I go back to the mouse AD paper above (Simultaneous Fe2+/Fe3+ ,,,,). It demonstrated that "The elevated Fe3+/Fe2+ ratio was mainly observed in amyloid plaque regions, suggesting a correlation between amyloid plaques and the accumulation of Fe3+ and/or conversion of Fe2+ to Fe3+".

With this, I return to this paper below ( posted earlier) that clearance of beta-amyloid by monocytes is related to AD severity. So it may be that not only the brain cells have mitochondrion problems in energy production but also the amyloid transporting cells have the same problem. Phagocytosis needs energy and ATH434 helps as has been demonstrated by Kosman's poster last year.

I admit that this is again my speculation but how would you improve the fagocytosis of the monocytes looking very tired and exhausted among pools of beta amyloin and unbalanced Fe2+ /Fe3+rattio disturbing energy production. My biased opinion is 434 will help also these monicytes.

Nat Commun

. 2024 Sep 12;15(1):7998.

doi: 10.1038/s41467-024-52396-1.

Clearance and transport of amyloid β by peripheral monocytes correlate with Alzheimer's disease progression

Xin Huang ^{1 2}, Chris Fowler ¹, Yihan Li ¹, Qiao-Xin Li ^{1 3}, Jiaqi Sun ¹, Yijun Pan ¹, Liang Jin ¹, Keyla A Perez ¹, Céline Dubois ¹, Yen Y Lim ⁴, Candace Drysdale ¹, Rebecca L Rumble ¹, Holly R Chinnery ^{5 6 7}, Christopher C Rowe ⁸, Ralph N Martins ⁹, Paul Maruff ^{1 10}, James D Doecke ¹¹, Yong Lin ¹², Abdel A Belaidi ¹, Kevin J Barnham ¹, Colin L Masters ¹³, Ben J Gu ^{14 15 16}

Affiliations Expand

• PMID: 39266542

PMCID: PMC11393069 DOI: 10.1038/s41467-024-52396-1

Abstract

Impaired clearance of amyloid β (Aβ) in late-onset Alzheimer's disease (AD) affects disease progression. The role of peripheral monocytes in Aβ clearance from the central nervous system (CNS) is unclear. We use a flow cytometry assay to identify Aβ-binding monocytes in blood, validated by confocal microscopy, Western blotting, and mass spectrometry. Flow cytometry immunophenotyping and correlation with AD biomarkers are studied in 150 participants from the AIBL study. We also examine monocytes in human cerebrospinal fluid (CSF) and their migration in an APP/PS1 mouse model. The assay reveals macrophage-like Aβ-binding monocytes with high phagocytic potential in both the periphery and CNS. We find lower surface Aβ levels in mild cognitive impairment (MCI) and AD-dementia patients compared to cognitively unimpaired individuals. Monocyte infiltration from blood to CSF and migration from CNS to peripheral lymph nodes and blood are observed. Here we show that Aβ-binding monocytes may play a role in CNS Aβ clearance, suggesting their potential as a biomarker for AD diagnosis and monitoring.