A fundamental question about the pathogenesis of Alzheimer’s disease (AD) is how monomeric, nontoxic amyloid β-protein (Aβ) is converted to its toxic aggregates in the brain. The author previously identified a unique Aβ species in the AD brain, which is characterized by its binding to GM1 ganglioside (GM1). On the basis of the molecular characteristics of GM1-bound Aβ (GAβ), the author hypothesized that GM1 plays a critical role in the process. The author recently examined this possibility using a novel monoclonal antibody raised against purified GAβ and validated that GAβ is endogenously generated in the brain and accelerates Aβ assembly by acting as a seed. Furthermore, the author provided a possibility that aging and the expression of apolipoprotein E4 facilitate Aβ assembly in the brain through an increase in the GM1 content in the neuronal membranes, which likely induces GAβ generation. The author’s results imply a mechanism underlying the onset of AD and also provide a new insight into development of novel therapeutic strategy.
Ariga T, Kobayashi K, Hasegawa A, Kiso M, Ishida H, Miyatake T.2001. Characterization of high-affinity binding between ganglio-sides and amyloid β-protein. Arch Biochem Biophys388:225-230.
2.
Choo-Smith LP, Garzon-Rodriguez W, Glabe CG, Surewicz WK. 1997. Acceleration of amyloid fibril formation by specific binding of Aβ-(1-40) peptide to ganglioside-containing membrane vesicles. J Biol Chem272:22987-22990.
3.
Choo-Smith LP, Surewicz WK. 1997. The interaction between Alzheimer amyloid β (1-40) peptide and ganglioside GM1-containing membranes. FEBS Lett402:95-98.
4.
Cras P, Van Harskamp F, Hendriks L, Ceuterick C, van Duijn CM, Stefanko SZ, and others. 1998. Presenile Alzheimer dementia characterized by amyloid angiopathy and large amyloid core type senile plaques in the APP 692Ala—Gly mutation. Acta Neuropathol (Berl)96:253-260.
5.
Davis J, Van Nostrand WE. 1996. Enhanced pathologic properties of Dutch-type mutant amyloid β-protein. Proc Natl Acad Sci U S A93:2996-3000.
6.
Ding TT, Harper JD. 1999. Analysis of amyloid-β assemblies using tapping mode atomic force microscopy under ambient conditions. Methods Enzymol309:510-525.
7.
Ehehalt R, Keller P, Haass C, Thiele C, Simons K.2003. Amyloidogenic processing of the Alzheimer β-amyloid precursor protein depends on lipid rafts. J Cell Biol160:113-123.
8.
Harper JD, Lansbury PT Jr.1997. Models of amyloid seeding in Alzheimer’s disease and scrapie: mechanistic truths and physiological consequences of the time-dependent solubility of amyloid proteins. Annu Rev Biochem66:385-407.
9.
Hayashi H, Igbavboa U, Hamanaka H, Kobayashi M, Fujita SC, Wood WG, and others. 2002. Cholesterol is increased in the exofacial leaflet of synaptic plasma membranes of human apolipoprotein E4 knock-in mice. Neuroreport13:383-386.
10.
Hayashi H, Kimura N, Yamaguchi H, Hasegawa K, Yokoseki T, Shibata M, and others. 2004. A seed for Alzheimer amyloid in the brain. J Neurosci24:4894-4902.
11.
Igbavboa U, Avdulov NA, Schroeder F, Wood WG.. 1996. Increasing age alters transbilayer fluidity and cholesterol asymmetry in synaptic plasma membranes of mice. J Neurochem66:1717-1725.
12.
Kakio A, Nishimoto SI, Yanagisawa K, Kozutsumi Y, Matsuzaki K.2001. Cholesterol-dependent formation of GM1 ganglioside-bound amyloid β-protein, an endogenous seed for Alzheimer amyloid. J Biol Chem276:24985-24990.
13.
Kakio A, Yano Y, Takai D, Kuroda Y, Matsumodo O, Kozutsumi Y, and others. 2004. Interaction between amyloid Bβ-protein aggregates and membranes. J Pept Sci10:612-621.
14.
Kakio A, Nishimoto S, Yanagisawa K, Kozutsumi Y, Matsuzaki K.2002. Interactions of amyloid β-protein with various gangliosides in raft-like membranes: importance of GM1 ganglioside-bound form as an endogenous seed for Alzheimer amyloid. Biochemistry41:7385-7390.
15.
