On October 2022 ATH published a paper: "ATH434 Rescues Pre-motor Hyposmia in a Mouse Model of Parkinsonism". As ATH434 is an iron chelator it is interesting to see what is caused when there is an overload of iron.

Now a Chinese group has made this "related but reverse study" in which they found iron overload to suppress hippocampal neurogenesis. The hippocampus is a very central organ in cognition etc. and on the other hand hyposmia is one of the first symptoms both in AD and PD.

Every ATH investor is happy about these results, but more is needed. The Chinese paper recommends "iron homeostasis modulation" and that is just what ATH434 does. Ph 2 study will give some answers in spite of not being on this histological level.

CNS Neurosci Ther

. 2023 Aug 7.

doi: 10.1111/cns.14394. Online ahead of print.

Iron overload suppresses hippocampal neurogenesis in adult mice: Implication for iron dysregulation-linked neurological diseases

Jie Li ¹, Yiqian Ding ¹, Jianhua Zhang ¹, Yating Zhang ¹, Yiduo Cui ¹, Yi Zhang ¹, Shiyang Chang ^{1 2}, Yan-Zhong Chang ¹, Guofen Gao ¹

Affiliations expand

• PMID: 37545321

DOI: 10.1111/cns.14394

Abstract

Aims: Adult hippocampal neurogenesis is an important player in brain homeostasis and its impairment participates in neurological diseases. Iron overload has emerged as an irreversible factor of brain aging, and is also closely related to degenerative disorders, including cognitive dysfunction. However, whether brain iron overload alters hippocampal neurogenesis has not been reported. We investigated the effect of elevated iron content on adult hippocampal neurogenesis and explored the underlying mechanism.

Methods: Mouse models with hippocampal iron overload were generated. Neurogenesis in hippocampus and expression levels of related molecules were assessed.

Results: Iron accumulation in hippocampus remarkably impaired the differentiation of neural stem cells, resulting in a significant decrease in newborn neurons. The damage was possibly attributed to iron-induced downregulation of proprotein convertase furin and subsequently decreased maturation of brain-derived neurotrophic factor (BDNF), thus contributing to memory decline and anxiety-like behavior of mice. Supportively, knockdown of furin indeed suppressed hippocampal neurogenesis, while furin overexpression restored the impairment.

Conclusion: These findings demonstrated that iron overload damaged hippocampal neurogenesis likely via iron-furin-BDNF pathway. This study provides new insights into potential mechanisms on iron-induced neurotoxicity and the causes of neurogenesis injury and renders modulating iron homeostasis and furin expression as novel therapeutic strategies for treatment of neurological diseases.