Neurogenesis is the production of new neurons from neural stem cell populations, and their integration into neural circuits. Neurogenesis is necessary to memory, learning, and what little regeneration the brain is capable of undertaking following injury. A sizable body of evidence suggests that increased neurogenesis is a good thing, beneficial to brain function, at any adult age. In later life, increased neurogenesis may be capable of compensating for at least some of the damage and dysfunction exhibited by the aging brain. Compensatory therapies are not as useful as treatments that address underlying causes, unfortunately, usually only capable of slowing the progression of a condition.
Today's research materials note an example of this sort of compensatory therapy applied to the progression of cognitive dysfunction in a mouse model of Alzheimer's disease. Such models are quite artificial, as mice do not naturally suffer from anything resembling Alzheimer's disease. The model itself incorporates major assumptions about which mechanisms and forms of pathology are important. One of the major challenges in the field of Alzheimer's research is that it is somewhat unclear as to whether a given result in an animal model is in any way relevant to the natural condition in humans.
Researchers boosted neurogenesis in Alzheimer's disease (AD) mice by genetically enhancing the survival of neuronal stem cells. The researchers deleted Bax, a gene that plays a major role in neuronal stem cell death, ultimately leading to the maturation of more new neurons. Increasing the production of new neurons in this way restored the animals' performance in two different tests measuring spatial recognition and contextual memory.
By fluorescently labeling neurons activated during memory acquisition and retrieval, the researchers determined that, in the brains of healthy mice, the neural circuits involved in storing memories include many newly formed neurons alongside older, more mature neurons. These memory-stowing circuits contain fewer new neurons in AD mice, but the integration of newly formed neurons was restored when neurogenesis was increased.
Further analyses of the neurons forming the memory-storing circuits revealed that boosting neurogenesis also increases the number of dendritic spines, which are structures in synapses known to be critical for memory formation, and restores a normal pattern of neuronal gene expression. Researchers confirmed the importance of newly formed neurons for memory formation by specifically inactivating them in the brains of AD mice. This reversed the benefits of boosting neurogenesis, preventing any improvement in the animals' memory.
Hippocampal neurogenesis is impaired in Alzheimer's disease (AD) patients and familial Alzheimer's disease (FAD) mouse models. However, it is unknown whether new neurons play a causative role in memory deficits. Here, we show that immature neurons were actively recruited into the engram following a hippocampus-dependent task. However, their recruitment is severely deficient in FAD. Recruited immature neurons exhibited compromised spine density and altered transcript profile. Targeted augmentation of neurogenesis in FAD mice restored the number of new neurons in the engram, the dendritic spine density, and the transcription signature of both immature and mature neurons, ultimately leading to the rescue of memory. Chemogenetic inactivation of immature neurons following enhanced neurogenesis in AD, reversed mouse performance, and diminished memory. Notably, AD-linked App, ApoE, and Adam10 were of the top differentially expressed genes in the engram. Collectively, these observations suggest that defective neurogenesis contributes to memory failure in AD.