Abstract Background- Natural killer (NK) cells are major cytotoxic lymphocytes subset with potent activity against hematopoietic malignancies and are strong candidates for immunotherapy. However, their clinical application is limited by our incomplete understanding of the transcriptional programs that control NK cell development and function. Human NK cells development from hematopoietic stem cells to mature NK cells is orchestrated by a network of lineage-committing transcription factors (TF). TAL1—a class II basic helix-loop-helix TF—is essential for early hematopoiesis and is maintained in several mature myeloid lineages, but it is absent from mature B- and T-cells. However, we recently discovered that mature human NK cells express TAL1, making them a rare lymphoid population retaining TAL1 expression. We also identified three TAL1 isoforms, suggesting isoform-specific roles in NK cell maturation and function. This suggests that TAL1 may shape NK cell identity and function. We hypothesize that TAL1 is a previously unrecognized regulator of human NK-cell development and cytotoxic activity. To test this, we used (a) an inducible TAL1 knockout mouse model to identify TAL1-dependent checkpoints in NK cell development and (b) TAL1 overexpression in NK-92 cells to characterize TAL1 binding partners. Method- For development and differentiation of NK cells, we generated an inducible TAL1fl/flMx1Cre knockout (KO) mouse model, in which poly(I:C) was used to activate Cre. Bone marrow and spleen tissues were then analyzed by flow cytometry. We used CRISPR/Cas9 to generate HEB, ID2, and E2A KO NK-92 cells and created a TAL1-overexpressing NK-92 line. Protein expression and interactions were assessed by Western blot and co-immunoprecipitation. Results- TAL1 KO in mouse showed a significantly increased percentage of NK progenitor cells (CD3ε-CD122+NK1.1-NCR1-; 91.3% in KO vs 33.0% in WT) and a reduction of immature and mature NK cells (CD3ε-CD122+NK1.1+ and CD3ε-CD122+NCR1+) in the bone marrow compared to control. Co-immunoprecipitation of TAL1 in NK92 cells revealed protein interactions with methylase SETD1A, and E-proteins HEB, and ID2. Conclusion- TAL1 KO mice show NK cell maturation arrested at the CD122+NK1.1+ progenitor stage, suggesting a central role for TAL1 in NK cell development. Co-immunoprecipitation in NK-92 cells revealed TAL1 interactions with SETD1A, HEB, and ID2. We propose that TAL1 forms a heterodimer with HEB that recruits the demethylase LSD1 to repress genes required for NK cell maturation. When ID2 joins the complex, it blocks LSD1 recruitment and instead brings in the methylase SETD1A to activate maturation-associated genes. Together, these findings raise the possibility that TAL1 recruits specific partners that influence NK cell maturation. Understanding the role of TAL1 in human NK cell development may enable the therapeutic modulation of NK cell function for clinical applications. Citation Format: Baomou Feng, Dandan Wang, Subramaniam Malarkannan, . Transcriptional regulation of human NK cells: TAL1 as a modulator [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1606.

BACKGROUND & AIMS: The complex tumor microenvironment (TME) of pancreatic ductal adenocarcinoma (PDAC) has hindered the development of reliable predictive biomarkers for targeted therapy and immunomodulatory strategies. A comprehensive characterization of the TME is necessary to advance precision therapeutics in PDAC. METHODS: A transcriptomic profiling platform for TME classification based on functional gene signatures was applied to 14 publicly available PDAC datasets (n = 1657) and validated in a clinically annotated independent cohort of patients with PDAC (n = 79). Four distinct subtypes were identified using unsupervised clustering and assessed to evaluate predictive and prognostic utility. RESULTS: TME fibrotic (IE/F); fibrotic (F); and immune depleted (D). The IE

