Nollet M, Ba W, Soto BA, Yin C, Lignos L, Jovic K, Vyssotski AL, Yustos R, Franks NP, Wisden W (2025) The selective amyloid-driven failure of cholinergic medial septal neurons in aging mice perturbs REM sleep, cognition and emotion, and broadcasts amyloid to other brain regions. bioRxiv 2025.07.09.663930. doi: 10.1101/2025.07.09.663930
Objective: To look genetically at the intersection of amyloid pathology and the cholinergic system in Alzheimer’s disease (AD).
Summary: The broadcasting of amyloid by medial septal cholinergic cells is a notable feature, and potentially important in human pathology, selective genetic lesioning of about one third of the medial septal cholinergic cells, independent of amyloid, gave the same REM sleep, cognitive and emotional phenotypes. Thus, it is the killing of the cholinergic cells by amyloid, and therefore the missing acetylcholine, and not the secreted/deposited amyloid in the hippocampus and other areas, that is the critical feature. These findings underscore the interest in revitalizing the classic cholinergic hypothesis of AD. Restricting pathological amyloid expression to MS cholinergic neurons, so that their health is compromised by amyloid, is sufficient to reproduce many AD-like symptoms, highlighting the critical role of these cells in early AD pathogenesis, REM sleep regulation, emotion and cognition.
Usage: Cholinergic neurons throughout the forebrain in mice were lesioned with mu p75-SAP. The loss of cholinergic innervation exacerbated neurovascular impairments and cerebral amyloid angiopathy progression in the cortex and hippocampus
Nazmuddin M, Stammes MA, Klink PC, Vernes MK, Bakker J, Langermans JAM, van Laar T, Philippens IHCHM (2025) Stereotactic lesioning of cholinergic cells by injection of ME20.4 Saporin in the nucleus basalis of Meynert in a rhesus monkey (Macaca mulatta). J Neuropathol Exp Neurol nlaf081. doi: 10.1093/jnen/nlaf081 PMID: 40673943
Objective: To describe a procedure to inject ME20.4-SAP, an immunotoxin that specifically binds to and depletes cholinergic neurons stereotactically into the nucleus basalis of Meynert (NBM) of a rhesus monkey (Macaca mulatta).
Summary: A digital non-human primate brain atlas was co-registered to the brain of the monkey. A custom-designed cranial chamber was also implanted to the skull to guide the injection. The effects of the ME20.4-SAP injections were evaluated in vivo with PET-CT using [18F]-FEOBV as a radiotracer. This approach yielded reliable spatial accuracy and successful delivery of ME20.4-SAP into the NBM. This saporin-mediated selective destruction of cholinergic neurons in the NBM, using MRI-guidance and a cranial chamber, offers a promising method to study the pathophysiology of NBM degeneration and possible therapeutic interventions.
Usage: The first dose was chosen based on previous NBM lesioning works in common marmosets where infusing 1.4 μg ME20.4-SAP (Cat. #IT-15, in a concentration of 0.20 μg/μl) into each side of the NBM produced partial NBM depletion. At the second injection session, 5 μg ME20.4-SAP (in 0.5 μg/μl solution) was administered into each NBM side.
Noble EE, Harris RBS (2025) Leptin in the VMH contributes to the initial overconsumption of palatable diets by rats. Am J Physiol Endocrinol Metab 329(1):E1-E17. doi: 10.1152/ajpendo.00090.2025 PMID: 40418155
Objective: To determine whether leptin receptor–expressing neurons in the ventromedial hypothalamus (VMH) contribute to the initial overconsumption of a high-fat diet in rats.
Summary: Ablation of VMH leptin receptor–expressing neurons using Leptin-SAP prevented the early hyperphagic response to a high-fat diet in male rats but had no long-term impact on energy intake, body weight, or glucose clearance. These findings suggest VMH leptin signaling plays a key role in initiating, but not maintaining, diet-induced hyperphagia.
Usage: Leptin-SAP (IT-47) or Blank-SAP (IT-21) was stereotaxically injected into the VMH of male and female rats (20 ng in 80 nL) to ablate leptin receptor–expressing neurons. This targeted lesion confirmed the role of VMH leptin signaling in mediating early-phase overeating in response to a high-fat diet.
