Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain, 2025, Chaubey et al.

[Chandelier]

Pharmacologic reversal of advanced Alzheimer’s disease in mice and identification of potential therapeutic nodes in human brain

Spoiler: Authors

Chaubey, Kalyani; Vázquez-Rosa, Edwin; Tripathi, Sunil Jamuna; Shin, Min-Kyoo; Yu, Youngmin; Dhar, Matasha; Chakraborty, Suwarna; Yamakawa, Mai; Wang, Xinming; Sridharan, Preethy S.; Miller, Emiko; Bud, Zea; Corella, Sofia G.; Barker, Sarah; Caradonna, Salvatore G.; Koh, Yeojung; Franke, Kathryn; Cintrón-Pérez, Coral J.; Rose, Sophia; Fang, Hua; Cintrón-Pérez, Adrian A.; Tomco, Taylor; Zhu, Xiongwei; Fujioka, Hisashi; Gefen, Tamar; Flanagan, Margaret E.; Williams, Noelle S.; Wilson, Brigid M.; Chen, Lawrence; Dou, Lijun; Cheng, Feixiong; Rexach, Jessica E.; Woo, Jung-A; Kang, David E.; Paul, Bindu D.; Pieper, Andrew A.

Highlights​

• Severity of Alzheimer’s disease (AD) correlates with NAD+ homeostasis dysregulation
• Preserving brain NAD+ homeostasis prevents AD in mice
• Restoring brain NAD+ homeostasis reverses advanced AD in mice
• Multiomics across human and mouse AD brain identifies nodes for human AD reversal

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.

Graphical abstract​

Web | DOI | Cell Reports Medicine

 

[Chandelier]

New study shows Alzheimer’s disease can be reversed to achieve full neurological recovery—not just prevented or slowed—in animal models | CWRU Newsroom | Case Western Reserve University

For more than a century, people have considered Alzheimer's disease (AD) an irreversible illness. Consequently, research has focused on preventing or ...

case.edu

New study shows Alzheimer’s disease can be reversed to achieve full neurological recovery—not just prevented or slowed—in animal models​

Researchers from Case Western Reserve University, University Hospitals and the Cleveland VA showed restoring brain’s energy balance led to both pathological and functional recovery

 

[ScoutB]

Last time I looked into it, Alzheimer’s research was having that big debate about how much amyloid beta was the core problem vs a downstream side effect. Has there been progress on that?

In particular, I remember reading that they designed mouse models based on the amyloid beta hypothesis (ie mice genetically predisposed to develop amyloid beta accumulation and seemingly as a result Alzheimer's symptoms as well) and it seems like that's what they used here.

The researchers used two of these mouse models: One carried multiple human mutations in amyloid processing; the other carried a human mutation in the tau protein.

Both lines of mice develop brain pathology resembling AD, including blood-brain barrier deterioration, axonal degeneration, neuroinflammation, impaired hippocampal neurogenesis, reduced synaptic transmission and widespread accumulation of oxidative damage. These mice also develop the characteristics of severe cognitive impairments seen in people with AD.

It is interesting that, despite using the amyloid/tau mouse model, they targeted a different area. Makes optimizing/restoring NAD+ seem like a panacea if these results hold up.

After finding that NAD+ levels in the brain declined precipitously in both human and mouse AD, the research team tested whether preventing loss of brain NAD+ balance before disease onset or restoring brain NAD+ balance after significant disease progression could prevent or reverse AD, respectively.

The study was based on their previous work, published in Proceeding of the National Academy of Sciences USA, showing that restoring the brain's NAD+ balance achieved pathological and functional recovery after severe, long-lasting traumatic brain injury.

This is basically the TLDR:

“Restoring the brain's energy balance achieved pathological and functional recovery in both lines of mice with advanced Alzheimer's. Seeing this effect in two very different animal models, each driven by different genetic causes, strengthens the new idea that recovery from advanced disease might be possible in people with AD when the brain's NAD+ balance is restored.”

 

[ScoutB]

NAD+ is a popular target, longevity bros talk about it a lot. Looks like a past trial of a NAD+ precursor in Long Covid did not impress us, or show real positive results: Effects of nicotinamide riboside on NAD+ levels, cognition, and symptom recovery in long-COVID: a randomized controlled trial.

The authors of the current study do say

Pieper emphasized that current over-the-counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer. The pharmacological approach in this study, however, uses a pharmacologic agent (P7C3-A20) that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress, without elevating NAD+ to supraphysiologic levels.