Natural killer (NK) cells, a subset of innate lymphocytes, produce proinflammatory cytokines and mediate anti-tumor cytotoxicity. GATA2 is a master transcription factor that is essential for the development of erythroid, myeloid, B, and NK cells. Patients with GATA2 haploinsufficiency lack CD56 brightNK cells (immature), with or without a reduction in the number of CD56 dimNK cells (mature). However, how GATA2 functions to establish and maintain genetic networks during the development and function of human NK cells is unknown. Here, we identify a novel GATA2-TGF-b1 axis that regulates NK cell development. We performed single-cell RNA-seq with NK cells from three GATA2 T354Mpatients and found significantly reduced expression of immediate early genes, which indicated that they are functionally-defective. We discovered a reduction in TGF-b1 transcripts and defective expression of TGF-b1 target genes in NK cells from GATA2 T354Mpatients. Using a reporter assay, we determined that GATA2 occupy to TGFB1 promoter, and this association was decreased in GATA2 T354MNK cells. ATAC-seq of GATA2 T354MNK cells indicates significantly altered chromatin accessibility. GATA2 CUT&Tag-seq validated that it occupies the TGFB1 promoter region, which correlated with activation of the TGFB1 locus in human NK cells. In summary, we define a mechanism by which GATA2 controls TGF-b1 production in human NK cells and thereby regulating their development. These findings provide vital clues for developmental and functional defects of NK cells in GATA2 T354Mpatients. ASH Graduate Hematology Award (D.W.); GIRT Award from MCW-C4I (D.W.); NIH R01 AI102893 and NCI R01 CA179363 (S.M.); HRHM Program of MACC Fund (S.M.), Nicholas Family Foundation (S.M.); Gardetto Family (S.M.); MCW-Cancer Center-Large Seed Grant (S.M. and M.S.T.); MACC Fund (S.M.); Ann’s Hope Mela- noma Foundation (S.M.); and Advancing Healthier Wisconsin (S.M.)

Introduction: Natural killer (NK) cells, as the major subset of innate lymphocytes, produce proinflammatory cytokines and mediate anti-tumor cytotoxicity (1-3). Since NK cells are not limited by clonotypic receptors, they can be utilized in cell therapies against a broad spectrum of malignancies. Irrespective of the clinical potentials, the transcriptional regulation of the development and functions of human NK cells is far from fully understood. A dysregulated NK cell development is a hallmark of GATA2 haploinsufficiency (4)(eg. GATA2 T354M mutation). The specific loss of the CD56 bright NK cell population is a significant striking feature in GATA2-deficient patients (4), with or without reduced total CD56 dim NK cells (4, 12, 13). Consequently, the effector functions of these NK cells are significantly reduced, including inflammatory cytokine production and anti-tumor cytotoxicity (4, 12). However, a mechanistic understanding of GATA2 functions is lacking. In humans, GATA2 forms a core heptad complex with six other transcription factors (TF), including TAL1, regulating more than 1000 target genes. However, the unique functions of the GATA2-TAL1 axis in immature and mature NK cell has not been established. Based on these, we hypothesize that GATA2-dependent and independent functions of TAL1 play an essential role in the development and functions of human NK cells. Results: To explore the mechanism of co-transcriptional regulation of GATA2 and TAL1, we transduced NK-92 cells with lentiviral vectors containing GATA2 WT or GATA2 T354M plasmid and quantified TAL1 mRNA levels by qPCR and protein levels by WB. TAL1 is upregulated in GATA2 T354M-expressing NK-92 cells both at mRNA ( Fig. 1A) and protein levels ( Fig. 1B). TAL1 is a TF activating GTPase of immunity-associated protein (GIMAP) family super-enhancer regions in HSC and T cells (11). As TAL1 target genes, we further quantify GIMAP mRNA levels by qPCR. The result indicates that genes from the GIMAP family were notably upregulated in GATA2 T354M-expressing NK-92 cells ( Fig. 1C). Knocking down TAL1 results in the significant downregulation of TAL1 and GIMAPs in GATA2 T354M-expressingcells ( Fig. 1D). To further validate the GATA2-TAL1 axis, sorted NK cells from PBMCs of three GATA2 T354M patients and five age-matched healthy controls (HC) were analyzed with single-cell RNA-seq. We identified the genes from GIMAP family were significantly upregulated in all three GATA2 T354M patients. The representative data from one patient is shown in Fig. 1E. To explore how GATA2 and TAL1 mediate transcriptional regulation, we performed GATA2 CUT&Tag experiments with human NK cells, in which TAL1 motif was predominately enriched in 63.2% of GATA2 targets among NK cells through HOMER motif enrichment analyses ( Fig. 1F). On the other hand, the TAL1 ChIP-seq data from the K562 cells (download from ENCFF101DBG) reveals that the GATA2 motif is enriched in approximately 44% of TAL1 targets ( Fig. 1G). Moreover, both GATA2 and TAL1 expression in NK cells are modified by H3K27Me3 instead of H3K4Me3, suggesting a repressive methylenation signature in their expression ( Fig. 1H). Conclusion: Based on this study, we uncover a novel role for the GATA2-TAL1 axis in human NK cells. we define the transcriptional regulation role of GATA2 and TAL1 complex and provide direct evidence for the mechanism of NK cell deficiency among GATA2 T354M patients. Importantly, through our current study, we will determine the unique role of TAL1 in NK development and function and its transcriptional network.