Bai J, Cheng K, Zhang N, Chen Y, Ni J, Wang Z (2025) Research advances in dysphagia animal models. Animal Model Exp Med doi: 10.1002/ame2.70054 PMID: 40566744
Objective: To summarize the establishment and evaluation of dysphagia animal models in stroke, Parkinson’s disease, and ALS, in three kinds of experimental animals, providing a basis for the selection of appropriate animal models of dysphagia.
Summary: There are very few studies of diseases such as stroke, PD, and ALS using other mammal and NHP dysphagia models. Moreover, there are substantial labor, cost, time, and ethics-related issues that limit the widespread use of these animal models in research. Nevertheless, large animal models serve as a crucial intermediary between rodent studies and clinical trials, significantly enhancing the translational potential of preclinical research findings.
Usage: Lori et al. used an ALS model created by intralingual injection of cholera toxin B conjugated to saporin (CTB-SAP) to induce apoptosis of sublingual motoneurons to study the effect of hypoglossal motor neuron death without many complications.
Szysiak N, Kosior-Korzecka U, longo V, Patkowski K, Greguła-Kania M, Nowakiewicz A, Bochniarz M,Junkuszew A (2025) Influence of neurokinin b, dynorphin a and kisspeptin-10 on in vitro gonadotropin secretion by anterior pituitary cells isolated from pubescent ewes. J Vet Res doi: 10.2478/jvetres-2025-0003
Objective: The aim of the study was to analyze the direct effect of the hypothalamic neuropeptides kisspeptin-10, neurokinin B, and dynorphin A on gonadotropin secretion by pituitary cells isolated from pubescent ewes.
Summary: Puberty is a multifactorial and complex process in animal development and in the case of livestock, timely attainment of sexual maturity contributes to increased reproductive efficiency, which leads to higher profitability. Studies revealed that kisspeptin, neurokinin B and dynorphin neuropeptides, collectively referred to as KNDy neuropeptides, are recognized as the key neuropeptides produced and secreted by the arcuate nucleus of the hypothalamus (ARC), and involved in the endocrine regulation of the onset of puberty. They all play roles in the endocrine regulation of the hypothalamic-pituitary-ovarian (HPO) axis in puberty. Kisspeptin-10, NKB and Dyn A had a direct impact on gonadotropin secretion by ovine pituitary cells. However, a detailed explanation of their role in gonadotropin secretion by the anterior pituitary gland in sheep and their impact on the regulation of the HPO axis during sexual maturation or in the pathomechanism of delayed puberty requires further studies.
Usage: Prepubertal ewes received 1 μL (0.7 μg) of NKB-SAP (NK3-SAP) [IT-63] or Blank-SAP (IT-21) injections aimed at the arcuate (ARC) nucleus to ablate neurons expressing NK3R.
Orciani C, Foret MK, Cuello AC, Carmo SD (2025) Long-term nucleus basalis cholinergic lesions alter the structure of cortical vasculature, astrocytic density and microglial activity in Wistar rats. Neurobiology of Aging 150:132-145. doi: 10.1016/j.neurobiolaging.2025.03.006 PMID: 40121723
Objective: To investigate the effects of the Basal forebrain cholinergic neurons (BFCNs) input on neurovascular unit (NVU) components.
Summary: To address this issue, the authors immunolesioned the nucleus basalis by administering injections of the cholinergic immunotoxin 192-IgG-SAP. Authors observed a significant reduction in cortical vesicular acetylcholine transporter-immunoreactive synapses. This was accompanied by changes in the diameter of cortical capillaries and precapillary arterioles, as well as lower levels of vascular endothelial growth factor A (VEGF-A). Additionally, the cholinergic immunolesion increased the density of cortical astrocytes and microglia in the cortex. The loss of nucleus basalis cholinergic input negatively impacts cortical blood vessels, NVU components, and microglia phenotype.
Usage: 192-IgG-SAP (2.6 mg/ml, IT-01) was injected at 0.5 μg/μl (1.0 μl/ hemisphere).
