Parkinson's Disease Dementia: Synergistic Effects of Alpha-Synuclein, Tau, Beta-Amyloid, and Iron

Abstract

Parkinson's disease dementia (PDD) is a common complication of Parkinson's disease that seriously affects patients' health and quality of life. At present, the process and pathological mechanisms of PDD remain controversial, which hinders the development of treatments. An increasing number of clinical studies have shown that alpha-synuclein (α-syn), tau, beta-amyloid (Aβ), and iron are closely associated with PDD severity. Thus, we inferred the vicious cycle that causes oxidative stress (OS), due to the synergistic effects of α-syn, tau, Aβ, and, iron, and which plays a pivotal role in the mechanism underlying PDD. First, iron-mediated reactive oxygen species (ROS) production can lead to neuronal protein accumulation (e.g., α-syn andAβ) and cytotoxicity. In addition, regulation of post-translational modification of α-syn by iron affects the aggregation or oligomer formation of α-syn. Iron promotes tau aggregation and neurofibrillary tangles (NFTs) formation. High levels of iron, α-syn, Aβ, tau, and NFTs can cause severe OS and neuroinflammation, which lead to cell death. Then, the increasing formation of α-syn, Aβ, and NFTs further increase iron levels, which promotes the spread of α-syn and Aβ in the central and peripheral nervous systems. Finally, iron-induced neurotoxicity promotes the activation of glycogen synthase kinase 3β (GSK3β) related pathways in the synaptic terminals, which in turn play an important role in the pathological synergistic effects of α-syn, tau and Aβ. Thus, as the central factor regulating this vicious cycle, GSK3β is a potential target for the prevention and treatment of PDD; this is worthy of future study.

Keywords: Parkinson’s disease dementia; alpha-synuclein; beta-amyloid; iron; tau.

Figure 1

The role of iron in the pathology of tau, α-syn, and Aβ. (A) Iron and tau kinase (GSK3β, CDKs, MAPK) play a role in the phosphorylation of tau; iron promotes tau aggregation and NFTs formation. (B) The binding of IRP to iron inhibited its binding to IRE, resulting in increased expression of α-syn; α-syn can promote an increase in iron levels; iron participates in the post-translational modification of α-syn and promotes the aggregation of α-syn. Iron can promote the increase of PUFA; PUFA are conjugated to CoA by ACSL4 allowing PUFA-CoA to be incorporated into the phospholipids (PL); free or phospholipid-bound PUFAs promote the aggregation of α-syn. (C) The binding of IRP to iron inhibits its binding to IRE, which results in increased APP expression. The synergistic effect of APP and FPN causes iron outflow; Aβ produced from APP processing; iron promotes Aβ aggregation.

Figure 2

Interaction of tau, α-syn, Aβ, iron, and GSK3β. (1) The synergistic effect of α-syn and Aβ. (2) Iron promotes the overexpression of α-syn and Aβ. (3) Iron promotes the activation of GSK3β. (4) α-Syn and Aβ can promote an increase in GSK3β, which can, in turn, promote the expression of α-syn and Aβ. (5) GSK3β promotes the phosphorylation of tau.