The animal study below demonstrates that hippocampal iron overload is related to depression symptoms. The Inhibition of iron accumulation effectively attenuated synaptic damage and improved depression symptoms.

Neuropsychiatric mood and motivation symptoms (depression, anxiety, apathy, impulse control disorders) in Parkinson's disease (PD) are highly disabling and difficult to treat. We know that Parkinson's symptoms are related to accumulated iron in the brain substantia nigra etc.

The latest ATH434 paper in the PD animal model demonstrated also positive effects on synapses and the number of dopaminergic neurons (ATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism). This is very similar to what did happen in this new paper below.

I am connecting the dots quite freely but to me, it seems clear that iron homeostasis is meaningful both in depression and PD as are synapses which will be damaged on iron overload. So, ATH434 could work (??) also in depression as we hope it works in PD. Something to be demonstrated in clinical studies in the future. SF-36 is part of the outcome measures in the ongoing MSA studies and with these, we will get more info if the common depression symptoms in MSA are alleviated by ATH434.

J Neuroinflammation

. 2023 Sep 21;20(1):212.

doi: 10.1186/s12974-023-02875-x.

Nrf2 regulates iron-dependent hippocampal synapses and functional connectivity damage in depression

Ting Zeng ^{# 1 2}, Junjie Li ^{# 1}, Lingpeng Xie ^{# 3}, Zhaoyang Dong ⁴, Qing Chen ¹, Sha Huang ¹, Shuwen Xie ¹, Yuqi Lai ¹, Jun Li ¹, Weixin Yan ⁵, YuHua Wang ¹, Zeping Xie ¹, Changlei Hu ¹, Jiayi Zhang ¹, Shanshan Kuang ¹, Yuhong Song ⁶, Lei Gao ⁷, Zhiping Lv ⁸

Affiliations expand

• PMID: 37735410

DOI: 10.1186/s12974-023-02875-x

Abstract

Neuronal iron overload contributes to synaptic damage and neuropsychiatric disorders. However, the molecular mechanisms underlying iron deposition in depression remain largely unexplored. Our study aims to investigate how nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2) ameliorates hippocampal synaptic dysfunction and reduces brain functional connectivity (FC) associated with excessive iron in depression. We treated mice with chronic unpredictable mild stress (CUMS) with the iron chelator deferoxamine mesylate (DFOM) and a high-iron diet (2.5% carbonyl iron) to examine the role of iron overload in synaptic plasticity. The involvement of Nrf2 in iron metabolism and brain function was assessed using molecular biological techniques and in vivo resting-state functional magnetic resonance imaging (rs-fMRI) through genetic deletion or pharmacologic activation of Nrf2. The results demonstrated a significant correlation between elevated serum iron levels and impaired hippocampal functional connectivity (FC), which contributed to the development of depression-induced CUMS. Iron overload plays a crucial role in CUMS-induced depression and synaptic dysfunction, as evidenced by the therapeutic effects of a high-iron diet and DFOM. The observed iron overload in this study was associated with decreased Nrf2 levels and increased expression of transferrin receptors (TfR). Notably, inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Nrf2^-/- mice exhibited compromised FC within the limbic system and the basal ganglia, particularly in the hippocampus, and inhibition of iron accumulation effectively attenuated CUMS-induced synaptic damage mediated by downregulation of brain-derived neurotrophic factor (BDNF). Activation of Nrf2 restored iron homeostasis and reversed vulnerability to depression. Mechanistically, we further identified that Nrf2 deletion promoted iron overload via upregulation of TfR and downregulation of ferritin light chain (FtL), leading to BDNF-mediated synapse damage in the hippocampus. Therefore, our findings unveil a novel role for Nrf2 in regulating iron homeostasis while providing mechanistic insights into poststress susceptibility to depression. Targeting Nrf2-mediated iron metabolism may offer promising strategies for developing more effective antidepressant therapies.

Keywords: Depression; Iron metabolism; Nrf2; Rs-fMR; Synapse damage.