It was reported that oral

It was reported that oral administration of CSZ to C57BL/6J mice significantly improved spatial learning and memory, and prevented Aβ-induced immunoresponse in Aβ25-35-injected mice. However, post-treatment with CSZ after Aβ25-35 administration, when Aβ was already accumulated, did not prevent Aβ-induced neuropathology. Furthermore, CSZ did not affect the neprilysin and insulin-degrading enzymes involved in the degradation of the Aβ peptide [35]. In addition, it was reported that CSZ significantly facilitates the clearance of soluble Aβ with rescue of cognitive deficits in a mouse model of cerebral amyloid angiopathy (Tg-SwDI mice) [22]. Finally, we showed that CSZ inhibits Aβ aggregation, especially the early stage of Aβ aggregation, low-order oligomerization. Several recent studies have revealed that low-order oligomeric forms of Aβ are especially toxic [7], [27], [32], [41], [42]. Low-order Aβ oligomers such as dimers and trimers from the conditioned medium of amyloid precursor protein (APP)-expressing CHO of course were found to cause progressive loss of synapses in rat hippocampal slices [41]. Aβ oligomers extracted from AD brains disrupted synaptic function, and dimers were the smallest oligomers showing activity [42]. A structure–cytotoxicity study using pure Aβ oligomer populations demonstrated that dimers, trimers, and tetramers are significantly more toxic than monomers [27]. This greater toxicity correlated with the β-sheet ratio as well as the capacity of the oligomers to function as seeds for fibril assembly [27]. Using PICUP and biological assays, we previously reported that inhibition of low-order Aβ oligomer formation reduced cellular toxicity and synaptic dysfunction induced by oligomers [29]. Thus, the potency of CSZ to block formation of low-order Aβ oligomers suggests possible therapeutic value for suppressing the formation of proximate neurotoxins in AD. There is also evidence that CSZ improves cognitive decline in patients with AD or MCI [14], [37], [44], [45]. Generally, patients take 100 mg CSZ orally twice a day as an antiplatelet drug, and one mechanism of the cognitive improvement may be through its anti-thrombotic activity. Plasma concentration at steady state after multiple doses ranges between 1.5–3.2 μM. Tissue concentrations of CSZ as measured by radioactive carbon were 993 ng/ml (2.69 μM) in plasma, 99 ng/g in cerebrum, and 946 ng/g in hypophysis after oral administration of 10 mg/kg CSZ to rats [1]. The effective concentrations identified in this anti-aggregation study are about 10 times higher than the serum concentration found in clinical settings and brain concentration might be lower than the serum concentration; however, cerebrospinal fluid levels of Aβ were reported to be 200–300 pg/ml (∼50 pM) in AD patients[13], which are about 1000,000 times lower than the Aβ concentration in this study. Thus, with our considering of the effective ratio of Aβ to CSZ (1:1 ∼ 1:4 ratio), we cannot rule out the possibility that low concentrations of CSZ may exhibit anti-oligomeric activities in vivo when administered at high doses for an extended period. Further studies using in vivo AD models and longer CSZ treatments are required for validation.
Conclusion The present study revealed that CSZ inhibits oligomerization as well as fibril formation of Aβ1-40 and Aβ1-42, and suggests that CSZ may contribute to AD prevention or control of disease progression.
Disclosures
Author contributions
Acknowledgments We thank Ms. Mika Honda for excellent technical support. This study was supported by Scientific Research (C) (26461266) from the Japanese Ministry of Education, Culture, Sports, Science and Technology, Japan (K.O.), and Takeda Foundation for Life Science Research (K.O.).
The amyloid hypothesis of Alzheimer’s disease (AD) holds that the accumulation of the amyloid-β (Aβ) peptide leads to synaptic dysfunction, neurodegeneration, and ultimately symptoms . The vast majority of potential disease-modifying treatments developed in recent years are directed against Aβ, including inhibitors of the synthetic enzymes gamma-secretase and beta-secretase, and Aβ aggregation inhibitors. However, the most elaborated anti-Aβ approach is immunotherapy, including both active vaccines to stimulate the immune system to produce its own antibodies and passive immunization through the administration of exogenous antibodies.