Goldstein LS.
Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo.
Hum Mol Genet. 2013 Jun 6;
PubMed.
Genetic Interactions Between Amyloid Precursor Protein and Presenilin During Transport
When proteolytically processed, amyloid precursor protein (APP) generates Aβ, a potentially toxic peptide that aggregates into senile plaques clogging the brain in Alzheimer’s disease. Presenilin (PS), a member of the γ-secretase complex, performs this cleavage. Over 20 years ago APP was found to be transported anterograde in neurons (Koo et al., 1990; Sisodia et al., 1993), yet the specific mechanism of this transport remains a matter of spirited discussion among Alzheimer’s researchers. If or how altered transport may contribute to dementia continues to be an area of intense investigation. A particularly sticky issue was whether APP was cargo within transport vesicles or mediated its own transport by directly interacting with anterograde motors, such as the kinesins. Reports that APP bound kinesin-1 light chain in vitro (Lazarov et al., 2005), and that APP, kinesin, and PS were co-transported (Satpute-Krishnan et al., 2006), lead to the audacious idea that PS cleavage of APP released the cytoplasmic domain from the surface of transport vesicles (see image below), thereby preventing APP-containing vesicles from binding kinesin-1. If this were true, then PS activity would regulate APP transport, an idea that was hotly disputed (Lazarov et al., 2005).
In the Bearer lab we demonstrated that APP is indeed sufficient to mediate its own transport. By linking peptides derived from APP to inert, fluorescent, nanoscale beads in a test tube, and then injecting the APP-beads into the giant axon of the squid (Satpute-Krishnan et al., 2006), we discovered that the carboxy terminus of APP drove anterograde transport without any other motor-receptor on the bead. More recently, we reported that negatively charged beads, known to interact with kinesin-1, also transported, but less efficiently, and that APP-beads had a high binding affinity for kinesin-1 from squid axons and rat brain (Seamster et al., 2012). Thus, from our work, a mechanism and motor for APP transport are now established.
Blocking kinesin-1: APP cleavage by PS results in 1) loss of motor attachment to vesicles, and 2) inhibition of transport by peptide competition for the cargo binding site on kinesin.
The recent report by Gunawardena et al. (6) demonstrates that decreased PS gene dose enhances APP transport, consistent with the idea that PS-dependent cleavage of APP’s cytoplasmic domain results in a loss of the ability to bind motors. With decreased PS dose, less cleavage would occur and more kinesin-1 could bind. Consistent with this interpretation, decreasing kinesin-1 dose in PS mutants decreases vesicle motility back to levels near normal, and above those seen in kinesin-1 mutants alone (Bearer et al., 2007). This demonstrates that the effect of PS mutation on motility is due to kinesin-1. This result is further validated by examining synaptotagmin transport, which demonstrated normal motility in all cases. By approaching this question with genetics, the results of Gunawardena et al. confirm previous reports from biochemical and biophysical experiments, and support the hypothesis proposed a dozen years ago that PS activity releases APP from transport vesicles.
How, then, might this interaction among APP, PS, kinesin-1, and axonal transport produce neuronal degeneration thought to underlie the cognitive impairment of Alzheimer’s disease? As we reported, peptides from the cytoplasmic tail of APP bind kinesin-1 (Seamster et al., 2012) and inhibit APP-bead transport when injected in the giant axon (Satpute-Krishnan et al., 2006), probably by occupying kinesin-1’s cargo binding site (see diagram above). Such general inhibition of transport may block trafficking of crucial signaling molecules and nerve growth factors required for neuronal viability. Taking a cue from Down's syndrome, where the gene for APP is triplicated on chromosome 21, transport in the anterograde direction is enhanced (Bearer et al., 2007), while retrograde transport of NGF is depressed, and cholinergic neurons of the medial septal nucleus degenerate (Salehi et al., 2006). Thus, accumulations of intracellular organelles occasioned by transport failures may induce injury responses, growth factor signaling defects, mitochondrial maldistribution, and other pathological processes that result in the clinical presentation of Alzheimer’s disease: cognitive impairment and memory loss.
