Past research has been done on solubility of α -synuclein and its effect on cognition. Various immunoreactivities were measured in the frontal cortex of elderly individuals with no cognitive impairment (NCI), mild cognitive impairment (MCI) and early AD subjects. In early AD patients, α-synuclein solubility in the frontal cortex was significantly lower than that in MCI and NCI individuals. There were no differences in soluble α-synuclein levels between MCI and NCI patients. It could be inferred that a decrease in level of soluble α -synuclein may be an early feature of cognitive decline in aging and AD [
28]. The levels of mRNA and protein of soluble α -synuclein have been measured in individuals with PDD, DLB, AD and matched controls. It was found that levels of soluble α-synuclein proteins were lower in DLB and PDD subjects. There was no evidence for a corresponding decrease in α-synuclein mRNA levels, which indicates that the alteration of soluble α -synuclein in PD and DLB is at protein level, not at the mRNA level [
29]. In addition, a study was done in which extracellular application of α-synuclein oligomers was found to increase intracellular Ca
2+ levels, induce calcineurin activity, decrease cAMP response and CREB transcriptional activity. This resulted in calcineurin-dependent cell death of the human neuroblastoma cells. Similarly, CaN induction and CREB inhibition were observed when α-synuclein oligomers were applied to organotypic brain slices, which opposed hippocampal long-term potentiation. Furthermore, α-synuclein oligomers induced CaN, inhibited CREB and caused memory impairment in mice that received acute intracerebroventricular injections of α-synuclein oligomers [
30]. The general mechanism of secretion of α-synuclein from the intracellular complex to the extracellular complex is still unknown. There are two pathways that are thought to be involved in the secretion of α-synuclein by neurons. One of them involves the non-classical calcium-dependent release of cytotoxic vesicular forms of α-synuclein from transfected SH-SY5Y cells. The other pathway involves the endoplasmatic reticulum/Golgi regulated exocytosis of α-synuclein in primary enteric neurons dependent on sodium channel depolarization of, α-synuclein and brefeldin-A [
31]. While the pathology of secreted α-synuclein remains unknown, it appears that α-synuclein can be secreted from neurons into the extracellular space, thereby affecting the homeostasis of neighboring cells. This was demonstrated in a study which found that COS-7 cells treated with exogenously applied α-synuclein secreted from differentiated SH-SY5Y cells, was taken up by dynamin-dependent endocytosis. Upon internalization, α-synuclein increased in the rate of transferrin receptor (TfR) internalization and recycling, a pathology presumed to be involved with PD [
32]. Compared to soluble Aβ and tau levels, the soluble α-synuclein levels showed a stronger correlation to cognitive impairment in AD [
33]
. It has been suggested that cognitive dysfunction could be associated with the misfolding of normal soluble α-synuclein by amyloid deposition, suggesting the accumulation of amyloid and α-synuclein caused the loss of solubility in the intracellular cytosolic proteins [
34].