Restoring energy balance in the brain cells could help repair afflicted brain in mouse models of Alzheimer’s disease.
Scientists have changed the belief that Alzheimer’s disease (AD) is irreversible. A groundbreaking discovery demonstrates that balancing the energy currency of the brain cells, known as NAD+ molecules, could significantly restore normal brain function and memory.(1✔ ✔Trusted Source
Pharmacologic reversal of Alzheimer’s disease in mice reveals potential therapeutic nodes in human brain
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The findings come from a study led by researchers from University Hospitals, Case Western Reserve University and the Cleveland VA Medical Center, published in Cell Reports Medicine.
Using mouse models, researchers identified that a failure to maintain normal NAD+ levels in the brain cells (happens naturally with aging), consequently results in severe cognitive decline, causing dementia and Alzheimer’s disease.
On successfully rebalancing this cellular fuel, the brain cells retained normal cell metabolism, improving memory and cognition. Researchers highlight that targeting NAD+ restoration could help tackle Alzheimer’s and cautioned that standard supplements may cause high levels of NAD+ that dangerously promote cancer risk.
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Is reversing #Alzheimers_disease possible? A cell energy breakthrough proves that reinstalling the “#powerhouses” (NAD+) of the brain cells can truly help restore #memory, a targeted method avoids cancer risks from standard supplements. #pharmacology #cognitive_decline #cellbiology #oncology #mentalhealth
Simulating Human Alzheimer’s Pathology in Laboratory Mice
While AD is a uniquely human condition, it can be studied in the laboratory with mice that have been engineered to express genetic mutations that cause AD in people. The researchers used two of these models.
One line of mice carried multiple human mutations in amyloid processing, and the other mouse line carried a human mutation in the tau protein.
Amyloid and tau pathology are two of the major early events in AD, and 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 severe cognitive impairments that resemble what is seen in people with AD.
Restoring the Cellular Fuel to Reverse the Brain damage
After finding that NAD+ levels in the brain declined precipitously in both human and mouse AD, the research team tested whether preventing the 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.
They restored NAD+ balance by administering a now well-characterized pharmacologic agent known as P7C3-A20, developed in the Pieper lab.
Cell Energy Discovery Proves that Damaged Brain Can Repair Itself
Remarkably, not only did preserving NAD+ balance protect mice from developing AD, but delayed treatment in mice with advanced disease also enabled the brain to fix the major pathological events caused by the genetic mutations.
Moreover, both lines of mice fully recovered cognitive function. This was accompanied by normalized blood levels of phosphorylated tau 217, a recently approved clinical biomarker of AD in people, providing confirmation of disease reversal and highlighting a potential biomarker for future clinical trials.
“We were very excited and encouraged by our results,” said Andrew A. Pieper, MD, PhD, senior author of the study and Director of the Brain Health Medicines Center, Harrington Discovery Institute at UH.
“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 idea that restoring the brain’s NAD+ balance might help patients recover from Alzheimer’s.”
Targeted NAD+ Therapy Reverses Alzheimer’s Without Dangerous Side Effects
The results prompt a paradigm shift in how researchers, clinicians, and patients can think about treating AD in the future. “The key takeaway is a message of hope – the effects of Alzheimer’s disease may not be inevitably permanent,” said Dr. Pieper. “The damaged brain can, under some conditions, repair itself and regain function.”
Dr. Chaubey further explained, “Through our study, we demonstrated one drug-based way to accomplish this in animal models, and also identified candidate proteins in the human AD brain that may relate to the ability to reverse AD.”
Dr. Pieper emphasized that currently available over the counter NAD+-precursors have been shown in animal models to raise cellular NAD+ to dangerously high levels that promote cancer.
The 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.
Researchers Aim to Test Brain Recovery From Laboratory Mice to Men
“This is important when considering patient care, and clinicians should consider the possibility that therapeutic strategies aimed at restoring brain energy balance might offer a path to disease recovery,” said Dr. Pieper.
This work also encourages new research into complementary approaches and eventual testing in patients, and the technology is being commercialized by Cleveland-based company Glengary Brain Health, co-founded by Dr. Pieper.
“This new therapeutic approach to recovery needs to be moved into carefully designed human clinical trials to determine whether the efficacy seen in animal models translates to human patients,” Dr. Pieper explained.
“Additional next steps for the laboratory research include pinpointing which aspects of brain energy balance are most important for recovery, identifying and evaluating complementary approaches to Alzheimer’s reversal, and investigating whether this recovery approach is also effective in other forms of chronic, age-related neurodegenerative disease.”
Reference:
- Pharmacologic reversal of Alzheimer’s disease in mice reveals potential therapeutic nodes in human brain – (https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(25)00608-1?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS2666379125006081%3Fshowall%3Dtrue)
Source-Eurekalert