References:
Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL.
Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport.
Proc Natl Acad Sci U S A. 1990 Feb;87(4):1561-5.
PubMed.
Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL.
Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system.
J Neurosci. 1993 Jul;13(7):3136-42.
PubMed.
Lazarov O, Morfini GA, Lee EB, Farah MH, Szodorai A, DeBoer SR, Koliatsos VE, Kins S, Lee VM, Wong PC, Price DL, Brady ST, Sisodia SS.
Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited.
J Neurosci. 2005 Mar 2;25(9):2386-95.
PubMed.
Satpute-Krishnan P, DeGiorgis JA, Conley MP, Jang M, Bearer EL.
A peptide zipcode sufficient for anterograde transport within amyloid precursor protein.
Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16532-7.
PubMed.
Seamster PE, Loewenberg M, Pascal J, Chauviere A, Gonzales A, Cristini V, Bearer EL.
Quantitative measurements and modeling of cargo-motor interactions during fast transport in the living axon.
Phys Biol. 2012 Oct;9(5):055005. Epub 2012 Sep 25
PubMed.
Gunawardena S, Yang G, Goldstein LS.
Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo.
Hum Mol Genet. 2013 Jun 6;
PubMed.
Bearer EL, Zhang X, Jacobs RE.
Live imaging of neuronal connections by magnetic resonance: Robust transport in the hippocampal-septal memory circuit in a mouse model of Down syndrome.
Neuroimage. 2007 Aug 1;37(1):230-42.
PubMed.
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC.
Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration.
Neuron. 2006 Jul 6;51(1):29-42.
PubMed.
Comments
Genetic Interactions Between Amyloid Precursor Protein and Presenilin During Transport
When proteolytically processed, amyloid precursor protein (APP) generates Aβ, a potentially toxic peptide that aggregates into senile plaques clogging the brain in Alzheimer’s disease. Presenilin (PS), a member of the γ-secretase complex, performs this cleavage. Over 20 years ago APP was found to be transported anterograde in neurons (Koo et al., 1990; Sisodia et al., 1993), yet the specific mechanism of this transport remains a matter of spirited discussion among Alzheimer’s researchers. If or how altered transport may contribute to dementia continues to be an area of intense investigation. A particularly sticky issue was whether APP was cargo within transport vesicles or mediated its own transport by directly interacting with anterograde motors, such as the kinesins. Reports that APP bound kinesin-1 light chain in vitro (Lazarov et al., 2005), and that APP, kinesin, and PS were co-transported (Satpute-Krishnan et al., 2006), lead to the audacious idea that PS cleavage of APP released the cytoplasmic domain from the surface of transport vesicles (see image below), thereby preventing APP-containing vesicles from binding kinesin-1. If this were true, then PS activity would regulate APP transport, an idea that was hotly disputed (Lazarov et al., 2005).
In the Bearer lab we demonstrated that APP is indeed sufficient to mediate its own transport. By linking peptides derived from APP to inert, fluorescent, nanoscale beads in a test tube, and then injecting the APP-beads into the giant axon of the squid (Satpute-Krishnan et al., 2006), we discovered that the carboxy terminus of APP drove anterograde transport without any other motor-receptor on the bead. More recently, we reported that negatively charged beads, known to interact with kinesin-1, also transported, but less efficiently, and that APP-beads had a high binding affinity for kinesin-1 from squid axons and rat brain (Seamster et al., 2012). Thus, from our work, a mechanism and motor for APP transport are now established.
The recent report by Gunawardena et al. (6) demonstrates that decreased PS gene dose enhances APP transport, consistent with the idea that PS-dependent cleavage of APP’s cytoplasmic domain results in a loss of the ability to bind motors. With decreased PS dose, less cleavage would occur and more kinesin-1 could bind. Consistent with this interpretation, decreasing kinesin-1 dose in PS mutants decreases vesicle motility back to levels near normal, and above those seen in kinesin-1 mutants alone (Bearer et al., 2007). This demonstrates that the effect of PS mutation on motility is due to kinesin-1. This result is further validated by examining synaptotagmin transport, which demonstrated normal motility in all cases. By approaching this question with genetics, the results of Gunawardena et al. confirm previous reports from biochemical and biophysical experiments, and support the hypothesis proposed a dozen years ago that PS activity releases APP from transport vesicles.
