Aggregation and fibril formation of amyloid-␤ (A␤) peptides A␤40 and A␤42 are central events in the pathogenesis of Alzheimer disease. Previous studies have established the ratio of A␤40 to A␤42 as an important factor in determining the fibrillogenesis, toxicity, and pathological distribution of A␤. To better understand the molecular basis underlying the pathologic consequences associated with alterations in the ratio of A␤40 to A␤42, we probed the concentration-and ratio-dependent interactions between well defined states of the two peptides at different stages of aggregation along the amyloid formation pathway. We report that monomeric A␤40 alters the kinetic stability, solubility, and morphological properties of A␤42 aggregates and prevents their conversion into mature fibrils. A␤40, at approximately equimolar ratios (A␤40/A␤42 ϳ 0.5-1), inhibits (>50%) fibril formation by monomeric A␤42, whereas inhibition of protofibrillar A␤42 fibrillogenesis is achieved at lower, substoichiometric ratios (A␤40/A␤42 ϳ 0.1). The inhibitory effect of A␤40 on A␤42 fibrillogenesis is reversed by the introduction of excess A␤42 monomer. Additionally, monomeric A␤42 and A␤40 are constantly recycled and compete for binding to the ends of protofibrillar and fibrillar A␤ aggregates. Whereas the fibrillogenesis of both monomeric species can be seeded by fibrils composed of either peptide, A␤42 protofibrils selectively seed the fibrillogenesis of monomeric A␤42 but not monomeric A␤40. Finally, we also show that the amyloidogenic propensities of different individual and mixed A␤ species correlates with their relative neuronal toxicities. These findings, which highlight specific points in the amyloid peptide equilibrium that are highly sensitive to the ratio of A␤40 to A␤42, carry important implications for the pathogenesis and current therapeutic strategies of Alzheimer disease.Alzheimer disease is a progressive neurodegenerative disorder characterized by age-related accumulation of amyloid-␤ (A␤) 2 proteins in the form of diffuse and neuritic plaques in regions of the brain that are affected by the disease (1-4). The discovery of A␤ fibrils as principal constituents of amyloid plaques led to the emergence of the amyloid hypothesis, which implicates the aggregation of A␤ as the primary trigger for a cascade of pathogenic events culminating in neurodegeneration and development of AD (1, 5-7). A␤ proteins are produced in neuronal and non-neuronal cells as a result of sequential proteolytic cleavage of the type I transmembrane amyloid precursor protein (APP) by ␤-and ␥-secretases (8 -12). Depending on the site of APP cleavage by ␥-secretase, A␤ proteins of various chain lengths are generated (13-16). The predominant A␤ species in human plasma and CSF, as well as in conditioned media of APP-expressing cells, is A␤40 (ϳ90%) followed by A␤42 (ϳ10%). Despite the preponderance of A␤40, in vivo studies reveal that A␤42 is a major constituent of amyloid plaques and suggest that A␤42 aggregation plays a critical role in the initiation of plaque f...

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Aggregation of amyloid-␤ (A␤)2 peptides and deposition into neuritic plaques are hallmark features of Alzheimer disease (AD) neuropathology (1, 2). Therefore, research efforts during the past 3 decades have focused on elucidating the mechanisms of A␤ fibrillization, identifying toxic species, and developing strategies to inhibit and/or reverse A␤ amyloid formation and toxicity in vivo (3,4).A␤ peptides are produced as soluble monomers (5, 6) and undergo oligomerization and amyloid fibril formation via a nucleation-dependent polymerization process (7,8). During the course of in vitro A␤ fibril formation, various nonfibrillar aggregation intermediates, collectively called soluble oligomers or protofibrils, have been shown to precede the emergence of fibrils. Increasing evidence from various sources points to A␤ oligomers/protofibrils as putative toxic species in AD pathogenesis and suggests that these species are potential therapeutic targets for treating AD (reviewed in Refs. 9, 10). Although the toxic oligomer hypothesis has emerged as one of the major current working hypotheses in AD research, the development of effective diagnostic tools and therapies on the basis of this hypothesis has yet to be realized (11-13). This is partially due to the fact that identification of a single toxic A␤ species that correlates with AD progression and severity remains elusive. Furthermore, the exact mechanisms by which these species contribute to A␤ toxicity in vivo and the nature of the toxic species are not yet fully understood. Recent evidence suggests that accelerating the process of A␤ fibrillization greatly enhances A␤ toxicity in vitro (14) and the spread of amyloid pathology in vivo (15-17).Despite significant efforts by different groups to isolate specific intermediates along the amyloid formation pathway (12, 18 -22), the inherent heterogeneity of the process and metastable nature of A␤ oligomers (11-13) have precluded the isolation of a single toxic species. Unless covalently crosslinked (23), A␤ oligomers do not exist as stable entities, i.e. they evolve into higher order aggregates and, if they are onpathway intermediates, convert into fibrils (19). Therefore, it is plausible to assume that the structural dynamics of oligomers and factors that govern their interconversion and/or growth might influence some of the disease-related cytotoxic effects of A␤. In other words, an ongoing polymerization

(H.K., M.M.) Xyloglucan endotransglucosylases/hydrolases (XTHs) that mediate cleavage and rejoining of the b (1-4)-xyloglucans of the primary cell wall are considered to play an important role in the construction and restructuring of xyloglucan cross-links. A novel rice (Oryza sativa) XTH-related gene, OsXTH8, was cloned and characterized after being identified by cDNA microarray analysis of gibberellin-induced changes in gene expression in rice seedlings. OsXTH8 was a single copy gene; its full-length cDNA was 1,298 bp encoding a predicted protein of 290 amino acids. Phylogenetic analysis revealed that OsXTH8 falls outside of the three established subfamilies of XTH-related genes. OsXTH8 was preferentially expressed in rice leaf sheath in response to gibberellic acid. In situ hybridization and OsXTH8 promoter GUS fusion analysis revealed that OsXTH8 was highly expressed in vascular bundles of leaf sheath and young nodal roots where the cells are actively undergoing elongation and differentiation. OsXTH8 gene expression was up-regulated by gibberellic acid and there was very little effect of other hormones. In two genetic mutants of rice with abnormal height, the expression of OsXTH8 positively correlated with the height of the mutants. Transgenic rice expressing an RNAi construct of OsXTH8 exhibited repressed growth. These results indicate that OsXTH8 is differentially expressed in rice leaf sheath in relation to gibberellin and potentially involved in cell elongation processes.