Wang L, Lashuel HA, Walz T, Colon W.
Murine apolipoprotein serum amyloid A in solution forms a hexamer containing a central channel.
Proc Natl Acad Sci U S A. 2002 Dec 10;99(25):15947-52.
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Serum amyloid A (SAA) is an apolipoprotein of uncertain function, whose concentration in serum can increase by as much as 1,000-fold during states of infection or inflammation. Chronic inflammatory states may lead to reactive AA amyloidosis, in which an N-terminal fragment of SAA (1-76) forms amyloid deposits in various tissues. The mechanism by which AA (or any) amyloid leads to tissue change is unknown. The channel hypothesis, originally proposed by Arispe et al., 1993, suggests that amyloid peptides form ion-permeable channels in cell membranes, thereby leading to noxious physiologic effects such as elevated Ca+2 levels, depolarization of membrane potential, changes in ion gradients, and induction of apoptosis (perhaps via direct channel formation in the mitochondial membrane). Evidence has shown that the Alzheimer’s amyloid Aβ can form channels in bilayers, fibroblasts, oocytes, and neurons of various kinds (reviewed in Kagan et al., 2002) and that these channels can disrupt Ca+2 homeostasis, inhibit LTP, and even kill cells. Further work has demonstrated that at least seven other amyloid proteins, including SAA, can form channels with similar physiologic and biologic properties (Kagan et al., 2002; Kourie, 2001).
Recently channel-forming activity was reported for a-synuclein, the amyloid peptide of Parkinson’s disease (PD), (Volles & Lansbury, 2001; see Alzforum interview with Peter Lansbury). Additionally, a ring-like structure for α-synuclein was seen in electron microscopy (EM), and mutations in α-synuclein that led to early onset PD caused increased formation of the ring structure.
The present paper reports that active SAA forms a hexamer with a "central channel" as assessed by EM. Taken together with previous evidence, this adds further strength to the idea that amyloid proteins form channel structures and that these channels are critical to the pathophysiology of amyloid disease. One implication of this hypothesis is that compounds which block these amyloid channels might find some use as therapeutic agents for amyloid diseases.
The present paper has some limitations, however. First, murine SAA differs from human SAA, and the SAA isoform used here (SAA2.2) does not cause amyloid disease in vivo. Second, the "appearance" of a channel in EM staining pictures does not assure that a physiological pathway for ions and other substances is actually found in cell membranes. Our own work however, (Hirakura & Kagan, 2002) suggests that this is likely the case. The actual channel structure in a membrane environment may differ from the solution structure observed. Third, the relative lack of β-sheet structure is surprising, since this seems to be a requirement for amyloid and channel formation.
Nevertheless, the overall impact of this paper is to tip the scales further in favor of the channel hypothesis. The critical test of this idea will be to identify these channels in vivo (perhaps already done; see Klapstein et al., 2001), block them, and see if amyloid disease can be halted (done in fibroblasts by Lin et al., 2002, but not yet accomplished in animals). —Bruce L. Kagan, University of California, Los Angeles.
Arispe N, Rojas E, Pollard HB.
Alzheimer disease amyloid beta protein forms calcium channels in bilayer membranes: blockade by tromethamine and aluminum.
Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):567-71.
Kagan BL, Hirakura Y, Azimov R, Azimova R, Lin MC.
The channel hypothesis of Alzheimer's disease: current status.
Peptides. 2002 Jul;23(7):1311-5.
Hirakura Y, Carreras I, Sipe JD, Kagan BL.
Channel formation by serum amyloid A: a potential mechanism for amyloid pathogenesis and host defense.
Amyloid. 2002 Mar;9(1):13-23.
Hirakura , Kagan.
The role of amyloid peptide channels in Alzheimer’s and other amyloidoses.
Einstein Q.J. Biol. Med. 2000
Klapstein GJ, Fisher RS, Zanjani H, Cepeda C, Jokel ES, Chesselet MF, Levine MS.
Electrophysiological and morphological changes in striatal spiny neurons in R6/2 Huntington's disease transgenic mice.
J Neurophysiol. 2001 Dec;86(6):2667-77.
Kourie JI, Henry CL, Farrelly P.
Diversity of amyloid beta protein fragment [1-40]-formed channels.
Cell Mol Neurobiol. 2001 Jun;21(3):255-84.
Lin H, Bhatia R, Lal R.
Amyloid beta protein forms ion channels: implications for Alzheimer's disease pathophysiology.
FASEB J. 2001 Nov;15(13):2433-44.
Lashuel HA, Hartley D, Petre BM, Walz T, Lansbury PT.
Neurodegenerative disease: amyloid pores from pathogenic mutations.
Nature. 2002 Jul 18;418(6895):291.
Volles MJ, Lansbury PT.
Vesicle permeabilization by protofibrillar alpha-synuclein is sensitive to Parkinson's disease-linked mutations and occurs by a pore-like mechanism.
Biochemistry. 2002 Apr 9;41(14):4595-602.
Some intriguing comparisons can be made between the SAA hexamers, and the hexameric, membrane inserting structure of Abeta that we have reported recently.
Curtain CC, Ali F, Volitakis I, Cherny RA, Norton RS, Beyreuther K, Barrow CJ, Masters CL, Bush AI, Barnham KJ.
Alzheimer's disease amyloid-beta binds copper and zinc to generate an allosterically ordered membrane-penetrating structure containing superoxide dismutase-like subunits.
J Biol Chem. 2001 Jun 8;276(23):20466-73.
Curtain CC, Ali FE, Smith DG, Bush AI, Masters CL, Barnham KJ.
Metal ions, pH, and cholesterol regulate the interactions of Alzheimer's disease amyloid-beta peptide with membrane lipid.
J Biol Chem. 2003 Jan 31;278(5):2977-82.
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