How, then, might this interaction among APP, PS, kinesin-1, and axonal transport produce neuronal degeneration thought to underlie the cognitive impairment of Alzheimer’s disease? As we reported, peptides from the cytoplasmic tail of APP bind kinesin-1 (Seamster et al., 2012) and inhibit APP-bead transport when injected in the giant axon (Satpute-Krishnan et al., 2006), probably by occupying kinesin-1’s cargo binding site (see diagram above). Such general inhibition of transport may block trafficking of crucial signaling molecules and nerve growth factors required for neuronal viability. Taking a cue from Down's syndrome, where the gene for APP is triplicated on chromosome 21, transport in the anterograde direction is enhanced (Bearer et al., 2007), while retrograde transport of NGF is depressed, and cholinergic neurons of the medial septal nucleus degenerate (Salehi et al., 2006). Thus, accumulations of intracellular organelles occasioned by transport failures may induce injury responses, growth factor signaling defects, mitochondrial maldistribution, and other pathological processes that result in the clinical presentation of Alzheimer’s disease: cognitive impairment and memory loss.
References:
Koo EH, Sisodia SS, Archer DR, Martin LJ, Weidemann A, Beyreuther K, Fischer P, Masters CL, Price DL. Precursor of amyloid protein in Alzheimer disease undergoes fast anterograde axonal transport. Proc Natl Acad Sci U S A. 1990 Feb;87(4):1561-5. PubMed.
Sisodia SS, Koo EH, Hoffman PN, Perry G, Price DL. Identification and transport of full-length amyloid precursor proteins in rat peripheral nervous system. J Neurosci. 1993 Jul;13(7):3136-42. PubMed.
Lazarov O, Morfini GA, Lee EB, Farah MH, Szodorai A, DeBoer SR, Koliatsos VE, Kins S, Lee VM, Wong PC, Price DL, Brady ST, Sisodia SS. Axonal transport, amyloid precursor protein, kinesin-1, and the processing apparatus: revisited. J Neurosci. 2005 Mar 2;25(9):2386-95. PubMed.
Satpute-Krishnan P, DeGiorgis JA, Conley MP, Jang M, Bearer EL. A peptide zipcode sufficient for anterograde transport within amyloid precursor protein. Proc Natl Acad Sci U S A. 2006 Oct 31;103(44):16532-7. PubMed.
Seamster PE, Loewenberg M, Pascal J, Chauviere A, Gonzales A, Cristini V, Bearer EL. Quantitative measurements and modeling of cargo-motor interactions during fast transport in the living axon. Phys Biol. 2012 Oct;9(5):055005. Epub 2012 Sep 25 PubMed.
Gunawardena S, Yang G, Goldstein LS. Presenilin controls kinesin-1 and dynein function during APP-vesicle transport in vivo. Hum Mol Genet. 2013 Jun 6; PubMed.
Bearer EL, Zhang X, Jacobs RE. Live imaging of neuronal connections by magnetic resonance: Robust transport in the hippocampal-septal memory circuit in a mouse model of Down syndrome. Neuroimage. 2007 Aug 1;37(1):230-42. PubMed.
Salehi A, Delcroix JD, Belichenko PV, Zhan K, Wu C, Valletta JS, Takimoto-Kimura R, Kleschevnikov AM, Sambamurti K, Chung PP, Xia W, Villar A, Campbell WA, Kulnane LS, Nixon RA, Lamb BT, Epstein CJ, Stokin GB, Goldstein LS, Mobley WC. Increased App expression in a mouse model of Down's syndrome disrupts NGF transport and causes cholinergic neuron degeneration. Neuron. 2006 Jul 6;51(1):29-42. PubMed.
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