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Adult neurogenesis and Alzheimer's disease Alzheimer's disease (AD) pathology destroys neurons and synapses in the brain, leading to dementia. The brain generates new neurons throughout life in the hippocampus, a process called adult hippocampal neurogenesis (AHN). Choi et al. found that blocking AHN exacerbated cognitive impairment in an AD mouse model (see the Perspective by Spires-Jones and Ritchie). Inducing neurogenesis alone did not improve cognition in AD mice, whereas inducing neurogenesis while simultaneously ameliorating the neuronal environment via exercise did. The use of genetic or pharmacological treatments that simultaneously induced neurogenesis and increased levels of brain-derived neurotrophic factor (BDNF) mimicked the benefits of exercise on cognition. Thus, inducing both neurogenesis and providing BDNF may be useful as an AD therapeutic. Science, this issue p. eaan8821; see also p. 975 Adult neurogenesis plays a critical role in neurodegeneration and cognition in a mouse model of Alzheimer’s disease. INTRODUCTION Alzheimer’s disease (AD) is the most common form of age-related dementia, characterized by cognitive impairment, neurodegeneration, β-amyloid (Aβ) deposition, neurofibrillary tangle formation, and neuroinflammation. The most popular therapeutic approach aimed at reducing Aβ burden has not yet proved effective in halting disease progression. A successful therapy would both remove the pathological hallmarks of the disease and provide some functional recovery. The hippocampus contains neural progenitor cells that continue to generate new neurons, a process called adult hippocampal neurogenesis (AHN). AHN is impaired before the onset of classical AD pathology in AD mouse models. Human AHN has also been reported to be altered in AD patients. However, evidence supporting a role for AHN in AD has remained sparse and inconclusive. RATIONALE Two fundamental questions remain: (i) whether AHN could be enhanced and exploited for therapeutic purposes for AD, and (ii) whether AHN impairment mediates aspects of AD pathogenesis. To address these questions, we increased AHN genetically (WNT3) and pharmacologically (P7C3) in AD transgenic 5×FAD mice and explored whether promoting AHN alone can ameliorate AD pathology and behavioral symptoms. We assessed the role of exercise, a known neurogenic stimulus, and explored whether promoting AHN in conjunction with the salutary biochemical changes induced by exercise can improve AD pathology and behavioral symptoms in mice. We also investigated whether AHN suppression, by irradiation, temozolomide, or dominant-negative WNT, contributes to AD pathogenesis and assessed the functional roles of AHN in AD. RESULTS Inducing AHN alone conferred minimal to no benefit for improving cognition in 5×FAD mice. Exercise-induced AHN improved cognition along with reduced Aβ load and increased levels of brain-derived neurotrophic factor (BDNF), interleukin-6 (IL-6), fibronectin type III domain–containing protein–5 (FNDC5), and synaptic markers. However, AHN activation was also required for exercise-induced improvement in memory. Inducing AHN genetically and pharmacologically in combination with elevating BDNF levels mimicked beneficial effects of exercise on AD mice. Conversely, suppressing AHN in early stages of AD exacerbated neuronal vulnerability in later stages of AD, leading to cognitive impairment and increased neuronal loss. However, no such effects from AHN ablation were observed in nontransgenic wild-type (WT) mice, suggesting that AHN has a specific role in AD. CONCLUSION Promoting AHN can only ameliorate AD pathology and cognitive deficits in the presence of a healthier, improved local brain environment, e.g., stimulated by exercise. Increasing AHN alone combined with overexpression of BDNF could mimic exercise-induced improvements in cognition, without reducing Aβ burden. Adult-born neurons generated very early in life are critical for maintaining hippocampal neuronal populations in the hostile brain environment created by AD later in life. Thus, AHN impairment may be a primary event that later mediates other aspects of AD pathogenesis. Future attempts to create pharmacological mimetics of the benefits of exercise on both increased AHN and BDNF may someday provide an effective means for improving cognition in AD. Moreover, increasing neurogenesis in the earliest stages of AD pathogenesis may protect against neuronal cell death later in the disease, providing a potentially powerful disease-modifying treatment strategy for AD. Role of adult-born neurons in AD. Inducing AHN alone by WNT3 and P7C3 together did not prevent cognitive dysfunction, whereas activating AHN through exercise improved memory in 5×FAD mice. Increasing AHN alone together with overexpression of BDNF could mimic exercise-induced improvement in cognition. Suppressing AHN exacerbated neuronal vulnerability, leading to cognitive impairment and increased neuronal loss in 5×FAD mice, but not in WT mice. 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.