bims-adhine 2026-09-13 papers

Theranostics. 2026 ;16(15): 8561-8579

Focused ultrasound-mediated blood-brain barrier modulation is associated with adult hippocampal neurogenic responses linked to zinc-dependent signaling.

Bo Young Choi, Jaewoo Shin, Chanho Kong, Min Kyu Park, Dae Ki Hong, Young-Soo Chung, Sang Won Suh, Won Seok Chang.

Rationale: Transcranial focused ultrasound (FUS)-mediated blood-brain barrier (BBB) modulation is a promising non-invasive therapeutic strategy for targeted brain drug delivery. However, its direct regenerative potential to actively remodel the brain microenvironment and promote adult hippocampal neurogenesis remains largely unexplored owing to elusive molecular mediators. Here, we investigated whether zinc-dependent signaling contributes to adult hippocampal neurogenic responses following FUS-mediated BBB modulation.
Methods: We integrated pharmacological and genetic approaches in adult rodent models subjected to hippocampal-targeted low-intensity FUS with microbubbles. Neural progenitor proliferation and differentiation were quantified using BrdU and DCX labeling. To assess the contributions of extracellular/labile zinc availability and ZnT3-associated vesicular zinc physiology, intracerebroventricular zinc chelation with CaEDTA was performed in rats, and ZnT3-/- mice were used. Molecular assays and exploratory bulk RNA sequencing were conducted to characterize candidate downstream molecular pathways.
Results: FUS-mediated BBB modulation significantly increased dentate gyrus progenitor proliferation, neuroblast abundance, and newborn neuron survival. These effects were markedly attenuated by acute zinc chelation and were not observed in ZnT3-/- mice, indicating that intact zinc availability and ZnT3-associated zinc physiology are required for the full FUS-associated neurogenic response. FUS was associated with increased expression of brain-derived neurotrophic factor, Zrt-/Irt-like protein 3 (ZIP-3), and Piezo1 proteins, and zinc chelation attenuated these increases. ZIP-3 and Piezo1 signals overlapped with NeuN-positive cells, suggesting neuronal enrichment. In addition, exploratory bulk transcriptomic profiling of whole hippocampal tissue revealed candidate signatures associated with neurovascular and glial responses following FUS in ZnT3+/+ mice, whereas the corresponding transcriptomic responses appeared reduced or altered in ZnT3-/- mice.
Conclusions: Our findings support a framework in which intact zinc availability, including ZnT3-associated zinc physiology, contributes to adult hippocampal neurogenic responses following FUS-mediated BBB modulation. This work provides a mechanistic framework for the development of ultrasound-guided therapeutic strategies aimed at promoting repair-associated plasticity in neurological disorders.

Keywords: adult hippocampal neurogenesis; blood–brain barrier; focused ultrasound; vesicular zinc; zinc transporter 3

DOI: https://doi.org/10.7150/thno.133902

J Ethnopharmacol. 2026 Sep 08. pii: S0378-8741(26)01211-0. [Epub ahead of print]374(Pt 1): 122356

Bushen-Yizhi formula promotes neurogenesis and ameliorates cognitive impairment by activating ST8Sia Ⅱ/Ⅳ-PSA-NCAM pathway in ibotenic acid induced mice.

Jingjing Zheng, Qiwen Tan, Guoqing Liu, Ruiye Xie, Qi Wang, Yong Liang.

