Ultracentrifugation of AD brain was reported to remove of A

Ultracentrifugation of AD Prednisone synthesis was reported to remove >99.95% of Aβ, while only reducing seeding capacity by 70% (Langer et al., 2011). This suggests that the most potent seeding Aβ species are relatively small soluble oligomers rather than larger insoluble fibrils. It was also noted that this potently seeding soluble Aβ is destroyed by PK-digestion (Langer et al., 2011); the Aβ of our prion-like clones is also PK-sensitive. However, seeding Aβ appears not to be present in CSF, as intracerebral injection of CSF, a cell-free physiological source of soluble Aβ, from aged AD patients failed to seed aggregation (Fritschi et al., 2014). A 2016 study showed that some of the seeding Aβ from a homogenized mouse brain with plaques was associated with mitochondrial membranes and was non-fibrillar (Marzesco et al., 2016); this is consistent with intracellular seeding Aβ in the brain, though after homogenization of plaque-ridden brain an extra or intra-cellular origin of a given pool of Aβ is difficult to ascertain. Theoretically it also seems plausible that oligomers can be more biologically active as seeds due to their higher surface area and higher molarity at equivalent weights compared to fibrils. Indeed, it has been observed that the prions in Creutzfeldt-Jakob disease with the greatest prion-like conversion potency are smaller protease sensitive oligomers (Kim et al., 2012). In humans it has been noted that the soluble pool of Aβ in AD brain correlates with cognitive decline (McLean et al., 1999; Wang et al., 1999). It has furthermore been observed that it is specifically the fibrillar (OC positive) oligomer load that correlates with cognitive decline and that they are absent in CSF (Tomic et al., 2009). Thus, it is noteworthy that the intracellular prion-like Aβ we report also seems to consist of fibrillar oligomers. However, while immunofluorescence and dot blot show more OC labeling in prion-like cells, the FTIR data is more ambiguous. The increased anti-parallel structures we observe are associated with Aβ oligomers, but more so with A11 than OC (Cerf et al., 2009; Wu et al., 2010); though those studies were based on pure protein preparations, not cells.
Conclusions
Introduction Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by the progressive decline of memory, cognitive functions, and changes in behavior and personality (Kandimalla et al., 2016). AD is also characterized by deposition of amyloid β (Aβ) plaques and neurofibrillary tangles in the brain (Sevigny et al., 2016). Recently, there are many studies to show an essential link between diabetes mellitus and AD such as common features of insulin resistance (Liu et al., 2011, Pugazhenthi et al., 2016). In addition, innate immunity plays an important role in the occurrence and development of diabetes and AD, which increases the risk of developing type 2 diabetes and AD (Huang et al., 2017). Insulin and its receptor are widely distributed in the brain (Havrankova et al., 1978a, Havrankova et al., 1978b). It has been reported that insulin exists also in cerebrospinal fluid, and that insulin elongates neuronal axon, potentiates protein synthesis in neurons, and increases synapse formation (Dickson, 2003, Kremerskothen et al., 2002, Laron, 2009, Song et al., 2003). Moreover, hypothalamic insulin inhibits feeding behavior (Obici et al., 2002, Vogt et al., 2014) and hippocampal insulin modulates memory and learning (McNay et al., 2010). These many reports suggest that insulin in brain is essential to maintain normal brain functions (Unger et al., 1991, Zhao et al., 1999). It was reported that brain insulin was partly derived from pancreatic β cells to be permeated through blood-brain barrier (Banks, 2004) but brain homogenates contained high concentrations of insulin independently of peripheral insulin levels (Havrankova et al., 1979). Among brain cells in rat, neurons have been reported to have mRNA expressions of preproinsulin 1 (ins1), which is an insulin precursor specific for rodents, and preproinsulin 2 (ins2), which is another insulin precursor comparable to human insulin, and also to express insulin protein (Nemoto et al., 2013, Schechter et al., 1996). On the other hand, it was suggested that insulin release from glial cells was much lower than that from neuronal cells (Clarke et al., 1986).