Isolation and Characterization of Patient-derived, Toxic, High Mass Amyloid beta-Protein (A beta) Assembly from Alzheimer Disease Brains

作者：Noguchi Akihiko; Matsumura Satoko; Dezawa Mari; Tada Mari; Yanazawa Masako; Ito Akane; Akioka Manami; Kikuchi Satoru; Sato Michio; Ideno Shouji; Noda Munehiro; Fukunari Atsushi; Muramatsu Shin ichi; Itokazu Yutaka; Sato Kazuki; Takahashi Hitoshi; Teplow David B; Nabeshima Yo ichi; Kakita Akiyoshi; Imahori Kazutomo; Hoshi Minako^*

来源：JOURNAL OF BIOLOGICAL CHEMISTRY, 2009, 284(47): 32895-32905.

DOI：10.1074/jbc.M109.000208

Amyloid beta-protein (A beta) assemblies are thought to play primary roles in Alzheimer disease (AD). They are considered to acquire surface tertiary structures, not present in physiologic monomers, that are responsible for exerting toxicity, probably through abnormal interactions with their target(s). Therefore, A beta assemblies having distinct surface tertiary structures should cause neurotoxicity through distinct mechanisms. Aiming to clarify the molecular basis of neuronal loss, which is a central phenotype in neurodegenerative diseases such as AD, we report here the selective immunoisolation of neurotoxic 10-15-nm spherical A beta assemblies termed native amylospheroids (native ASPDs) from AD and dementia with Lewy bodies brains, using ASPD tertiary structure-dependent antibodies. In AD patients, the amount of native ASPDs was correlated with the pathologic severity of disease. Native ASPDs are anti-pan oligomer A11 antibody-negative, high mass (> 100 kDa) assemblies that induce degeneration particularly of mature neurons, including those of human origin, in vitro. Importantly, their immuno-specificity strongly suggests that native ASPDs have a distinct surface tertiary structure from other reported assemblies such as dimers, A beta-derived diffusible ligands, and A11-positive assemblies. Only ASPD tertiary structure-dependent antibodies could block ASPD-induced neurodegeneration. ASPDs bind presynaptic target(s) on mature neurons and have a mode of toxicity different from those of other assemblies, which have been reported to exert their toxicity through binding postsynaptic targets and probably perturbing glutamatergic synaptic transmission. Thus, our findings indicate that native ASPDs with a distinct toxic surface induce neuronal loss through a different mechanism from other A beta assemblies.

• 出版日期2009-11-20