Alzheimer’s disease (AD) is characterized by progressive cognitive decline strongly associated with impaired adult hippocampal neurogenesis (AHN). Mounting evidence suggests that this impairment results from both the intrinsic dysfunction of neural stem cells (NSCs)—such as transcriptional alterations in quiescent states—and extrinsic niche disruptions, including the dysregulation of the Reelin signaling pathway and heightened neuroinflammation. Notably, AHN deficits may precede classical amyloid-β and Tau pathology, supporting their potential as early biomarkers of disease progression. In this review, we synthesize recent advances in therapeutic strategies aimed at restoring AHN, encompassing pharmacological agents, natural products, and non-pharmacological interventions such as environmental enrichment and dietary modulation. Emerging approaches—including BDNF-targeted nanocarriers, NSC-derived extracellular vesicles, and multimodal lifestyle interventions—highlight the translational promise of enhancing neurogenesis in models of familial AD. We further propose the Neurogenesis Impairment Index (NII)—a novel composite metric that quantifies hippocampal neurogenic capacity relative to amyloid burden, while adjusting for demographic and cognitive variables. By integrating neurogenic potential, cognitive performance, and pathological load, NII provides a framework for stratifying disease severity and guiding personalized therapeutic approaches. Despite ongoing challenges—such as interspecies differences in neurogenesis rates and the limitations of stem cell-based therapies—this integrative perspective offers a promising avenue to bridge mechanistic insights with clinical innovation in the development of next-generation AD treatments.

We previously discovered WS-6 as a new antidepressant in correlation to its function of stimulating neurogenesis. Herein, several different scaffolds (stilbene, 1,3-diphenyl 1-propene, 1,3-diphenyl 2-propene, 1,2-diphenyl acrylo-1-nitrile, 1,2-diphenyl acrylo-2-nitrile, 1,3-diphenyl trimethylamine), further varied through substitutions of twelve amide substituents plus the addition of a methylene unit and an inverted amide, were examined to elucidate the SARs for promoting adult rat neurogenesis. Most of the compounds could stimulate proliferation of progenitors, but just a few chemicals possessing a specific structural profile, exemplified by diphenyl acrylonitrile 29b, 32a, and 32b, showed better activity than the clinical drug NSI-189 in promoting newborn cells differentiation into mature neurons. The most potent diphenyl acrylonitrile 32b had an excellent brain AUC to plasma AUC ratio (B/P = 1.6), suggesting its potential for further development as a new lead.

This study aimed to screen the active components of Thymus quinquecostatus with antidepressant effects and to explore the underlying mechanisms based on hippocampal neuroplasticity. A chronic restraint stress (CRS) mouse model of depression was established. The intervention effects of five active components—thyme volatile oil, thymol, carvacrol, p-cymene, and β-caryophyllene (BCP)—were systematically evaluated using behavioral, endocrine, histomorphological, and molecular approaches (50 mg/kg, intraperitoneal injection, once daily for 14 days). All active components significantly reduced serum corticosterone levels (decreased by 27.1%–64.7%, P < 0.001) and increased the sucrose preference rate (increased by 39.5%–55%, P < 0.05). Thymol, carvacrol, and p-cymene significantly shortened immobility time in the tail suspension test (decreased by 8.4%–20.9%), whereas thymol, BCP, and volatile oil effectively reduced feeding latency in the novelty-suppressed feeding test (decreased by 63.4%–67.8%). p-Cymene, BCP, and volatile oil significantly increased the number of BrdU⁺ proliferating cells and DCX+ immature neurons in the hippocampal dentate gyrus (P < 0.05–0.001). All five components increased the number of microglial terminal endpoints by 41%–70%, indicating a shift toward a resting/anti-inflammatory phenotype, and some components also restored astrocyte morphology and density (P < 0.05). All five components significantly activated AKT (p-AKT/AKT increases of more than 91%), whereas only volatile oil, carvacrol, and p-cymene significantly activated CREB (p-CREB/CREB increases of 34%–50%); suggesting that AKT/CREB signaling participates in the regulation of neuronal survival and plasticity. The active components of thyme ameliorated depression-like behaviors in mice through multi-target synergistic effects, including inhibiting HPA axis overactivation, promoting neurogenesis, inducing glial anti-inflammatory phenotype transformation, and activating AKT/CREB survival signaling. Among them, p-cymene, BCP, carvacrol, and volatile oil displayed promising therapeutic potential, providing an experimental basis for the development of natural multi-target antidepressants based on neural stem cell–glial cell network regulation.