bims-adhine 2026-09-06 papers

Methods Enzymol. 2026 ;pii: S0076-6879(26)00186-2. [Epub ahead of print]734 269-299

A short guide on in vivo transfection of flag-HDAC4 in dentate gyrus for study of adult neurogenesis in repetitive mild traumatic brain injury.

Singh Ankit Satyaprakash, Nitesh Kumar Gupta, Humaira Farooq, Surya Pratap Singh, Rajaneesh Kumar Gupta.

HDAC4, a class II epigenetic regulator, plays a critical role in adult hippocampal neurogenesis and determines the fate of newly proliferating and/or differentiating neural stem cells (NSCs). However, repetitive mild traumatic brain injury (rmTBI) impairs neurogenesis, contributing to the pathophysiology of cognitive deficits observed in neurodegenerative and neuropsychiatric disorders. Here, we present a protocol: (1) to induce rmTBI in mice using a closed head injury (CHI) device and to validate the model by assessing cognitive/behavioral performances and (2) to perform intracranial injection of FLAG-HDAC4 into the dentate gyrus of adult mice using a stereotaxic apparatus, in order to investigate the role of HDAC4 in impaired adult neurogenesis. This is achieved by analyzing BrdU⁺ and Nestin⁺ cells (markers of NSC proliferation), DCX⁺ and ND1⁺ cells (markers of neuronal differentiation), along with immunohistochemistry, fluorescence microscopy, and image analysis.

Keywords: Adult neurogenesis; Cognitive impairment; HDAC4; In vivo transfection; Repeated mild traumatic brain injury

DOI: https://doi.org/10.1016/bs.mie.2026.05.058

Environ Int. 2026 Sep 01. pii: S0160-4120(26)00461-7. [Epub ahead of print]215 110503

PFAS disrupt adult hippocampal neurogenesis and synaptic remodeling associated with NOX2/ROS/Ferroptosis activation.

Xingcheng Li, Xiao Li, Cimei Li, Lingfen Cao, Siteng Li, Xiaoping Wang, Kangchao Du, Yaoyao Cui, Yuxiang Ma, Xu Wang, Xing Xing, Huigen Feng, Ciqing Yang, Xianwei Wang, Cixia Li.

Per- and polyfluoroalkyl substances (PFAS) accumulate in the hippocampus, yet their effects on adult hippocampal neurogenesis (AHN) remain unclear. In this study, adult male mice were orally exposed to PFOA or GenX (2 or 10 mg/kg/day) for 28 days. Behavioral performance, AHN, synaptic remodeling, microglial morphology, and redox status were evaluated using behavioral assays, Nissl and Golgi staining, BrdU immunolabeling, microglial morphometric analyses, and Western blotting. PFOA exposure and high-dose GenX exposure reduced time spent and distance traveled in the center area of the open field and impaired spatial learning and memory performance in the Morris water maze, as indicated by increased escape latency and fewer platform crossings. In contrast, PFOA and low-dose GenX exposure reduced exploration of the open arms in the elevated plus maze. PFOA and GenX reduced dendritic spine density with fewer mushroom/thin spines and more stubby spines. PFOA preferentially decreased PSD95 (postsynaptic marker), whereas GenX reduced synaptophysin (presynaptic marker). In the subgranular zone (SGZ), survival and neuronal differentiation of neural stem cells were diminished, and asymmetric divisions of radial glia-like cells increased, suggesting stem-cell pool depletion. Microglia exhibited a hyper-ramified/bushy reactive phenotype. Hippocampal ROS/MDA rose, NOX2 components (GP91phox/P22phox) were upregulated, and ferroptosis defenses (SLC7A11/GLS2/GPX4) were downregulated. Collectively, PFOA and GenX disrupt hippocampal synaptic remodeling and AHN and are associated with increased oxidative stress and ferroptosis-related alterations. Differential pre- versus postsynaptic vulnerabilities may contribute to the distinct behavioral alterations observed following PFOA and GenX exposure. This work provides new insights into the neurotoxic effects of PFOA and GenX and identifies potential pathways involved in PFAS-induced hippocampal dysfunction.

