Alzheimer disease (AD) is the most common type of dementia in individuals over 65 years of age. The neuropathological hallmarks of the condition are Tau neurofibrillary tangles and Amyloid-β senile plaques. Moreover, certain susceptible regions of the brain experience a generalized lack of neural plasticity and marked synaptic alterations during the progression of this as yet incurable disease. One of these regions, the hippocampus, is characterized by the continuous addition of new neurons throughout life. This phenomenon, named adult hippocampal neurogenesis (AHN), provides a potentially endless source of new synaptic elements that increase the complexity and plasticity of the hippocampal circuitry. Numerous lines of evidence show that physical activity and environmental enrichment (EE) are among the most potent positive regulators of AHN. Given that neural plasticity is markedly decreased in many neurodegenerative diseases, the therapeutic potential of making certain lifestyle changes, such as increasing physical activity, is being recognised in several non-pharmacologic strategies seeking to slow down or prevent the progression of these diseases. This review article summarizes current evidence supporting the putative therapeutic potential of EE and physical exercise to increase AHN and hippocampal plasticity both under physiological and pathological circumstances, with a special emphasis on neurodegenerative diseases and AD.

The addition of new neurons to the existing hippocampal circuitry persists in the adult dentate gyrus (DG). During this process, named adult hippocampal neurogenesis (AHN), adult hippocampal progenitor cells (AHPs) give rise to newborn dentate granule cells (DGCs). The acquisition of a neuronal lineage by AHPs is tightly regulated by numerous signaling molecules and transcription factors. In this regard, glycogen synthase kinase 3β (GSK-3β) is a master regulator of the maturation of AHPs in vitro. Here we analyzed the cell-autonomous effects of overexpressing a constitutively active form of GSK-3β (GSK-3β S9A) in AHPs in vivo. To this end, we stereotaxically injected a GSK-3β S9A-encoding retrovirus (GSK-3β-V5) into the DG of young adult C57BL6/J Ola Hsd female mice and studied the cell lineage acquisition, migratory and marker expression patterns, and the morphological maturation of the infected cells over time. Strikingly, GSK-3β S9A-transduced cells expressed glial fibrillary acidic protein (GFAP) and NG2, thereby acquiring an immature astroglial phenotype, which differed markedly from the neuronal phenotype observed in cells transduced with a control retrovirus that encoded GFP. Accordingly, the morphology and migration patterns of cells transduced by the two retroviruses are remarkably divergent. These observations support the role of GSK-3β as a cornerstone that regulates the balance between new astocytes/neurons generated in the adult murine DG.

The rodent hippocampus generates new neurons throughout life. This process, named adult hippocampal neurogenesis (AHN), is a striking form of neural plasticity that occurs in the brains of numerous mammalian species. Direct evidence of adult neurogenesis in humans has remained elusive, although the occurrence of this phenomenon in the human dentate gyrus has been demonstrated in seminal studies and recent research that have applied distinct approaches to birthdate newly generated neurons and to validate markers of adult-born neurons. Our data point to the persistence of AHN until the 10th decade of human life, as well as to marked impairments in this process in patients with Alzheimer's disease. Moreover, our work demonstrates that the methods used to process and analyze postmortem human brain samples can limit the detection of various markers of AHN to the point of making them undetectable. In this Dual Perspectives article, we highlight the critical methodological aspects that should be strictly controlled in human studies and the robust evidence that supports the occurrence of AHN in humans. We also put forward reasons that may account for current discrepancies on this topic. Finally, the unresolved questions and future challenges awaiting the field are highlighted.