For over a century, Alzheimer’s disease (ALD) has been considered irreversible. Consequently, basic research has focused on disease prevention or slowing, rather than recovery. Despite billions of dollars spent on decades of research, there has never been a clinical trial of a drug for AD with an outcome goal of reversing disease and recovering function. Now, a joint research team from Case Western Reserve University and the Louis Stokes Cleveland VA Medical Center has challenged this long-held dogma in the field. They tested whether brains already badly afflicted with advanced ALD could recover. Through studying diverse preclinical mouse models and human ALD brains, the team showed that the major driver of ALD is brain’s failure to maintain normal levels of a central cellular energy molecule, NAD+.
NAD+ levels decline naturally across the body, including the brain, as people age. Without proper NAD+ balance, cells eventually become unable to execute critical processes required for proper functioning and survival. In this study, the team showed that the decline in NAD+ is even more severe in the brains of people with AD, and that this also occurs in mouse models of the disease. While ALD is a uniquely human condition, it can be studied in the laboratory with mice that have been engineered to express genetic mutation that cause ALD 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. After finding that NAD+ levels in the brain declined precipitously in both human and mouse ALD, 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 PNAS 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 their lab. Remarkably, not only did preserving NAD+ balance protect mice from developing ALD, 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 ALD in people.
The results prompt a paradigm shift in how researchers, clinicians, and patients can think about treating AD in the future, having them confirmation of disease reversal and highlighting a potential biomarker for future clinical trials. Scientists 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. These include nicotinamide riboside (NAR) and its monophosphate (NAM). The approach in this study, however, uses a compound that enables cells to maintain their proper balance of NAD+ under conditions of otherwise overwhelming stress. The substance works by activating NAMPT (NicotinAmide Phosphoribosyl-Transferase), the rate-limiting step in NAD+ synthesis.
NAMPT senses cellular energy stress (via AMP/ATP levels) and helps regulate cell survival and metabolic adaptation, regulates glucose balance and insulin secretion as well. This is a connecting node with the latest hypothesis speculating that ALD could be a “neuro-form” of diabetes, since glucose metabolism and insulin sensitivity are both altered in this condition.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry.
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