A recent study highlights the presence of a unique memory-like natural killer (NK) cell subset, which accumulates with aging and appears to associate withdisease severity in COVID-19 patients. While the clinical relevance of memory in NK cells is being debated, the molecular identity of this subset in the form of a single-cell transcriptome is essential to define their origin, longevity, functions, and disease relevance.

Immunological memory is a fundamental feature of the adaptive immune system that protects the host from recurrent infections from pathogens. Natural killer (NK) cells are a predominant member of the innate immune system that lack clonotypic receptors, which are essential for memory formation. However, evidence demonstrates that a unique subpopulation of NK cells develops adaptive-like features using germline-encoded receptors. Recent studies have shown that infection of cytomegalovirus (CMV) leads to clonal expansion of NKG2C+ and Ly49H+ NK cells, in humans and mouse, respectively. These activation receptors have the capability to recognize CMV-encoded proteins and facilitate a recall response upon reinfection. Although NK cells do not rearrange genes encoding their activating receptors as seen in B and T cells, they possess a selective process to generate memory features and a long-lived progeny. Here, we describe an established in vivo protocol for infecting mice with mouse cytomegalovirus (MCMV) to study an adaptive NK cell response.

The signaling adapter MyD88 is critical for immune cell activation in response to viral or bacterial pathogens via several TLRs, IL-1 beta R and IL-18R. However, the essential role of MyD88 during activations mediated by germlineencoded NK cell receptors (NKRs), such as Ly49H or NKG2D, has yet to be investigated. To define the NK cellintrinsic function of MyD88, we generated a novel NK cell conditional knockout mouse for MyD88 (Myd88fl/ flNcr1Cre/+). Phenotypic characterization of these mice demonstrated that MyD88 is dispensable for NK cell development and maturation. However, the MyD88-deficient NK cells exhibited significantly reduced cytotoxic potentials in vivo. In addition, the lack of MyD88 significantly reduced the NKG2D-mediated inflammatory cytokine production in vitro. Consistent with this, mice lacking MyD88 were unable to respond and clear MCMV infection. Transcriptomic analyses of splenic NK cells following MCMV infection revealed that inflammatory gene signatures were upregulated in Ly49H+. In contrast, Ly49H- NK cells have significant enrichment in G2M checkpoint genes, revealing distinct transcriptomic profiles of these subsets. Our results identify a central role for MyD88 in Ly49H-dependent gene signatures, including alterations in genes regulating proliferation in Ly49H+ NK cells. In summary, our study reveals a previously unknown function of MyD88 in Ly49H-dependent signaling and in vivo functions of NK cells.

Innate and adaptive immune systems are evolutionarily divergent. Primary signaling in T and B cells depends on somatically rearranged clonotypic receptors. In contrast, NK cells use germline-encoded non-clonotypic receptors such as NCRs, NKG2D, and Ly49H. Proliferation and effector functions of T and B cells are dictated by unique peptide epitopes presented on MHC or soluble humoral antigens. However, in NK cells, the primary signals are mediated by self or viral proteins. Secondary signaling mediated by various cytokines is involved in metabolic reprogramming, proliferation, terminal maturation, or memory formation in both innate and adaptive lymphocytes. The family of common gamma (γc) cytokine receptors, including IL-2Rα/β/γ, IL-7Rα/γ, IL-15Rα/β/γ, and IL-21Rα/γ are the prime examples of these secondary signals. A distinct set of cytokine receptors mediate a ‘third’ set of signaling. These include IL-12Rβ1/β2, IL-18Rα/β, IL-23R, IL-27R (WSX-1/gp130), IL-35R (IL-12Rβ2/gp130), and IL-39R (IL-23Rα/gp130) that can prime, activate, and mediate effector functions in lymphocytes. The existence of the ‘third’ signal is known in both innate and adaptive lymphocytes. However, the necessity, context, and functional relevance of this ‘third signal’ in NK cells are elusive. Here, we define the current paradigm of the ‘third’ signal in NK cells and enumerate its clinical implications.