ETHNOPHARMACOLOGICAL RELEVANCE: Bushen-Yizhi formula (BSYZ), a traditional Chinese herbal prescription, has been widely used to treat kidney deficiency syndrome and alleviate cognitive impairment associated with Alzheimer's disease (AD). Loss of polysialylation of the neural cell adhesion molecule (PSA-NCAM) is closely associated with cognitive dysfunction. However, whether BSYZ regulates PSA-NCAM polysialylation and the underlying mechanisms remain unclear.
AIM OF THE STUDY: This study aimed to investigate whether BSYZ promotes hippocampal neurogenesis and ameliorates cognitive impairment through activation of the ST8Sia II/IV-PSA-NCAM pathway.
METHODS: An AD-like mouse model was established by bilateral ibotenic acid (IBO) injections into the basal nuclei of C57BL/6 mice. Animals were randomly assigned to five groups: control, model, low- BSYZ (1.46 g/kg), high-dose BSYZ (5.84 g/kg), and donepezil (3 mg/kg). Cognitive function was evaluated using the open field test (OFT), novel object recognition test (NORT), and Morris water maze (MWM). Hippocampal PSA-NCAM expression was assessed by immunofluorescence staining and further investigated using proteomic analysis combined with network pharmacology. PSA-NCAM-associated polysialic acid levels were quantified by hydrochloric acid hydrolysis followed by 4,5-methylenedioxy-1,2-phenylenediamine dihydrochloride (DMB) derivatization coupled with mass spectrometry. The mRNA and protein expression levels of α-2,8-sialyltransferase II and IV (ST8Sia II/IV) were determined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. Hippocampal neurogenesis was evaluated by immunofluorescence double-labeling. The bioactive compounds targeting ST8Sia II/IV were identified using HPLC-Q-TOF MS/MS, followed by molecular docking and molecular dynamics simulations to predict their binding affinities.
RESULTS: The IBO-induced mouse model exhibited significant cognitive deficits, confirming successful model establishment. Behavioral assessments demonstrated that both low- and high-dose BSYZ significantly improved learning and memory performance. Proteomic analysis and immunofluorescence staining revealed that BSYZ markedly increased hippocampal PSA-NCAM expression (**P < 0.01, n = 5). Quantitative analysis further showed that PSA-NCAM-associated polysialic acid levels increased by 78% (*P < 0.05, n = 5) and 102% (**P < 0.01, n = 5) following low- and high-dose BSYZ treatment. BSYZ significantly increased the number of PSA-NCAM+/DCX+ cells in the hippocampal dentate gyrus (*P < 0.05), accompanied by significant increases in Nestin+/BrdU+ (*P < 0.05), DCX+/BrdU+ (**P < 0.01), and NeuN+/BrdU+ (**P < 0.01) double-positive cells, indicating enhanced neurogenesis and neuronal maturation. Furthermore, BSYZ significantly upregulated both the mRNA and protein expression of ST8Sia II (**P < 0.01) and ST8Sia IV (**P < 0.01) in the hippocampus. HPLC-Q-TOF MS/MS, molecular docking, and molecular dynamics simulations identified isoimperatorin as a major active constituent of BSYZ with strong binding affinity toward both ST8Sia II/IV, exhibiting docking energies of -8.7 and -7.6 kcal/mol, respectively (n = 3, RSD < 2%).
CONCLUSIONS: Our study demonstrates BSYZ promotes hippocampal neurogenesis to ameliorate cognitive impairment by activating ST8Sia II/IV-PSA-NCAM pathway. These findings provide mechanistic evidence supporting the therapeutic potential of BSYZ for AD treatment.

Keywords: Alzheimer's disease; Bushen-yizhi formula; Hippocampal neurogenesis; PSA-NCAM; ST8Sia II/IV

DOI: https://doi.org/10.1016/j.jep.2026.122356

J Affect Disord Rep. 2026 Jul;25 101071

In the absence of Alzheimer's Disease pathology, PET-measured hippocampal tau is reduced in association with greater depressive symptoms: Could tau PET be sensitive to physiological tau involved in neurogenesis?

Seyed Hani Hojjati, Xiuyuan Hugh Wang, Liangdong Zhou, Samantha Keil, Emily Tanzi, Tom Maloney, Farnia Feiz, Sudhin Shah, Lidia Glodzik, Yi Li, Gloria C Chiang, Tracy A Butler.

Background: Tau Positron Emission Tomography (PET) visualizes hyperphosphorylated tau tangles which, together with Aβ plaques, are hallmark pathologies of Alzheimer's disease (AD). Greater tau, measured by PET or neuropathology, is robustly linked to worse cognition in AD, but associations with mood are less studied. We previously reported an unexpected inverse relationship between depressive symptoms and PET-measured medial temporal tau in individuals without AD. Here, we confirm and extend this finding in an independent cohort.
Methods: We analyzed cross-sectional data from 403 Alzheimer's Disease Neuroimaging Initiative participants who underwent flortaucipir (tau) PET, Aβ PET, MRI, and clinical assessments including the Geriatric Depression Scale (GDS). Participants were categorized as Aβ- or Aβ+. Associations between GDS scores and mean hippocampal flortaucipir uptake were assessed using Spearman correlation and multiple regression.
Results: In Aβ- individuals (n = 252), higher hippocampal tau was significantly associated with lower depression scores, whereas Aβ+ individuals (n = 151) showed a trend-level positive association. This difference was supported by a significant interaction between depression and Aβ status in regression analyses. Results were unchanged after adjustment for age, diagnostic group, and hippocampal volume.
Conclusions: In the absence of AD pathology, greater severity of depressive symptoms is associated with lower PET-measured hippocampal tau. Because impaired hippocampal neurogenesis is considered a key mechanism in depression, and tau is a normal component of cell division including neurogenesis, this replicated inverse relationship may reflect reduced hippocampal neurogenesis. Whether tau PET can provide a window into this process in humans requires further study.

Keywords: Alzheimer’s disease; Amyloid; Depression; Hippocampus; Neurogenesis; Positron emission tomography (PET); Tau

DOI: https://doi.org/10.1016/j.jadr.2026.101071

J Mol Histol. 2026 Sep 06. pii: 299. [Epub ahead of print]57(5):

The neuroprotective potential of thymoquinone and intermittent fasting on aluminum chloride-induced Alzheimer's disease like model in rat hippocampus: insights into neurogenesis and autophagy.

