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Breast carcinoma amplified sequence 2 rescues adult hippocampal neurogenesis and cognitive deficits in Alzheimer’s disease via regulating BDNF/TrkB signaling [Bcas2_KD_hippo_snRNA_seq]

ABSTRACT: Adult hippocampal neurogenesis (AHN) occurs throughout lifespan of humans and rodents and is correlated with memory performance and cognitive plasticity. In Alzheimer’s disease (AD), AHN is impeded, while the molecular basis behind this impairment remains to be elucidated. Here we identified Breast carcinoma amplified sequence 2 (BCAS2), a core component of the CDC5L/Prp19 spliceosome complex, regulating AHN in AD. Using Bcas2 conditional knockout mice, AD mouse model APP/PS1 mice, established mouse primary adult neural stem cells and single cell sequencing, we demonstrate that BCAS2 replacement in adult mouse hippocampus promotes NSC activation and differentiation to neuron, restore AHN and relevant memory deficits through BDNF/TrkB signaling. Our findings corroborate the significance of AHN in AD and reveal the possible therapeutic potential of targeting BCAS2 in neurodegeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE331441 | GEO | 2026/06/01

REPOSITORIES: GEO

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Breast carcinoma amplified sequence 2 rescues adult hippocampal neurogenesis and cognitive deficits in Alzheimer’s disease via regulating BDNF/TrkB signaling

Project description:Adult hippocampal neurogenesis (AHN) occurs throughout lifespan of humans and rodents and is correlated with memory performance and cognitive plasticity. In Alzheimer’s disease (AD), AHN is impeded, while the molecular basis behind this impairment remains to be elucidated. Here we identified Breast carcinoma amplified sequence 2 (BCAS2), a core component of the CDC5L/Prp19 spliceosome complex, regulating AHN in AD. Using Bcas2 conditional knockout mice, AD mouse model APP/PS1 mice, established mouse primary adult neural stem cells and single cell sequencing, we demonstrate that BCAS2 replacement in adult mouse hippocampus promotes NSC activation and differentiation to neuron, restore AHN and relevant memory deficits through BDNF/TrkB signaling. Our findings corroborate the significance of AHN in AD and reveal the possible therapeutic potential of targeting BCAS2 in neurodegeneration.

2026-06-01 | GSE331130 | GEO

MDGA2 constrains the BDNF/TrkB signaling

Project description:MDGA2 is an excitatory synaptic suppressor and its mutations have been associated with autism spectrum disorder (ASD). However, the detailed physiological function of MDGA2 and the mechanism underlying MDGA2 deficiency-caused ASD has yet to be elucidated. Herein, we not only confirm that Mdga2+/- mice exhibit increased excitatory synapse transmission and ASD-like behaviors, but also identify aberrant BDNF/TrkB signaling activation in these mice. We demonstrate that MDGA2 interacts with TrkB through its MAM domain, thereby competing the binding of BDNF to TrkB. Both loss of MDGA2 and the ASD-associated MDGA2 V930I mutation promote the BDNF/TrkB signaling activity. Importantly, we demonstrate that inhibiting the BDNF/TrkB signaling by both small molecular compound and MDGA2-derived peptide can attenuate the increase of AMPA receptor-mediated excitatory synaptic activity and social deficits in MDGA2 deficient mice. These results highlight a novel MDGA2-BDNF/TrkB-dependent mechanism underlying the synaptic function regulation, which may become a therapeutic target for ASD.

2025-02-06 | PXD050810 | Pride

Activation of hypothalaActivation of hypothalamic-enhanced adult-born neurons is sufficient to restore cognitive and noncognitive function in Alzheimer's diseasemic-enhanced adult-born neurons is sufficient to restore cognitive and noncognitive function in Alzheimer's diseaseActivation of hypothalamic-enhanced adult-born neurons is sufficient to restore cognitive and noncognitive function in Alzheimer's disease

Project description:Patients with Alzheimer’s disease (AD) exhibit progressive memory loss, depression, and anxiety, accompanied by impaired adult hippocampal neurogenesis (AHN). Whether modulating AHN is sufficient to improve these cognitive and noncognitive symptoms in AD remains elusive. Here we report that chronic stimulation of hypothalamic supramammillary nucleus (SuM) during early AD restores AHN in an otherwise impaired neurogenic niche. Strikingly, activation of SuM-enhanced adult-born neurons (ABNs) is sufficient to restore memory and emotion deficits in 5×FAD mice. Interestingly, activation of SuM-enhanced ABNs in AD mice increases CA3 and CA1 activity. To probe ABN-activity-dependent changes, we performed quantitative phosphoproteomics and found activation of SuM-enhanced ABNs promotes activation of the canonical pathways related to synaptic plasticity and microglia phagocytosis. Functional assays further confirm increased CA1 long-term potentiation and enhanced microglia phagocytosis of plaques upon activation of SuM-enhanced ABNs. Our findings reveal a robust AHN-promoting strategy that is sufficient to restore AD-associated deficits and highlight ABN-activity-dependent mechanisms underlying functional improvement in AD.