Fanconi anemia (FA) is an inherited disorder characterized by diverse congenital malformations, progressive pancytopenia, and predisposition to hematological malignancies and solid tumors. The role of the Fanconi anemia pathway in DNA repair mechanisms and genome instability is well studied. However, the consequences of inherited mutations in genes encoding the FA proteins and the acquired mutations due to impaired DNA repair complex in immune cells are far from understood. Patients with FA show bone marrow failure (BMF) and have a higher risk of developing myelodysplasia (MDS) or acute myeloid leukemia (AML) which are directly related to having chromosomal instability in hematopoietic stem cells and their subsequent progeny. However, immune dysregulation can also be seen in FA. As mature descendants of the common lymphoid progenitor line, NK cells taken from FA patients are dysfunctional in both NK cell-mediated cytotoxicity and cytokine production. The molecular bases for these defects are yet to be determined. However, recent studies have provided directions to define the cause and effect of inherited and acquired mutations in FA patients. Here, we summarize the recent studies in the hematopoietic dysfunction, focusing on the impairment in the development and functions of NK cells in FA patients, and discuss the possible mechanisms and future directions.

Natural killer (NK) cells are major innate lymphocytes. NK cells do not require prior antigen exposure to mediate antitumor cytotoxicity or proinflammatory cytokine production. Since they use only nonclonotypic receptors, they possess high clinical value in treatment against a broad spectrum of malignancies. Irrespective of this potential, however, the transcriptional regulation that governs human NK cell development remains far from fully defined. Various environmental cues initiate a complex network of transcription factors (TFs) during their early development, one of which is GATA2, a master regulator that drives the commitment of common lymphoid progenitors (CLPs) into immature NK progenitors (NKPs). GATA2 forms a core heptad complex with six other TFs (TAL1, FLI1, RUNX1, LYL1, LMO2, and ERG) to mediate its transcriptional regulation in various cell types. Patients with GATA2 haploinsufficiency specifically lose CD56bright NK cells, with or without a reduced number of CD56dlm NK cells. Here, we review the recent progress in understanding GATA2 and its role in human NK cell development and functions.

Interleukin-12 (IL-12) is an inflammatory cytokine that has demonstrated efficacy for cancer immunotherapy, but systemic administration has detrimental toxicities. Lentiviral transduction eliciting IL-12-producing human sarcoma for autologous reintroduction provides localized delivery for both innate and adaptive immune response augmentation. Sarcoma cell lines and primary human sarcoma samples were transduced with recombinant lentivirus engineering expression of human IL-12 (hu-IL-12). IL-12 expressing sarcomas were assessed in vitro and in vivo following implantation into humanized NSG and transgenic human IL-15 expressing (NSG.Tg(Hu-IL-15)) murine models. Lentiviral transduction (LV/hu-IL-12) of human osteosarcoma, Ewing sarcoma and rhabdomyosarcoma cell lines, as well as low-passage primary human sarcomas, engendered high-level expression of hu-IL-12. Hu-IL-12 demonstrated functional viability, eliciting specific NK cell-mediated interferon-γ (IFN-γ) release and cytotoxic growth restriction of spheroids in vitro. In orthotopic xenograft murine models, the LV/hu-IL-12 transduced human sarcoma produced detectable IL-12 and elicited an IFN-γ inflammatory immune response specific to mature human NK reconstitution in the NSG.Tg(Hu-IL-15) model while restricting tumor growth. We conclude that LV/hu-IL-12 transduction of sarcoma elicits a specific immune reaction and the humanized NSG.Tg(Hu-IL-15) xenograft, with mature human NK cells, can define in vivo anti-tumor effects and systemic toxicities. IL-12 immunomodulation through autologous tumor transduction and reintroduction merits exploration for sarcoma treatment.

Natural killer (NK) cells are the major lymphocyte subset of the innate immune system. Their ability to mediate anti-tumor cytotoxicity and produce cytokines is well-established. However, the molecular mechanisms associated with the development of human or murine NK cells are not fully understood. Knowledge is being gained about the environmental cues, the receptors that sense the cues, signaling pathways, and the transcriptional programs responsible for the development of NK cells. Specifically, a complex network of transcription factors (TFs) following microenvironmental stimuli coordinate the development and maturation of NK cells. Multiple TFs are involved in the development of NK cells in a stage-specific manner. In this review, we summarize the recent advances in the understandings of TFs involved in the regulation of NK cell development, maturation, and effector function, in the aspects of their mechanisms, potential targets, and functions.

