Amyloid β-protein (Aβ42) oligomerization is an early event in Alzheimer’s disease (AD). Current diagnostic methods using sequence-specific antibodies against less toxic fibrillar and monomeric Aβ42 run the risk of overdiagnosis. Hence, conformation-specific antibodies against neurotoxic Aβ42 oligomers have garnered much attention for developing more accurate diagnostics. Antibody 24B3, highly specific for the toxic Aβ42 conformer that has a turn at Glu22 and Asp23, recognizes a putative Aβ42 dimer, which forms stable and neurotoxic oligomers more potently than the monomer. 24B3 significantly rescues Aβ42-induced neurotoxicity, whereas sequence-specific antibodies such as 4G8 and 82E1, which recognizes the N-terminus, do not. The ratio of toxic to total Aβ42 in the cerebrospinal fluid of AD patients is significantly higher than in control subjects as measured by sandwich ELISA using antibodies 24B3 and 82E1. Thus, 24B3 may be useful for AD diagnosis and therapy.

The formation of soluble oligomers of amyloid β42 and 40 (Aβ42, Aβ40) is the initial event in the pathogenesis of Alzheimer's disease (AD). Based on previous systematic proline replacement and solid-state NMR, we proposed a toxic dimer structure of Aβ42, a highly aggregative alloform, with a turn at positions 22 and 23, and a hydrophobic core in the C-terminal region. However, in addition to Aβ42, Aβ40 dimers can also contribute to AD progression because of the more abundance of Aβ40 monomer in biological fluids. Here, we describe the synthesis and characterization of three dimer models of the toxic-conformation constrained E22P-Aβ40 using l,l-2,6-diaminopimeric acid (DAP) or l,l-2,8-diaminoazelaic acid (DAZ) linker at position 30, which is incorporated into the intermolecular parallel β-sheet region, and DAP at position 38 in the C-terminal hydrophobic core. E22P-A30DAP-Aβ40 dimer (1) and E22P-A30DAZ-Aβ40 dimer (2) existed mainly in oligomeric states even after 2 weeks incubation without forming fibrils, unlike the corresponding monomer. Their neurotoxicity toward SH-SY5Y neuroblastoma cells was very weak. In contrast, E22P-G38DAP-Aβ40 dimer (3) formed β-sheet-rich oligomeric aggregates, and exhibited more potent neurotoxicity than the corresponding monomer. Ion mobility-mass spectrometry suggested that high molecular-weight oligomers (12-24-mer) of 3 form, but not for 1 and 2 after 4 h incubation. These findings indicate that formation of the hydrophobic core at the C-terminus, rather than intermolecular parallel β-sheet, triggers the formation of toxic Aβ oligomers. Compound 3 may be a suitable model for studying the etiology of Alzheimer's disease.

Herein we report that a preferable inhibition of the nucleation phase of Aβ42, related to the formation of toxic oligomers, by triterpenoids from medicinal herbs originates from a salt bridge of their carboxy groups with Lys16 and 28 in Aβ42. Such a direct interaction targeting the monomer, dimer, and trimer suppressed further oligomerization. In contrast, the corresponding congeners without carboxy groups failed to do so.

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The only trimer model to exhibit weak but significant neurotoxicity against SH-SY5Y cells was the one which was linked at position 38.

The prevention of amyloid aggregation is promising for the treatment of age-related diseases such as Alzheimer's (AD) and type 2 diabetes (T2D). Ten antioxidant flavonoids isolated from the medicinal halophyte Tamarix gallica were tested for their amyloid aggregation inhibition potential. Glucuronosylated flavonoids show relatively strong inhibitory activity of Amyloid β (Aβ) and human islet amyloid polypeptide (hIAPP) aggregation compared to their aglycone analogs. Structure-activity relationship of the flavonoids suggests that the catechol moiety is important for amyloid aggregation inhibition, while the methylation of the carboxyl group in the glucuronide moiety and of the hydroxyl group in the aglycone flavonoids decreased it.Key words amyloid aggregation; glucuronosylated flavonoid; Tamarix gallica; Alzheimer's disease; type 2 diabetes The incidence of both disturbances Alzheimer's disease (AD) and type 2 diabetes (T2D) is increasing and has become a major public health concern in many industrialized countries. Despite intense research, best strategies to treat/prevent these costly diseases are still under investigation. However, it is now widely recognized that AD and T2D share many pathophysiological features including increased oxidative stress and amyloid aggregation. 1-4)Amyloid β (Aβ) is the component of the amyloid deposits in the AD brain, 5) while the component of the amyloidogenic peptide deposit in the diabetic pancreatic islets of Langerhans is identified as islet amyloid polypeptide (IAPP), a 37-amino acid peptide. 6,7) Although the amino acid sequences of amyloidogenic proteins are diverse, they all adopt a similar structure in aggregates called cross-β-spine.8) Extensive studies in the past years have found that, similar to Aβ 1-42 , IAPP forms early intermediate assemblies as spherical oligomers 9,10) that are recognized by soluble Aβ oligomers antibody, 11) implicating that these oligomers possess a common folding pattern or conformation.4) The similarities in Aβ 1-42 and IAPP oligomers can be used to investigate the prevention of oxidative stress and amyloid aggregation inhibition related to AD and T2D, since potent therapeutic agents such as antioxidants with a catechol moiety, proved to inhibit Aβ aggregation, 12-16) may play a key role inhibiting the aggregation of human IAPP (hIAPP) in case of patients with diabetes.The powerful antioxidant activity of the medicinal halophyte Tamarix gallica L. has been reported as exhibiting a remarkable spectrum of biochemical and pharmacological activities. Although traditionally used for the treatment of various liver disorders and marketed as a herbal medicine in many countries, [17][18][19] there have been no reports on the use of this plant for the treatment or prevention of AD or T2D. Therefore, the aim of this research is to investigate the protective effect of T. gallica towards both disturbances by isolation and identification of the Aβ and hIAPP aggregation inhibitors with antioxidant potential. MATERIALS AND METHODS MaterialsThe aerial par...

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Amyloid fibrils in senile plaque mainly consist of the 40-mer and 42-mer amyloid β-proteins (Aβ40 and Aβ42). Although Aβ42 plays more important role in the pathogenesis of Alzheimer's disease (AD), Aβ40 could be involved in the progression of AD pathology because of its large amount. Recent studies revealed that variable sizes of Aβ oligomers contributed to the neuronal death and cognitive dysfunction. However, how large oligomeric species are responsible for AD pathogenesis remains unclear. We previously proposed a toxic dimer model of Aβ with turn structure at positions 22 and 23 using solid-state NMR and systematic proline replacement. Based on this model, we herein show the synthesis and biological activities of an E22P-Aβ40 dimer at position 30, which was connected to l,l-2,6-diaminopimeric acid. The E22P-Aβ40 dimer formed stable 6∼8-mer oligomers without amyloid fibrils, but was not neurotoxic on human neuroblastoma cells. On the other hand, E22P-Aβ40 generated high molecular-weight oligomers into fibrils, and showed the neurotoxicity. These results suggest that such kind of Aβ40 dimer with a parallel β-sheet might not be pathological.