Thioredoxin-1 in Alzheimer disease

Abstract

Oxidative stress is one of the earliest signs in Alzheimer Disease (AD) brain. In order to protect themselves against oxidative stress, neurons use antioxidants as a defense mechanism. Such an antioxidant is Thioredoxin-1 (Trx1). Previous studies have shown that the levels of Trx1 are reduced in the brains of AD patients. The aim of this thesis was to further examine the function of Trx1 in AD pathogenesis.

In Paper I and III, the role of Trx1 in the mechanisms behind risk-modulating factors is investigated. The incidence of AD is higher in women than in men and one reason for this is thought to be the post-menopausal lack of estrogen. In addition, estrogen was shown to have neuroprotective effects both in vitro and in vivo. In Paper I we studied the protective effect of estrogen against amyloid-beta (Aβ) toxicity in vitro. We found that estrogen is protective via phosphorylation of Protein kinase B (AKT) and inhibition of the Apoptosis signal-regulating kinase 1 (ASK-1) pathway. However, this occurs independently of Trx1 expression. In Paper III we investigated the effect of Apolipoprotein E (ApoE) isoforms on Trx1 in the brain. The ApoE isoform ε4 (ApoE4) is the most important genetic risk factor for sporadic AD and it is also associated with increased oxidative stress in the brain. Furthermore, ApoE4 is suggested to have direct toxic effects via apoptosis. We found that presence of ApoE4 causes a reduction in Trx1 levels, both in vivo, in hippocampus of ApoE Target Replacement Mice, and in vitro, in human primary cortical neurons and neuroblastoma cells. This occurred after leakage of the lysosomal membrane and cytosolic release of Cathepsin D, and it induced apoptotic cell death via activation of the ASK-1 pathway.

Thioredoxin-1 can be truncated into an 80 amino acid long peptide called Thioredoxin-80 (Trx80). In Paper II and IV, we demonstrate for the very first time that this peptide is present in the brain, mainly in neurons. The levels were reduced significantly in AD patients and this was also seen in the cerebrospinal fluid (CSF). The reduction in CSF was present already in patients with mild cognitive impairment (MCI). Furthermore, we demonstrate that the peptide is generated by α-secretase cleavage of Trx1 and is secreted from cells in exosomes. The peptide inhibits the aggregation of Aβ and prevents its toxic effects both in vitro and in a Drosophila Melanogaster model of AD. In addition, Trx80 lowers the levels of Aβ, possibly through a mechanism that involves autophagy.

These findings give support to the view that oxidative stress in general, and Trx1 in particular, has a key role in AD pathogenesis. It also presents Trx80 as a completely new player to the field that has potential as a specific biomarker for the disease. In addition, therapeutic strategies based on these two peptides could be a possibility in AD that should be further investigation.