Reem Ahmed Abd El-Salam, Azza Radwan El-Hadidy, Nesreen Moustafa Omar, Nahla Reda Sarhan.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder. Thymoquinone (TQ) is the active component of black seeds with many health benefits. Intermittent fasting (IF) is a dietary pattern with antioxidant and neuro-regenerative effects. This study explored the neuroprotective potential of TQ, IF or their combination on hippocampus of AD-like rat model with emphasis on the underlying mechanisms as neurogenesis and autophagy. Eighty adult male rats were divided into 7 groups: control, TQ given TQ (50 mg/kg/day orally), IF underwent IF for 14 h/day, AL given Aluminum chloride (AlCl3) (300 mg/kg/day orally) to induce AD-like pathology, AL + TQ, AL + IF and AL + TQ+ IF for 4 weeks. AD-like pathology was evaluated by behavioral tests, histopathology, immunostaining for apoptosis (Bax), microglia (CD68) and neurogenesis (nestin). Expressions of p-Tau, oxidative stress & autophagy markers (P62 and LC3B II) were assessed by western blot. AL group showed histological and ultrastructural AD-like features as apoptotic neurons, amyloid β deposition, significant elevation in MDA, p-Tau and P62, reduction in SOD and LC3B II, upregulation of Bax immune-expression and number of CD68 + activated microglia and diminished nestin positive cell number. TQ and IF mitigated these changes particularly when used in combination. In conclusion, TQ and IF protect against AlCl3-induced hippocampal AD-like pathology through reduction of oxidative stress, apoptosis, amyloid deposits, p-Tau expression and their modulatroy effects on microglia activation, neurogenesis and autophagy. The neuroprotective potential of IF is superior to TQ, while the optimal neuroprotection is achieved by the combination of both.

Keywords: Alzheimer’s disease; Autophagy; Intermittent fasting; Neurogenesis; Thymoquinone

DOI: https://doi.org/10.1007/s10735-026-10946-5

Mol Psychiatry. 2026 Sep 09.

Novel insight into the effects of the metabolites from gut microbiota in both unmedicated depressive adolescents and mice: key roles of indole derivatives-aryl hydrocarbon receptor signaling in neurogenesis and microglial homeostasis.

Xi Wang, Miaoyang Hu, Weilan Wu, Jing Liu, Zhiru Tang, A Yiguzaili Manglike, Jin Wei, S Thameem Dheen, Yuan Lin, Gang Liu, Jie Cheng, Wenjuan Wang, Rong Gao, Xufeng Chen, Jun Wang.

Adolescent depression is undergoing a rapid surge and has become a severe global public health challenge. However, current therapeutic approaches are limited and often accompanied by significant side effects primarily due to the elusive underlying mechanisms. The gut-brain axis has recently gained growing attention for its pivotal roles in neuropsychiatric disorders, particularly the tryptophan (Trp) metabolism by the microbiota. With the 16S rRNA gene sequencing, the abundance of Bacteroidetes, a microbiota phylum that includes several taxa involved in tryptophan metabolism and indole derivative production was significantly reduced in unmedicated adolescents with depression. The in-depth analysis showed that levels of key indole derivatives, including IAA, IPA and IAld, were markedly decreased in depressed patients; crucially, these reductions showed a significant negative correlation with depression severity scores. Consistent with the clinical findings, a similar decline in IAA, IPA, and IAld levels was observed in adolescent mice with depression induced by chronic restraint stress (CRS). Notably, depression-like behaviors in these mice were substantially ameliorated by a high-Trp diet (CRS + 1.19% Trp) and direct supplementation with indole derivatives. In a reciprocal experiment, a low-Trp diet (0.09% Trp) was found to de novo induce depressive behaviors in otherwise healthy mice. Morphological analysis of brain tissue uncovered another critical insight, the microglial cells in CRS mice exhibited hallmark features of overactivation. Remarkably, both the high-Trp diet and indole derivative supplementation exerted consistent protective effects, shown as restored microglial morphology and neurogenesis. Mechanistically, the indole derivatives were shown to activate AhR signaling, which in turn balanced the expression of anti-inflammatory factors (e.g., IL-10, TGF-β) and pro-inflammatory factors (e.g., IL-1β, CD68), thereby remodeling microglial morphology and promoting neurogenesis in hippocampus. A series of loss-of-function and gain-of-function experiments further confirmed AhR's essential role: the salutary effects of indole derivatives on anti-depression were substantially attenuated in AhR-/- mice; reciprocally, conditional microglia-specific overexpression of AhR in the hippocampus of CRS mice significantly ameliorated CRS-induced depressive-like changes, accompanied by suppression of microglial activation and upregulation of anti-inflammatory factors. Collectively, the present study revealed a previously unrecognized the microbiota-derived indole derivatives ameliorated CRS-induced adolescent depression via the AhR signaling pathway. These findings highlight that targeting the indole derivative-AhR signaling axis may represent a novel therapeutic strategy for adolescent depression, one with the potential to minimize side effects and address the unmet clinical needs of this vulnerable population.

DOI: https://doi.org/10.1038/s41380-026-03895-8