The paper below is from Harvard and it demonstrates that beta-amyloid increases mitochondrial oxidative stress when observed by real-time imaging. I would think that Prof. Masters is very pleased about this finding when he is with PBT2 targeting the very early amyloid plaques (my understanding about his license of PBT2).

But this is not the only important thing in this paper because it talks also about calcium influx into the mitochondria in AD. The paper by Standford University ( posted here on the 12th and 20th of Dec, : A mitochondrial inside-out iron-calcium signal reveals drug targets for Parkinson's disease) and a paper from the Netherlands (Negative modulation of mitochondrial calcium uniporter complex protects neurons against ferroptosis) explained well the role of calcium overload in PD and also in AD.

Now this new paper below demonstrates also the role of calcium, now in real-time animal models. Unfortunately, it does not tell the role of iron chelation in controlling this calcium influx. That side is told best in the Stanford paper and the paper from the Netherlands.

But this is a good paper, also for ATH434. Here is the abstract:

Mol Neurodegener

. 2024 Jan 18;19(1):6.

doi: 10.1186/s13024-024-00702-2.

Real-time imaging of mitochondrial redox reveals increased mitochondrial oxidative stress associated with amyloid β aggregates in vivo in a mouse model of Alzheimer's disease

Maria Calvo-Rodriguez ^{1 2}, Elizabeth K Kharitonova ¹, Austin C Snyder ¹, Steven S Hou ¹, Maria Virtudes Sanchez-Mico ¹, Sudeshna Das ¹, Zhanyun Fan ¹, Hamid Shirani ³, K Peter R Nilsson ³, Alberto Serrano-Pozo ¹, Brian J Bacskai ⁴

Affiliations expand

• PMID: 38238819

PMCID: PMC10797952 DOI: 10.1186/s13024-024-00702-2Free PMC article

Abstract

Background: Reactive oxidative stress is a critical player in the amyloid beta (Aβ) toxicity that contributes to neurodegeneration in Alzheimer's disease (AD). Damaged mitochondria are one of the main sources of reactive oxygen species and accumulate in Aβ plaque-associated dystrophic neurites in the AD brain. Although Aβ causes neuronal mitochondria reactive oxidative stress in vitro, this has never been directly observed in vivo in the living mouse brain. Here, we tested for the first time whether Aβ plaques and soluble Aβ oligomers induce mitochondrial oxidative stress in surrounding neurons in vivo, and whether this neurotoxic effect can be abrogated using mitochondrial-targeted antioxidants.

Methods: We expressed a genetically encoded fluorescent ratiometric mitochondria-targeted reporter of oxidative stress in mouse models of the disease and performed intravital multiphoton microscopy of neuronal mitochondria and Aβ plaques.

Results: For the first time, we demonstrated by direct observation in the living mouse brain exacerbated mitochondrial oxidative stress in neurons after both Aβ plaque deposition and direct application of soluble oligomeric Aβ onto the brain, and determined the most likely pathological sequence of events leading to oxidative stress in vivo. Oxidative stress could be inhibited by both blocking calcium influx into mitochondria and treating with the mitochondria-targeted antioxidant SS31. Remarkably, the latter ameliorated plaque-associated dystrophic neurites without impacting Aβ plaque burden.

Conclusions: Considering these results, combination of mitochondria-targeted compounds with other anti-amyloid beta or anti-tau therapies hold promise as neuroprotective drugs for the prevention and/or treatment of AD.