BACKGROUND Aberrant microRNA (miRNA) expression affects biologic processes and downstream genes that are crucial to CKD initiation or progression. The miRNA miR-204-5p is highly expressed in the kidney but whether miR-204-5p plays any role in the development of chronic renal injury is unknown. METHODS We used real-time PCR to determine levels of miR-204 in human kidney biopsies and animal models. We generated Mir204 knockout mice and used locked nucleic acid-modified anti-miR to knock down miR-204-5p in mice and rats. We used a number of physiologic, histologic, and molecular techniques to analyze the potential role of miR-204-5p in three models of renal injury. RESULTS Kidneys of patients with hypertension, hypertensive nephrosclerosis, or diabetic nephropathy exhibited a significant decrease in miR-204-5p compared with controls. Dahl salt-sensitive rats displayed lower levels of renal miR-204-5p compared with partially protected congenic SS.13BN26 rats. Administering anti-miR-204-5p to SS.13BN26 rats exacerbated interlobular artery thickening and renal interstitial fibrosis. In a mouse model of hypertensive renal injury induced by uninephrectomy, angiotensin II, and a high-salt diet, Mir204 gene knockout significantly exacerbated albuminuria, renal interstitial fibrosis, and interlobular artery thickening, despite attenuation of hypertension. In diabetic db/db mice, administering anti-miR-204-5p exacerbated albuminuria and cortical fibrosis without influencing blood glucose levels. In all three models, inhibiting miR-204-5p or deleting Mir204 led to upregulation of protein tyrosine phosphatase SHP2, a target gene of miR-204-5p, and increased phosphorylation of signal transducer and activator of transcription 3, or STAT3, which is an injury-promoting effector of SHP2. CONCLUSIONS These findings indicate that the highly expressed miR-204-5p plays a prominent role in safeguarding the kidneys against common causes of chronic renal injury.

The mammalian visual cortex is immature at birth and undergoes postnatal structural and functional adjustments. The exact timing of the vulnerable period in rodents remains unclear. The critical period is characterized by inhibitory GABAergic maturation reportedly dependent on brain-derived neurotrophic factor (BDNF). However, most of the studies were performed on experimental/transgenic animals, questioning the relationship in normal animals. The present study aimed to conduct in-depth analyses of the synaptic and neurochemical development of visual cortical neurons in normal and monocularly-deprived rats and to determine specific changes, if any, during the critical period. We found that (i) against a gradual increase in excitation and inhibition with age, a transient period of synaptic and neurochemical imbalance existed with suppressed excitation and enhanced inhibition at postnatal days 28 to 33/34; (ii) during this window, the expression of BDNF and tropomyosin-related kinase B (TrkB) receptors decreased, along with glutamatergic GluN1 and GluA1 receptors and the metabolic marker cytochrome oxidase, whereas that of GABA(A)R alpha 1 receptors continued to rise; (iii) monocular deprivation reduced both excitatory and inhibitory synaptic activity and neurochemicals mainly during this period; and (iv) in vivo TrkB agonist partially reversed the synaptic imbalance in normal and monocularly-deprived neurons during this time, whereas a TrkB antagonist accentuated the imbalance. Thus, our findings highlight a transitory period of synaptic imbalance with a negative relationship between BDNF and inhibitory GABA. This brief critical period may be necessary in transitioning from an immature to a more mature state of visual cortical functioning.

