Oligomers of β-amyloid 42 (Aβ42), rather than fibrils, drive the pathogenesis of Alzheimer's disease (AD). In particular, toxic oligomeric species called protofibrils (PFs) have attracted significant attention. Herein, we report RNA aptamers with higher affinity toward PFs derived from a toxic Aβ42 dimer than toward fibrils produced from WT Aβ42 or from a toxic, conformationally constrained Aβ42 variant, E22P–Aβ42. We obtained these RNA aptamers by using the preincubated dimer model of E22P–Aβ42, which dimerized via a linker located at Val-40, as the target of in vitro selection. This dimer formed PFs during incubation. Several physicochemical characteristics of an identified aptamer, E22P–AbD43, suggested that preferential affinity of this aptamer toward PFs is due to its higher affinity for the toxic dimer unit (KD = 20 ± 6.0 nm) of Aβ42 than for less-toxic Aβ40 aggregates. Comparison of CD data from the full-length and random regions of E22P–AbD43 suggested that the preferential binding of E22P–AbD43 toward the dimer might be related to the formation of a G-quadruplex structure. E22P–AbD43 significantly inhibited the nucleation phase of the dimer and its associated neurotoxicity in SH-SY5Y human neuroblastoma cells. Of note, E22P–AbD43 also significantly protected against the neurotoxicity of WT Aβ42 and E22P–Aβ42. Furthermore, in an AD mouse model, E22P–AbD43 preferentially recognized diffuse aggregates, which likely originated from PFs or higher-order oligomers with curvilinear structures, compared with senile plaques formed from fibrils. We conclude that the E22P–AbD43 aptamer is a promising research and diagnostic tool for further studies of AD etiology.

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Objective Telomere shortening is correlated with cell turnover and aging, but it has been recently suggested to occur not only by aging but by several biochemical fac- Results The results demonstrated that HCand/or DM patients with coronary diseases have significantly shorter telomere length than healthy controls (p=0.0014). Conclusion Telomere shortening may be involved in the mechanismsthat promote coronary diseases under some circumstances of metabolic disorders. (Internal Medicine 42: 150-153, 2003)

Background: The basal lipid peroxide concentration in the plasma of patients with hyperlipidemia may be related to atherosclerosis. Quantitative determination of lipid peroxides in the plasma is an important step in the overall evaluation of the biochemical processes leading to oxidative injury. Unfortunately, the currently available methods for lipid peroxidation lack specificity and sensitivity. Methods: Hyperlipidemic patients (44 males and 50 females), ages 12–82 years (mean ± SE, 53 ± 2.3 years for males, 58 ± 2.0 years for females, and 56 ± 14 years for total cases), and normolipidemic volunteers (controls, 32 males and 15 females), ages 13–90 years (49 ± 4 years for males, 65 ± 4 years for females, and 55 ± 24 years for total cases), were recruited in the present study. Plasma phosphatidylcholine hydroperoxide (PCOOH) was determined by chemiluminescence-HPLC (CL-HPLC). Results: Plasma PCOOH concentrations increased with age in both controls and hyperlipidemic patients. However, the mean plasma PCOOH concentration in patients with hyperlipidemia (331 ± 19 nmol/L; n = 94) was significantly (P <0.001) higher than in the controls (160 ± 65 nmol/L; n = 47). Plasma PCOOH concentrations were similar in three hyperlipidemic phenotypes: hypercholesterolemia (IIa), hypertriglyceridemia (IV), and combined hyperlipidemia (IIb). The mean plasma PCOOH in patients with treatment-induced normalized plasma lipids was 202 ± 17 nmol/L. There was no significant correlation between plasma PCOOH concentration and total cholesterol, triglycerides, or phospholipids in hyperlipidemic patients. For all subjects, there was a significantly positive correlation between plasma PCOOH and each lipid (total cholesterol, P = 0.0002; triglycerides, P = 0.0137; and phospholipids, P <0.0001). Analysis of fatty acids composition of plasma phosphatidylcholine showed significantly low concentrations of n-6 fatty acids moieties (linoleic acid and arachidonic acid) in patients compared with controls. Conclusions: Our results suggest that an increase in plasma PCOOH in patients with hyperlipidemia may be related to the development and progression of atherosclerosis, particularly in the elderly. Measurement of plasma PCOOH is useful for in vivo evaluation of oxidative stress.

In the present study, we focus on the proliferation of human arterial smooth muscle cells (SMCs) from NIDDM patients (DM-SMCs) to clarify the reactivity to the growth factor(s) in fetal calf serum (FCS) and the factor(s) secreted by T-cells. The proliferation of DM-SMCs was significantly greater than SMCs from nondiabetic patients (nonDM-SMC). DM-SMC conditioned medium (DM-condMed) increased the growth of nonDM-SMCs. These results suggest that the growth factor is secreted from DM-SMCs as an autocrine system, which increases the proliferation of nonDM-SMCs. T-cells increased DNA synthesis of SMCs, and DM-SMCs strikingly reacted to T-cells. The present results support a function of T-cells in stimulating SMC growth. In conclusion, human arterial SMC proliferation is increased in diabetes in the same fashion as in experimentally induced diabetes in animals through responses to growth factors and an increased autocrine system. These results provide a mechanism for the increase in atherosclerotic disease in diabetes.