A Ganglioside-induced Toxic Soluble Aβ Assembly

Abstract

The mechanism underlying plaque-independent neuronal death in Alzheimer disease (AD), which is probably responsible for early cognitive decline in AD patients, remains unclarified. Here, we show that a toxic soluble A␤ assembly (TA␤) is formed in the presence of liposomes containing GM1 ganglioside more rapidly and to a greater extent from a hereditary variant-type ("Arctic") A␤ than from wild-type A␤. TA␤ is also formed from soluble A␤ through incubation with natural neuronal membranes prepared from aged mouse brains in a GM1 gangliosidedependent manner. An oligomer-specific antibody (anti-Oligo) significantly suppresses TA␤ toxicity. Biophysical and structural analyses by atomic force microscopy and size exclusion chromatography revealed that TA␤ is spherical with diameters of 10 -20 nm and molecular masses of 200 -300 kDa. TA␤ induces neuronal death, which is abrogated by the small interfering RNA-mediated knockdown of nerve growth factor receptors, including TrkA and p75 neurotrophin receptor. Our results suggest that soluble A␤ assemblies, such as TA␤, can cause plaque-independent neuronal death that favorably occurs in nerve growth factor-dependent neurons in the cholinergic basal forebrain in AD.The poor correlation between amyloid load in the brain and the degree of neurological deficits in patients with Alzheimer disease (AD) 2 (1) or animal models of AD (2, 3) argues against amyloid fibrils being the primary toxic A␤ species. Recently, soluble A␤ assemblies, also referred to as A␤ oligomers (4), protofibrils (5, 6), or A␤-derived diffusible ligands (7), have attracted attention because of their potency to impair neuronal function or induce neuritic degeneration (7-13). Several possibilities have been proposed in regard to the toxicities of soluble A␤ assemblies (e.g. the binding of assemblies to target molecules on neuronal membranes (7,14) and the ubiquitous disruption of the plasma membrane in association with the perturbation of ionic homeostasis (15)). It is also noteworthy that neurotoxicities induced by soluble A␤ assemblies are mediated, at least in part, by the activation of signal transduction pathways, including those involving Src family kinases, extracellular signal-regulated kinase, or sphingomyelinases (7,11,16,17). Notably, the level of soluble A␤ assemblies increases in the brain and cerebrospinal fluid of AD patients (18,19,20,21,22), and oligomer-specific immunoreactivity is readily observed in the AD brain (23). Furthermore, the inhibition of long term potentiation and the impairment of cognitive function in vivo can be induced by natural A␤ oligomers (9, 24) or a specific A␤ assembly called A␤ ૽ 56, which has recently been isolated from Tg2576 mice (expressing a human amyloid precursor protein variant-linked familial AD) (25). Additionally, recent studies using AD mouse models revealed that soluble A␤ assemblies may play a role in the induction of tau pathology (26) and that the genetic deletion of ␤-secretase, which is responsible for A␤ production, rescues temporal memory deficit ...

Alzheimer's Therapeutics Targeting Amyloid Beta 1–42 Oligomers I: Abeta 42 Oligomer Binding to Specific Neuronal Receptors Is Displaced by Drug Candidates That Improve Cognitive Deficits

“…2 ). The non-saturable monomer binding may represent fibrils formed from high concentration monomer nucleated by binding to negatively charged surface molecules located on the cell body, and subsequent polymerization [59].…”

Up-and-down topological mode of amyloid β-peptide lying on hydrophilic/hydrophobic interface of ganglioside clusters

“…Thus, this Aβ species has been proposed to act as a seed for Aβ fibrillogenesis in the brain [8]. Furthermore, an enhanced formation of a GM1-induced toxic soluble Aβ(1-40) assembly has been reported in a hereditary variant-type Aβ termed Arctic [9]. It is also noteworthy that Aβ(1-40) forms toxic fibrils upon specific interaction with GM1 micelles [10].…”

Disease Modifying Therapies for Alzheimer's Disease Targeting AβOligomers: Implications for Therapeutic Mechanisms

“…ThT assay was performed as described previously [24]. A β solutions at 12.5  μ M were incubated with Abs (72D9 and IgG2b) at the indicated concentration and at 37°C for 24 h. The ThT fluorescence intensity in the incubation mixtures was determined using a spectrofluorophotometer (RF-5300PC) (Shimadzu Co., Kyoto, Japan).…”

“…We conducted the A β -induced toxicity assay in the presence or absence of Abs according to previously published methods [24]. Briefly, human neuroblastoma SH-SY5Y cells were cultured in DMEM (Invitrogen, Carlsbad, CA, USA) supplemented with 10% heat-inactivated horse serum (Invitrogen) and 5% FBS (Invitrogen).…”