The current results also demonstrated tendencies toward decr

The current results also demonstrated tendencies toward decreased serum Aβ40 levels and increased Aβ42 levels during the 1-year follow-up. These tendencies are consistent with the results of a previous study that evaluated Aβs in the CSF of patients with late-life depression (Pomara et al., 2016). That previous study also demonstrated decreased CSF Aβ40 levels and increased Aβ42 levels during a 3-year follow-up, similar to our results. Moreover, the study showed that the changes in Aβ42 levels were associated with the severity of depression and that the changes in the Aβ40 levels were associated only with age. The authors suggested that Aβ42 may have state-dependency and that Aβ40 may be associated with age. Based on the results of the present study, we also suggest that the serum Aβ42 levels and Aβ40/Aβ42 ratios may recover toward a healthy level from the acute phase of depression to remission depending on the patient's state. In contrast, a longitudinal study that investigated associations between plasma Aβs and depression demonstrated that the plasma Aβ42/Aβ40 ratios were associated with the development of depression in ApoE4 carriers, independent of dementia (Metti et al., 2013). The authors suggested that plasma Aβ may be a biomarker for some types of depression. Recent animal studies have demonstrated that Aβ-treated rats show depression-related behavioral and biochemical changes (Colaianna et al., 2010) and that these Aβ-induced changes recover by treatment with antidepressants (Schiavone et al., 2017). These previous reports indicate that Aβ might influence the occurrence of depressive symptoms. Combining these previous findings and the present results, we also speculate that AD and some types of depression may have a common underlying pathway. The present study has several limitations. First, all of the patients with MDD were receiving antidepressant medication, and it is a possible that serum LY 2389575 hydrochloride synthesis and Aβ levels might have been influenced by this medication. However, it has been reported that plasma Aβ42 levels do not change with antidepressant treatment (Pomara et al., 2006, Sun et al., 2007, Baba et al., 2012, Namekawa et al., 2013), and a multiple regression analysis of the present results also showed no correlation between total antidepressant dose and Aβ indices or cortisol levels (data not shown). Therefore, antidepressant treatment is unlikely to be a major factor influencing the present results. Second, the blood samples in this study were collected at 7:00A.M. Plasma cortisol levels show diurnal variation, with the mean peak occurring at around 8:00A.M. and the mean nadir occurring at around midnight. Additionally, the mean difference in plasma cortisol levels between depressed patients and healthy subjects seems to be small at the circadian peak (Wong et al., 2000). This might explain the lack of correlation between the cortisol and serum Aβ levels at admission. Thus, lack of consideration of circadian changes in the serum cortisol levels is a limitation of this study. Third, the number of follow-up patients was only 27. The small number of patients is a limitation, and further studies with larger numbers of patients are needed. Fourth, some studies have demonstrated a relationship between blood and CSF Aβ levels (Kawarabayashi et al., 2001, Mehta et al., 2001), while several other studies have failed to show this relationship (Giedraitis et al., 2007, Le Bastard et al., 2009). The lack of CSF data is another limitation of the present study. However, because it is less invasive, obtaining serum samples may be better than obtaining CSF samples for measurements at multiple time points.
Acknowledgments This work was supported by grants from the Research Support Foundation of the Juntendo Institute of Mental Health.
Introduction Amyloid depositions of protein aggregation are associated with more than 25 degenerative diseases, including Alzheimer's disease [1,2], Parkinson's disease [3,4], prion conditions [5] and type-2 diabetes [[6], [7], [8]]. Despite differences in sequence and length of aggregating proteins, different amyloid proteins show similar all-or-none sigmoidal aggregation kinetics and common fibrillar morphology with the characteristic cross-β core of their final aggregates. These similarities together with the shared symptoms of different amyloid diseases suggest a potentially common mechanism for amyloid cytotoxicity [[9], [10], [11]]. Although mature fibrils were long suspected to be the toxic disease agents, more and more experimental studies with different amyloid proteins suggested that the small soluble oligomer intermediates populated during aggregation are more toxic [[12], [13], [14]]. These oligomer intermediates correspond to the mixture of many small aggregates with continuous distributions in sizes and secondary structure contents, not all of which are cytotoxic. In addition, several non-fibril intermediates have been shown important and applicable to develop small molecules that are able to regulate Aβ aggregation and cytotoxicity [[15], [16], [17], [18]]. As the aggregation intermediates, these oligomers are highly heterogeneous, polymorphic and transient in nature, imposing major experimental challenges for pinpointing and characterizing the exact toxic species of amyloid aggregation.