Kawarabayashi T, Shoji M, Younkin LH, Wen-Lang L, Dickson DW, Murakami T, and others. 2004. Dimeric amyloid β protein rapidly accumulates in lipid rafts followed by apolipoprotein E and phosphorylated tau accumulation in the Tg2576 mouse model of Alzheimer’s disease. J Neurosci24:3801-3809.
16.
Kumar-Singh S, Cras P, Wang R, Kros JM, van Swieten J, Lubke U, and others. 2002. Dense-core senile plaques in the Flemish variant of Alzheimer’s disease are vasocentric. Am J Pathol161:507-520.
17.
Levy E, Carman MD, Fernandez-Madrid IJ, Power MD, Lieberburg I, van Duinen SG, and others. 1990. Mutation of the Alzheimer’s disease amyloid gene in hereditary cerebral hemorrhage, Dutch type. Science248:1124-1126.
18.
Matsuzaki K, Horikiri C.1999. Interactions of amyloid β-peptide (1-40) with ganglioside-containing membranes. Biochemistry38:4137-4142.
19.
McLaurin J, Chakrabartty A.1996. Membrane disruption by Alzheimer β-amyloid peptides mediated through specific binding to either phospholipids or gangliosides. Implications for neurotoxicity. J Biol Chem271:26482-26489.
20.
McLaurin J, Franklin T, Fraser PE, Chakrabartty A.1998. Structural transitions associated with the interaction of Alzheimer β-amyloid peptides with gangliosides. J Biol Chem273:4506-4515.
21.
Naiki H, Nakakuki K.1996. First-order kinetic model of Alzheimer’s β-amyloid fibril extension in vitro. Lab Invest74:374-383.
22.
Nilsberth C, Westlind-Danielsson A, Eckman CB, Condron MM, Axelman K, Forsell C, and others. 2001. The ‘Arctic’APP mutation (E693G) causes Alzheimer’s disease by enhanced Aβ protofibril formation. Nat Neurosci4:887-893.
23.
Parton RG.. 1994Ultrastructural localization of gangliosides; GM1 is concentrated in caveolae. J Histochem Cytochem42:155-166.
24.
Rozemuller AJ, Roos RA, Bots GT, Kamphorst W, Eikelenboom P, Van Nostrand WE. 1993. Distribution of β/A4 protein and amyloid precursor protein in hereditary cerebral hemorrhage with amyloidosis-Dutch type and Alzheimer’s disease. Am J Pathol142:1449-1457.
25.
Selkoe DJ. 1994. Cell biology of the amyloid β-protein precursor and the mechanism of Alzheimer’s disease. Annu Rev Cell Biol10:373-403.
26.
Selkoe DJ. 1997. Alzheimer’s disease: genotypes, phenotypes, and treatments. Science275:630-631.
27.
Simons K, Ikonen E.1997. Functional rafts in cell membranes. Nature387:569-572.
28.
Suzuki N, Iwatsubo T, Odaka A, Ishibashi Y, Kitada C, Ihara Y.1994. High-tissue content of soluble β1-40 is linked to cerebral amyloid angiopathy. Am J Pathol145:452-460.
29.
Telling GC, Scott M, Mastrianni J, Gabizon R, Torchia M, Cohen FE, and others. 1995. Prion propagation in mice expressing human and chimeric PrP transgenes implicates the interaction of cellular PrP with another protein. Cell83:79-90.
30.
Van Nostrand WE, Melchor JP, Ruffini L.1998. Pathologic amyloid beta-protein cell surface fibril assembly on cultured human cerebrovascular smooth muscle cells. J Neurochem70:216-223.
31.
Yamamoto N, Hasegawa K, Matsuzaki K, Naiki H, Yanagisawa K.2004. Environment- and mutation-dependent aggregation behavior of Alzheimer amyloid β-protein. J Neurochem90:62-69.
32.
Yamamoto N, Igbavboa U, Shimada Y, Ohno-Iwashita Y, Kobayashi M, Wood WG, and others. 2004. Accelerated Aβ aggregation in the presence of GM1-ganglioside-accumulated synaptosomes of aged apoE4-knock-in mouse brain. FEBS Lett569:135-139.
33.
Yanagisawa K, McLaurin J, Michikawa M, Chakrabartty A, Ihara Y.1997. Amyloid β-protein (Aβ) associated with lipid molecules: immunoreactivity distinct from that of soluble Aβ. FEBS Lett420:43-46.
34.
Yanagisawa K, Odaka A, Suzuki N, Ihara Y.1995. GM1 ganglioside-bound amyloid β-protein (Aβ): a possible form of preamyloid in Alzheimer’s disease. Nat Med1:1062-1066.