2023-03-08 | PXD034176 | Pride

A BDNF-TrkB autocrine loop enhances senescent cell viability [RNA-seq]

Project description:Cellular senescence is characterized by cell cycle arrest, resistance to apoptosis, and a senescence-associated secretory phenotype (SASP) whereby cells secrete pro-inflammatory and tissue-remodeling factors. Given that the SASP exacerbates age-associated pathologies, some aging interventions selectively eliminate senescent cells. In this study, a drug library screen uncovered TrkB (NTRK2) inhibitors as selectively capable of triggering apoptosis of senescent, but not proliferating, human fibroblasts. Senescent cells expressed high levels of TrkB, which supported senescent cell viability, and secreted the TrkB ligand BDNF. The reduced viability of senescent cells after ablating BDNF function supported an autocrine function for TrkB and BDNF, and the increased expression of BCL2L2 through ERK5, downstream of BDNF-TrkB, favored senescent cell survival. Strikingly, treatment with TrkB inhibitors reduced the accumulation of senescent cells in aged mouse organs. Our results suggest that the SASP factor BDNF promotes cell survival by activating TrkB and is a promising therapeutic target to reduce the senescent cell burden.

2022-09-20 | GSE190998 | GEO

BDNF-TrkB signaling orchestrates the buildup process for local sleep

Project description:Using pharmacology and optogenetics perturbations, we showed that cortical brain-derived neurotrophic factor (BDNF) regulates the intensity of SWA via the activation of Tyrosine kinase B (TrkB) receptor and cAMP-response element-binding protein (CREB). We identified that the circuitry mediating TrkB-induced sleep SWA involves excitatory pyramidal cells of the cortex's layer 5. We found that increased neuronal firing alone in the somatosensory cortex was not sufficient to increase SWA. Using mathematical modeling of a local network in the brain, we model how BDNF’s effects on synaptic strength can increase SWA in ways not achieved through increased firing alone. Together, our findings implicate BDNF-TrkB-CREB signaling pathway in local SWA control during sleep.

2024-06-22 | PXD045652 | Pride

microRNA-132 regulates adult neural stem cells and their progeny to restore adult hippocampal neurogenesis and memory deficits in Alzheimer’s disease

Project description:Neural stem cells residing in the hippocampal neurogenic niche sustain life-long neurogenesis in the adult brain. Adult hippocampal neurogenesis (AHN) is functionally linked to mnemonic and cognitive plasticity in humans and rodents. In Alzheimer’s disease (AD), the process of generating new neurons at the hippocampal neurogenic niche is impeded, yet the mechanisms involved are unknown. Here we identify miR-132, one of the most consistently downregulated microRNAs in AD, as a potent regulator of AHN, exerting cell-autonomous pro-neurogenic effects in the adult neural stem cells and their progeny. Using distinct AD mouse models, cultured human primary and established neural stem cells, and human patient material, we demonstrate that AHN is directly impacted by AD pathology. miR-132 replacement in adult mouse AD hippocampus restores AHN and relevant memory deficits. Our findings corroborate the significance of AHN in AD and reveal the possible therapeutic significance of targeting miR-132 in neurodegeneration.

2021-06-21 | GSE172402 | GEO

Stat3-Bdnf-TrkB axis promotes alveolar regeneration [scRNA-seq]

Project description:Regenerating new alveolar epithelium is essential for recovery from many lung diseases. This multi-cellular regenerative process occurs when type II alveolar pneumocytes (AT2), with support from mesenchymal niche cells, proliferate to generate more AT2 cells and transdifferentiate in type I pneumocytes. To elucidate how coordinated events between AT2 cells and mesenchyme restore alveolar epithelium we used unbiased genome-wide analysis of chromatin accessibility and gene expression in both cell types following acute lung injury. We observed that chromatin acessability in AT2 cells changes signficantly following acute lung injury. Newly accessible chromatin reveals new STAT3 binding motifs adjacent to genes that regulate essential regenerative pathways in AT2 cells. Restoration of alveolar structures following both sterile and infectious lung injuries was inhibited when STAT3 signaling was lost in AT2 cells. Single-cell transcriptome analysis of regenerating AT2 cells identified brain neurotrophic factor (Bdnf) as the sole STAT3 target gene whose chromatin becomes newly accessible in a regenerating population of AT2 cells. BDNF increased alveolar organoid size and forming efficiency in murine and human models. The receptor for BDNF, TrkB, is uniquely? expressed on mesenchymal alveolar niche cells (MANC). Exposure of BDNF to TrkB increases expression of fibroblast growth factor 7 (Fgf7), an essential regenerative cytokine, in MANCs. Blocking Bdnf signaling with a TrkB receptor antagonist abrogated murine and human alveolar organoid formation. Finally, a small molecule TrkB agonist improved functional and histological outcomes in vivo following sterile and infectious lung injuries. Collectively, these data highlight the biological and therapeutic importance of the Stat3-Bdnf-TrkB axis in orchestrating alveolar epithelial regeneration

2020-06-01 | GSE132533 | GEO