Although appropriate exercise is beneficial for enhancing brain functions, high‐intensity exercise (HIE)‐induced cognitive dysfunction is causing more and more concerns nowadays. In the present study, we observed the effects of high‐intensity treadmill running on the spatial learning of the adult Sprague Dawley male rats in Y‐maze (n = 16 per group), and investigated its possible electrophysiological and molecular mechanisms by examining in vivo hippocampal long‐term potentiation (LTP), central inflammatory responses, and JNK/p38/ERK signal pathway. The Y‐maze active avoidance test showed that high‐intensity treadmill running impaired spatial learning ability of rats, with increased error times and prolonged training time in recognizing safety condition. Associated with the cognitive dysfunction, the induction and maintenance of hippocampal LTP were also impaired by the HIE. Furthermore, accompanied by elevated levels of inflammatory factors IL‐1β, TNF‐α, and iNOS, overactivation of microglia and astrocytes was also found in the CA1 region of hippocampus in the excessive exercise group, indicating an inflammatory response induced by HIE. In addition, Western blot assay showed that the phosphorylation of JNK/p38/ERK proteins was enhanced in the exercise group. These results suggest that exercise stress–induced neuronal inflammatory responses in the hippocampus are associated with HIE‐induced cognitive deficits, which may be involved in the upregulation of the JNK/p38/ERK pathway. © 2016 Wiley Periodicals, Inc.

The accumulation and neurotoxicity of amyloid β protein (Aβ) in the brain is one of major pathological hallmarks of Alzheimer's disease (AD). The effective drugs against Aβ have been still deficient up to now. According to a most recent study, (D-Ser2) Oxm, a new antidiabetic drug, not only improves the disorders in plasma glucose and insulin in type 2 diabetes mellitus (T2DM) rats, but also exerts positive effects on hippocampal neurogenesis and synaptogenesis. However, it is still unclear whether (D-Ser2)Oxm can directly protect cultured neurons against Aβ1-42-induced cytotoxicity. In the present study, we investigated the neuroprotective effects of (D-Ser2)Oxm on the cultured primary hippocampal neurons by testing the cell viability, neuronal apoptosis, mitochondrial membrane potential and intracellular calcium concentration. The results showed that treatment with (D-Ser2)Oxm effectively reversed Aβ1-42-induced decline in cell viability (P < 0.001), and this protective effect could be inhibited by the pretreatment with exendin(9-39), a GLP-1 receptor blocker. (D-Ser2)Oxm treatment also decreased Aβ1-42-induced neuronal early apoptosis and down-regulated apoptotic protein caspase3. Meantime, (D-Ser2)Oxm treatment inhibited Aβ1-42-induced [Ca(2+)]i elevation, mitochondrial membrane potential depolarization, and glycogen synthase kinase-3β (GSK3β) activation. These results suggest that (D-Ser2)Oxm can protect hippocampal neurons against Aβ1-42-induced cytotoxicity and this effect may be related to activation of GLP-1 receptors, regulation of intracellular calcium homeostasis and stabilization of mitochondrial membrane potential.

Aggregation of amyloid [Formula: see text] protein (A[Formula: see text] and progressive loss of memory are the main characteristics of Alzheimer's disease (AD). It is noteworthy that approximately 40% of AD patients have depressive symptom. The close correlation between cognitive deficits and mental depression suggests a possibility that antidepression treatment might be beneficial to cognitive improvement in AD. The present study, by using tail-suspension test (TST), forced swimming, alternative electro-stimulus Y maze test and immunohistochemistry, examined the neuroprotective effects of desipramine, a newer generation tricyclic antidepressants (TCA), and investigated its possible molecular mechanism. The results showed that: (1) intra-hippocampal injection of A[Formula: see text] induced depression-like behavior and associative learning deficits in mice, with an increased mean immobility time in tail-suspension and forced swimming test and an increased mean error times in Y maze test; (2) after treatment with desipramine (10[Formula: see text]mg/kg, i.p.), the average immobility time significantly decreased, from [Formula: see text][Formula: see text]s in A[Formula: see text] group to [Formula: see text][Formula: see text]s in A[Formula: see text] plus desipramine group ([Formula: see text]) in TST and from [Formula: see text][Formula: see text]s to [Formula: see text][Formula: see text]s ([Formula: see text] or 9, [Formula: see text]) in forced swimming test, respectively;the mean error times of mice in Y maze test also significantly decreased, from [Formula: see text] in A[Formula: see text] group to [Formula: see text] in A[Formula: see text] plus desipramine group ([Formula: see text], [Formula: see text]); (3) desipramine administration significantly prevented against A[Formula: see text]-induced down-regulation of phosphorylated cAMP response element binding protein (p-CREB) in the hippocampus. These results indicate that A[Formula: see text] could concurrently mimic the depression-like behavior and working memory disorder in mice, while desipramine could effectively reverse both the deficits induced by A[Formula: see text]. The neuroprotection of desipramine may be involved in the up-regulation of p-CREB level in the hippocampus of mice.