Reciprocal Induction Between α-Synuclein and β-Amyloid in Adult Rat Neurons

Abstract

In spite of definite roles for β-amyloid (Aβ) in familial Alzheimer's disease (AD), the cause of sporadic AD remains unknown. Amyloid senile plaques and Lewy body pathology frequently coexist in neocortical and hippocampal regions of AD and Parkinson's diseases. However, the relationship between Aβ and α-synuclein (α-Syn), the principle components in the pathological structures, in neuronal toxicity and the mechanisms of their interaction are not well studied. As Aβ and α-Syn accumulate in aging patients, the biological functions and toxicity of these polypeptides in the aging brain may be different from those in young brain. We examined the neurotoxicity influences of Aβ1-42 or α-Syn on mature neurons and the effects of Aβ1-42 or α-Syn on the production of endogenous α-Syn or Aβ1-40 reciprocally using a model of culture enriched with primary neurons from the hippocampus of adult rats. Treatment of neurons with high concentrations of Aβ1-42 or α-Syn caused significant apoptosis of neurons. Following Aβ1-42 treatment at sub apoptotic concentrations, both intra- and extra-cellular α-Syn levels were significantly increased. Reciprocally, the non-toxic levels of α-Syn treatment also increased intra- and extra-cellular Aβ1-40 levels. The phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002, suppressed α-Syn-induced Aβ1-40 elevation, as well as Aβ1-42-induced α-Syn elevation. Thus, high concentrations of Aβ1-42 and α-Syn exert toxic effects on mature neurons; however, non-toxic concentration treatment of these polypeptides induced the production of each other reciprocally with possible involvement of PI3K pathway.

Parkinson's disease as a member of Prion-like disorders

“…One of the first reports of recombinant alpha-synuclein seeding alphasynuclein aggregation in cortical neurons is that by Danzer et al (2009) in their study primary neuronal cultures are exposed to alpha-synuclein oligomers resulting on the accumulation of alphasynuclein inside the cells during the next 4 h. Exposure to in vitro generated alpha-synuclein fibrils has been shown to be toxic to hippocampus primary neurons (Volpicelli-Daley et al, 2011;Majd et al, 2013). Furthermore, these neurons have been used to show that pathological alpha-synuclein can be transmitted from cell to cell.…”

Response of α-Synuclein Expression to Amyloid β40 and Amyloid β42 administration into Rat Brain

“…In the in vitro studies Aβ 42 was administered extracellularly was able to affect synuclein intracellularly, but the in vivo data was still lacking. Study performed in vitro in adult rat neurons by Majd et al [26] also showed the increase α-synuclein protein levels in the presence of Aβ 42 .…”

Cdk5 at crossroads of protein oligomerization in neurodegenerative diseases: facts and hypotheses

“…; Majd et al . ). Although Cdk5 is not responsible for the aberrant phosphorylation of neuronal ASN in AD, it is possible that this enzyme mediates the elevation of ASN protein level induced by Aβ.…”

“…Previously it has been hypothesized that Ab and ASN mutually affect their accumulation and toxicity (Kallhoff et al 2007;Kazmierczak et al 2008;Bachhuber et al 2015). In vitro data indicated that subtoxic concentrations of Ab1-42 induce the significant increase in intra-and extracellular ASN levels in neuronal cells, as well as promote ASN aggregation in a cell-free system (Masliah et al 2001;Majd et al 2013). Although Cdk5 is not responsible for the aberrant phosphorylation of neuronal ASN in AD, it is possible that this enzyme mediates the elevation of ASN protein level induced by Ab.…”

“…The idea of ASN-Ab interaction was greatly extended by the studies showing that ASN may also intensify the secretion and toxicity of Ab to the point where it caused cell death (Kazmierczak et al 2008;Majd et al 2013). However, the mechanisms underlying this phenomenon remain largely unknown.…”