Pharmacologic reversal of advanced Alzheimer’s disease in mice using PC73-A20

#1

AI overview of PC73-A20
P7C3-A20 is a potent, brain-penetrant small molecule known for its strong neuroprotective and proneurogenic effects, showing promise in preclinical models for treating brain injuries (like TBI, stroke) and neurodegenerative diseases by activating the enzyme NAMPT, boosting NAD+ levels, and protecting neurons from death. It also demonstrates antidepressant-like effects and helps repair the blood-brain barrier, but its mechanism isn’t fully understood and research continues.

Paper:
https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1

Summary

Alzheimer’s disease (AD) is traditionally considered irreversible. Here, however, we provide proof of principle for therapeutic reversibility of advanced AD. In advanced disease amyloid-driven 5xFAD mice, treatment with P7C3-A20, which restores nicotinamide adenine dinucleotide (NAD+) homeostasis, reverses tau phosphorylation, blood-brain barrier deterioration, oxidative stress, DNA damage, and neuroinflammation and enhances hippocampal neurogenesis and synaptic plasticity, resulting in full cognitive recovery and reduction of plasma levels of the clinical AD biomarker p-tau217. P7C3-A20 also reverses advanced disease in tau-driven PS19 mice and protects human brain microvascular endothelial cells from oxidative stress. In humans and mice, pathology severity correlates with disruption of brain NAD+homeostasis, and the brains of nondemented people with Alzheimer’s neuropathology exhibit gene expression patterns suggestive of preserved NAD+ homeostasis. Forty-six proteins aberrantly expressed in advanced 5xFAD mouse brain and normalized by P7C3-A20 show similar alterations in human AD brain, revealing targets with potential for optimizing translation to patient care.

Looks like it helps restore NAD levels…

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#2

Scientists reverse Alzheimer’s in mice and restore memory

For more than 100 years, Alzheimer’s disease has been treated as a one-way decline—but new research is turning that belief on its

(Scientists reverse Alzheimer’s in mice and restore memory | ScienceDaily)

A study reveals that restoring the brain’s energy balance may not just slow Alzheimer’s – but actually reverse it.

  • For more than a century, Alzheimer’s disease has been widely viewed as permanent and untreatable once it begins. As a result, most research has focused on preventing the disease or slowing its progression rather than attempting to reverse it.
  • By studying multiple mouse models of Alzheimer’s alongside human Alzheimer’s brain tissue, researchers identified a critical biological problem at the center of the disease. They found that the brain’s inability to maintain healthy levels of a vital cellular energy molecule called NAD+ plays a major role in driving Alzheimer’s.
  • In animal models, maintaining normal brain NAD+ levels prevented Alzheimer’s from developing. Even more striking, restoring NAD+ balance after the disease was already advanced allowed the brain to repair damage and fully restore cognitive function.
  • These results suggest that treatments aimed at restoring the brain’s energy balance could potentially move Alzheimer’s therapy beyond slowing decline and toward meaningful recovery.
  • The findings also open the door to further research, including the exploration of complementary strategies and carefully designed clinical trials to determine whether these results can translate to patients.
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