Lauer LT, Decarie-Spain L, Hayes AMR, Suarez AN, Bashaw A, Klug ME, Kao AE, Cheng R, Rea JJ, Subramanian KS, Nourbash A, Donohue KN, Schier LA, Myers K, Kanoski SE (2025) The vagus nerve promotes memory via septo-hippocampal acetylcholine: Implications for obesity-induced cognitive dysfunction. bioRxiv 2025.06.11.659206.
Objective: To demonstrate that nutrient consumption promotes hippocampal-dependent memory function via vagus nerve-mediated acetylcholine (ACh) release in the dorsal hippocampus (HPCd) from medial septum (MS) neurons.
Summary: Results identify a neurobiological mechanism whereby nutrient consumption promotes memory function, and reveals that disruption of this vagal-brain signaling system mediates Western Diet-associated memory impairments.
Usage: The antineuronal immunotoxin 192-IgG-SAP, which has been validated as an agent that selectively ablates neurons that produce acetylcholine was injected in the medial septum; 200nL (0.16mg/mL) were infused in three different coordinates that span the medial septum.
Ren X, Wang Y, Zhang Y (2025) Targeted depletion of dysfunctional hematopoietic stem cells mitigates myeloid-biased differentiation in aged mice. Cell Discov 11:56. doi: 10.1038/s41421-025-00810-3 PMID: 40490480
Objective: To develop and evaluate a targeted strategy for depleting dysfunctional, myeloid-biased CD150-high hematopoietic stem cells (HSCs) in aged mice to restore balanced hematopoiesis and mitigate aging-related blood disorders.
Summary: The study used an antibody-toxin conjugate to selectively eliminate CD150-high HSCs, improving lymphoid-to-myeloid ratios, reducing platelet hyperproduction, and restoring hematopoietic balance in aged mice. Treatment preserved functional CD150-low HSCs and showed minimal off-target or systemic toxicity.
Usage: Streptavidin-ZAP (IT-27) was combined with a biotinylated anti-CD150 antibody to generate Anti-CD150-SAP (IT-103). This conjugate was used at doses of 1–2 mg/kg in vivo and as low as 0.01 nM in vitro to specifically deplete CD150-high HSCs while sparing CD150-low populations.
Konturek-Ciesla A, Zhang Q, Kharazi S, Bryder D (2025) A non-genotoxic stem cell therapy boosts lymphopoiesis and averts age-related blood diseases in mice. Nat Commun 16(1):5129. doi: 10.1038/s41467-025-60464-3 PMID: 40456713
Objective: Application of Hematopoietic stem cell (HSC) transplantation leads to treatment toxicity. Therefore, authors employed a murine transplantation model based on low-intensity conditioning protocols using antibody-mediated HSC depletion to improve hematopoietic output and ameliorate age-compromised lymphopoiesis.
Summary: Authors demonstrate that young HSCs, once effectively engrafted in aged hosts, improve hematopoietic output and ameliorate age-compromised lymphopoiesis. This culminated in a strategy that robustly mitigates disease progression in a genetic model of myelodysplastic syndrome. These results suggest that non-genotoxic HSC transplantation could fundamentally change the clinical management of age-associated hematological disorders, offering a prophylactic tool to delay or even prevent their onset in elderly patients.
Usage: CD45-SAP (3 mg/kg) was administered to young (2 months) and aged (16 months) C57BL/6-CD45.2 mice
Anderson KL (2025) Neural mechanisms of context-sensitive behavior in the adult male zebra finch. City Univ NY Thesis.
Objective: To test whether oxytocin and dopamine mediate the influence of the social behavior network on the vocal control network in songbirds, enabling context-dependent changes to song.
Summary: The study reveals direct anatomical links between hypothalamic nodes of the social behavior network and the vocal control network. Blocking oxytocin receptors disrupts appropriate female-directed song and correlated network activity.
Usage: To assess brain access and persistence of intranasal compounds, Oxytocin-SAP (IT-46) was delivered intranasally at 1 μg/ml (12 μL total, 0.0012 mg per bird).