Keywords: Adult hippocampal neurogenesis; Ferroptosis; Microglia; PFAS; Synaptic plasticity

DOI: https://doi.org/10.1016/j.envint.2026.110503

Alzheimers Dement. 2026 Sep;22(9): e71784

Extracellular matrix remodeling upregulates hippocampal neurogenic niche stiffness and impairs neurogenesis in Alzheimer's disease.

INTRODUCTION: Preserving adult hippocampal neurogenesis alleviates cognitive deficits in Alzheimer's disease (AD), yet how biophysical alterations in such as stiffness in the neurogenic niche regulate neurogenesis remains unclear.
METHODS: Stiffness in the hippocampal dentate gyrus subgranular cell zone (SGZ) of 5×FAD mice was measured using atomic force microscopy. Extracellular matrix (ECM) components in mice and AD patients were profiled through proteomics. Hydrogels were supplemented in the SGZ to upregulate local stiffness in wildtype mice, while glycosaminoglycanases was injected to downregulated stiffness in 5×FAD mice. Gene expression in the neurogenic lineage was analyzed through single nucleus sequencing. Conditional knockdown or overexpression of mechanosensors and/or Yes-associated protein 1 (YAP1) were achieved using viral vectors.
RESULTS: We found SGZ stiffening occured early in 3-month 5×FAD mice, associating with ECM remodeling and neurogenesis impairment. Upregulation of tissue stiffness in the SGZ of wild-type mice via supplementing high-density hydrogel suppressed neurogenesis, whereas downregulaion of the niche stiffness in AD mice using hyaluronidase-1 (HAase1) and other glycosaminoglycanases preserved neurogenesis. Single-nucleus transcriptomics reveals that the HAase1 treatment reshaped transcriptome of the neural stem cells (NSCs) lineage. Specifically, we found that the integrin-YAP1 mechanotransduction axis played important roles in the stiffness-induced neurogenesis deficits. Conditional knockdown of both integrin β1 and YAP in the NSC lineage mitigated stiffness-induced deficits. Consistently, the association of ECM remodeling and neurogenesis impairments were also observed in post mortem AD patients.
DISCUSSION: ECM stiffness plays as a critical regulator of hippocampal neurogenesis, providing potential targets for pro-neurogenic therapeutics of AD.

Keywords: Alzheimer's disease; Yes1‐associated protein; adult hippocampal neurogenesis; extracellular matrix; integrin

DOI: https://doi.org/10.1002/alz.71784

Front Cell Neurosci. 2026 ;20 1887577

The hippocampal subgranular zone neurogenic niche: a modular perspective on neural stem cell regulation.

Tengyu Zhao, Yuhan Zhou, Pengyu Pan, Ying Jia, Xinyue Zhang, Zeyuan An, Jingdong Yan, Quan Li, Yanyan Zhou.

The subgranular zone (SGZ) of the hippocampus represents a principal site of adult neurogenesis and exhibits distinct structural and organizational features. Increasing evidence indicates that neural stem cell (NSC) behavior in the SGZ is not solely determined by intrinsic cellular properties, but is critically shaped by its surrounding neurogenic niche. However, current studies largely describe niche-derived regulatory factors in isolation, and a systematic framework integrating these diverse signals remains lacking. In this review, we propose a structured perspective that links the unique anatomical and organizational characteristics of the SGZ to its regulatory mechanisms. We conceptualize SGZ niche regulation as a multi-dimensional and non-hierarchical system, in which multiple interacting components-including spatial organization, metabolic-vascular support, neural circuit activity, immune modulation, and extracellular matrix-mediated signaling-collectively govern NSC state transitions. Within this framework, neurogenesis is understood as an emergent outcome of coordinated changes across these regulatory dimensions rather than the result of single-factor control. We further discuss how shifts in the neurogenic niche under pathological conditions-such as aging, Alzheimer's disease, and chronic cerebral hypoperfusion (CCH) -reshape NSC behavior, driving maladaptive responses that may ultimately lead to dysregulated neurogenesis. By providing a modular and system-level perspective, this review offers a conceptual basis for understanding SGZ regulation and may help identify potential targets for restoring neurogenic capacity.

Keywords: Alzheimer’s disease; aging; microenvironment; neural stem cells; neurogenesis; neurogenic niche; subgranular zone

DOI: https://doi.org/10.3389/fncel.2026.1887577