Hippocampal Reprogramming Reversed Alzheimer's in Mice and Restored Their Bones
Hippocampal Reprogramming Reversed Alzheimer's in Mice and Restored Their Bones
Chinese researchers injected a virus carrying three Yamanaka factors, omitting the fourth oncogenic one, into the hippocampus of mice modeling Alzheimer's disease. The hippocampus is the brain region responsible for memory. At both early and advanced stages of the disease, amyloid plaque accumulation decreased, brain inflammation subsided, and learning and memory improved. In the same mice, trabecular bone in the femur, which the disease had thinned, also recovered, through particles that the brain began releasing into the bloodstream after treatment.
On May 28, a team from Xiangya Hospital in Changsha published a paper in Journal of Neuroinflammation. On September 27, David Sinclair, a Harvard professor who studies the same genes but was not involved in this work, summarized the findings in a tweet.
The genes in question are Oct4, Sox2, and Klf4 (OSK), three of the four Yamanaka factors for which Shinya Yamanaka received the 2012 Nobel Prize. All four together can revert an adult cell to a stem state, but at a price: the cell may lose its identity and give rise to a tumor, because the fourth factor, c-Myc, is oncogenic. Without c-Myc, OSK only partially rejuvenates the cell without reverting it to a stem state. The authors tested this more cautious variant.
The OSK virus was injected into the hippocampus, one of the first brain regions affected in Alzheimer's, of mice carrying human mutations that accelerate amyloid accumulation. One group received the injection at four months of age, before the full disease picture had developed; the other at six months, when plaques, inflammation, and memory loss were already pronounced. After treatment, learning and memory improved in both groups across three tests (the Morris water maze, the Y-maze, and novel object recognition): in mice at the advanced stage, object recognition recovered as strongly as at the early stage, while spatial memory improved only partially.
Before the in vivo experiments, the authors tested the main safety concern: whether stemness markers would appear in cultured microglia and neurons. No such markers appeared, and only after this verification was the virus injected into the brain. OSK did not reduce levels of amyloid precursor protein; instead, it suppressed BACE1, the enzyme that cleaves this protein into toxic fragments. Microglia, the brain's immune cells that become locked in an inflammatory state in Alzheimer's, returned to their resting form. Neurons, synapses, and myelin were preserved, and two months of treatment produced no organ damage and no brain tumors.
The mechanism was identified through DNA methylation sequencing, which maps the chemical marks that switch genes on and off: in treated mice, the disease-associated changes in these marks on neuronal circuit genes had disappeared. The enzyme responsible was Tet2, which removes such marks; when Tet2 was knocked out in cultured cells, the effect of OSK vanished entirely.
The same laboratory had previously shown that in Alzheimer's disease, the brain releases extracellular vesicles into the bloodstream that shift bone marrow stem cell fate toward fat instead of bone, which is how the femoral trabecular bone thins. After hippocampal reprogramming, levels of microRNA miR-483-5p in these vesicles dropped, and bone marrow cells resumed building bone, even though only the brain had been treated. Blocking this single molecule without any brain intervention reproduced the same effect, confirming that this is a verified signaling channel rather than a conjecture.
In February, Ukhvat wrote about targeted reprogramming of memory neurons in aged mice: Johannes Gräff's laboratory at EPFL had repaired only the neurons encoding a single memory. In the present study, the virus was delivered across the entire hippocampus, without that selectivity. The result turned out to go further: plaques were markedly reduced, and the effect reached bone at the other end of the body.