TBG096 Ameliorates Memory Deficiency in AD Mouse Model via Promoting Neurogenesis and Regulation of Hsc70/HK2/PKM2/LAMP2A Signaling Pathway

Topic: Brain proteins, microglia and lab models

In previous studies, we isolated a series of novel gentisides with nerve growth factor (NGF)-mimic activities from Gentiana rigescens Franch and conducted continuous structure–activity relationship (SAR) studies. Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood–brain barrier (BBB). At the cell level, TBG096 exerts NGF-mimic activity by regulation of heat-shock cognate protein 70 (Hsc70) and downstream proteins. Subsequently, high-fat diet (HFD)-induced Alzheimer disease (AD) mouse models were used to evaluate the anti-AD efficacy of the compound. TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively. In order to elucidate the mechanism of action of the compound against AD, the RNA-sequence analysis of transcriptomics, quantitative real-time polymerase chain reaction (qRT-PCR), immunofluorescence staining, and Western blot analysis were performed using animal samples. TBG096 significantly increased the expression of the Wnt gene family (Wnt10b, Wnt5a, and Wnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively. At the same time, it reduced the activity of microglia, astrocyte cells, and expression of inducible nitric oxide synthase (INOS) in the brain. Moreover, this compound significantly increased phosphorylated-adenosine 5′-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level. These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway.

Key findings

• Recently, a lead compound named TBG096 was discovered with significant NGF-mimic activity, low toxicity, and ability to pass through the blood–brain barrier (BBB).
• TBG096 significantly improved the memory dysfunction of AD mice at doses of 0.1, 5, and 20 mg/kg, respectively.
• TBG096 significantly increased the expression of the Wnt gene family (Wnt10b, Wnt5a, and Wnt1) and the number of mature neurons and newborn neurons in the hippocampus and cerebral cortex of AD mice, respectively.
• Moreover, this compound significantly increased phosphorylated-adenosine 5′-monophosphate-activated protein kinase (AMPK), Hsc70, and lysosomal-associated membrane protein 2a (LAMP2A) and decreased the expression of hexokinase 2 (HK2), pyruvate kinase M2 (PKM2), amyloid precursor protein (APP), microtubule-associated protein tau (Tau), phosphoryl-Tau, and β-amyloid (Aβ) at the protein level.
• These results suggest that TBG096 produced the NGF-mimic activity and the anti-AD effect via promoting neurogenesis and modification of the Hsc70/HK2/PKM2/LAMP2A signaling pathway, proposing a potential novel approach to counteracting cognitive decline by developing small molecules that promote neurogenesis and the Hsc70 signaling pathway.

Why it matters

In a high-fat diet-induced Alzheimer's disease mouse model, the compound TBG096 improved memory dysfunction and increased mature and newborn neurons in the hippocampus and cortex. This is an animal study, so it does not establish that TBG096 treats Alzheimer's disease in people.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.3390/ijms26062804
• PubMed: 40141445
• Original source →
• Free full text: International Journal of Molecular Sciences →

Full text: free to read — OpenAlex lists this copy as free to read: the link above (checked 6 Feb 1020).

@article{chen2025-40141445,
  author  = {Chen, Danni and Fasina, Opeyemi B. and Lin, Jiahui and Zeng, Jiayuan and Manzoor, Majid and Ohno, Hiroshi and Xiang, Lan and Qi, Jianhua},
  title   = {{TBG096 Ameliorates Memory Deficiency in AD Mouse Model via Promoting Neurogenesis and Regulation of Hsc70/HK2/PKM2/LAMP2A Signaling Pathway}},
  journal = {International Journal of Molecular Sciences},
  year    = {2025},
  doi     = {10.3390/ijms26062804},
  pmid    = {40141445},
  url     = {https://doi.org/10.3390/ijms26062804}
}

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