According to a study led by scientists at Massachusetts General Hospital, exercise-induced neurogenesis improves cognition in a mouse model of Alzheimer’s disease, yielding more benefits than drug-induced adult neurogenesis. The scientists were able to figure out the difference between the two types of induced neurogenesis and pharmacologically reproduce the same benefits provided by exercise [1].

Study abstract Adult hippocampal neurogenesis (AHN) is impaired before the onset of Alzheimer’s disease (AD) pathology. We found that exercise provided cognitive benefit to 5×FAD mice, a mouse model of AD, by inducing AHN and elevating levels of brain-derived neurotrophic factor (BDNF). Neither stimulation of AHN alone, nor exercise, in the absence of increased AHN, ameliorated cognition. We successfully mimicked the beneficial effects of exercise on AD mice by genetically and pharmacologically inducing AHN in combination with elevating BDNF levels. Suppressing AHN later led to worsened cognitive performance and loss of preexisting dentate neurons. Thus, pharmacological mimetics of exercise, enhancing AHN and elevating BDNF levels, may improve cognition in AD. Furthermore, applied at early stages of AD, these mimetics may protect against subsequent neuronal cell death.

Alzheimer’s disease and neurogenesis

The hallmarks of Alzheimer’s disease are neurodegeneration, cognitive impairment, beta-amyloid deposition, the formation of neurofibrillary tangles, and neuroinflammation. Despite decades of research and attempts to develop a treatment for it, the disease keeps eluding a working cure; at the same time, it remains enigmatic in that not all patients who show significant accumulation of beta-amyloids, which has long been thought to be the cause of the disease, go on to develop full-blown Alzheimer’s.

Adult neurogenesis has also been a rather controversial topic, with evidence both in favor of and against its existence. However, it is known that it does take place at least in two brain structures, the hippocampus and the striatum; without adult neurogenesis in the hippocampus, learning and preserving memories wouldn’t be possible, but the authors of this study wanted to see whether impairing adult hippocampal neurogenesis (AHN) would have any effect on Alzheimer’s disease in a mouse model. Impairment of AHN is observed both in classical mouse models of AD and in human patients, but its role in pathology remains unclear.

The study







Exercise is known to induce adult hippocampal neurogenesis; however, this can also be induced pharmacologically or genetically. While the latter did successfully induce AHN in the animals, the team found that the approach only yielded rather limited benefits in terms of cognitive performance and reduction of beta-amyloid levels. By contrast, exercise-induced AHN improved the animals’ cognition, reduced beta-amyloid deposits, and improved memory.

According to the scientists, the reason behind this difference was that exercise not only induced neurogenesis but also stimulated the production of the so-called brain-derived neurotrophic factor (BDNF). This protein, encoded by the homonymous gene, promotes growth and differentiation of neurons and synapses while supporting the survival of existing neurons. Pharmacologically and genetically induced adult hippocampal neurogenesis did not stimulate the production of BDNF, which did not allow the newly created neurons to survive within the inflamed brains of Alzheimer’s mice; this is why this method did not yield tangible benefits despite promoting neurogenesis.

At this point, the scientists employed a pharmacological and gene-therapeutic approach to both induce neurogenesis and increase the production of brain-derived neurotrophic factor; the approach was successful in mimicking the same beneficial effects on cognitive function that exercise had had in the animals. This shows how important it is to not only stimulate the growth of new neurons but also ensure that they can thrive in the surrounding environment.

This part of the experiment showed how adult hippocampal neurogenesis can ameliorate Alzheimer’s disease in mice; conversely, lack of AHN appears to be deleterious. The team verified that suppressing AHN in the early stages of murine Alzheimer’s disease led to greater cognitive impairment and neuronal death during later stages. This was observed only in mice engineered to develop Alzheimer’s disease, which, according to the scientists, suggests that AHN plays a specific role in the pathology.

Conclusion







Currently, there are no pharmacological approaches to induce AHN and production of BDNF in humans, but the results of this study may help scientists figure out how to achieve these effects in people in the future; this, and finding out whether the same approach could be used for prevention, are the next goals that the authors of the study have set for themselves.

Literature

[1] Choi, S. H., Bylykbashi, E., Chatila, Z. K., Lee, S. W., Pulli, B., Clemenson, G. D., … Tanzi, R. E. (2018). Combined adult neurogenesis and BDNF mimic exercise effects on cognition in an Alzheimer’s mouse model. Science, 361(6406), eaan8821.