alzheimers-disease

Björklund A, Barker RA (2024) The basal forebrain cholinergic system as target for cell replacement therapy in Parkinson’s disease. Brain awae026. doi: 10.1093/brain/awae026 PMID: 38279949

Objective: Review the use of cholinergic cell replacement as a potential therapeutic strategy in Parkinson’s Disease (PD) and how rodent models of PD-like cognitive decline can be used by analyzing rodent and primate studies.

Summary: Although therapies targeting the cholinergic system have so far been focused mainly on patients with Alzheimer´s disease, PD with dementia may be a more relevant condition. In PD with dementia the Basal Forebrain system undergoes progressive degeneration, and the magnitude of cholinergic cell loss has been shown to correlate with the level of cognitive impairment. Thus, cell therapy aimed to replace the lost basal forebrain cholinergic neurons represents an interesting strategy to combat some of the major cognitive impairments in patients with PD dementia.

Usage: Rats were given 192-IgG-SAP (IT-01), 0.2-0.4 μg, delivered as a single 0.3-1.0 μl injection into either the substantia innominate/nucleus basalis of Meynert (SI/NBM) or the medial septum/ventral diagonal band (MS/VDB).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Wu D, Yu N, Gao Y, Xiong R, Liu L, Lei H, Jin S, Liu J, Liu Y, Xie J, Liu E, Zhou Q, Liu Y, Li S, Wei L, Lv J, Yu H, Zeng W, Zhou Q, Xu F, Luo MH, Zhang Y, Yang Y, Wang JZ (2023) Targeting a vulnerable septum-hippocampus cholinergic circuit in a critical time window ameliorates tau-impaired memory consolidation. Mol Neurodegener 18(1):23. doi: 10.1186/s13024-023-00614-7 PMID: 37060096

Objective: There is an urgent need to study the targeting strategy for the MS-hippocampus cholinergic pathway to rescue tau-impaired memory.

Summary: Abnormal tau accumulation and cholinergic degeneration are hallmark pathologies in the brains of patients with Alzheimer’s disease (AD). However, the sensitivity of cholinergic neurons to AD-like tau accumulation and strategies to ameliorate tau-disrupted spatial memory in terms of neural circuits still remain elusive. The authors found that cholinergic neurons with an asymmetric discharge characteristic in the MS-hippocampal CA1 pathway are vulnerable to tau accumulation. Photoactivating MS-CA1 cholinergic inputs within a critical 3 h time window during memory consolidation efficiently improved tau-induced spatial memory deficits in a theta rhythm dependent manner. 192-IgG-Saporin was used to create an Alzheimer’s Disease animal model.

Related Products: 192-IgG-SAP (Cat. #IT-01)

See Also:

• Dornan WA et al. Comparison of site-specific injections into the basal forebrain on water maze and radial arm maze performance in the male rat after immunolesioning with 192 IgG saporin. Behav Brain Res 82:93-101, 1996.

Singh SA, Vellapandian C (2023) The promising guide to LC–MS analysis and cholinesterase activity of Luffa cylindrica (L.) fruit using in vitro and in-silico analyses. Futur J Pharm Sci 9:33. doi: 10.1186/s43094-023-00478-0

Objective: Identify and analyze the extract of the plant Luffa cylindrica for bioactive and biochemical properties, particularly as it relates to bioactivity in neurological diseases.

Summary: Luffa cylindrica contains a total of 80 compounds that were identified in the ethanolic extract from LC–MS analysis. The bioactive compounds were screened for activity in receptors responsible for causing oxidative stress-associated Alzheimer’s disease. Perlolyrine was chosen to perform in-silico docking. An in vitro activity of cholinesterase showed highest inhibition at 500 μg/ml. In-silico docking of perlolyrine showed better binding affinity and score. Results revealed that out of 10 docked receptors, amyloid beta showed the highest binding affinity with an energy of −46.1 kcal/mol showing promising drug for Alzheimer’s disease. The study reports the presence of a promising, bioactive compound (perlolyrine) with promisng applications in vivo, oxidative stress-related Alzheimer’s disease.

Related Products: Saporin (Cat. #PR-01)

See Also:

• Santosh et al (2015) Mechanism of Anti-HIV Activity of Ribosome Inactivating Protein, Saporin. Protein & Peptide Letters. 22(6): 497-503. doi: 10.2174/0929866522666150428120701

Leanza G, Zorec R (2023) Towards astroglia-based noradrenergic hypothesis of Alzheimer’s disease. Function (Oxf) 4(1):zqac060., IT. doi: 10.1093/function/zqac060 PMID: 36590326

Summary: These results indicate a prominent role of NA-neurons vs. ACh neurons in impairments of working memory, relevant for AD, and are consistent with an astrocyte-specific metabolic impairment in a mouse model of intellectual disability.

Usage: Bilateral icv injection of 192-IgG-SAP and/or Anti-DBH-SAP

Related Products: 192-IgG-SAP (Cat. #IT-01), Anti-DBH-SAP (Cat. #IT-03)

Zhou XA, Ngiam G, Qian L, Sankorrakul K, Coulson EJ, Chuang KH (2022) The basal forebrain volume reduction detected by MRI does not necessarily link with the cholinergic neuronal loss in the Alzheimer’s disease mouse model. Neurobiol Aging 117:24-32. doi: 10.1016/j.neurobiolaging.2022.03.017 PMID: 35640461

Objective: Assess basal forebrain (BF) cholinergic neuron number by histological counts and compare with the volume measurements from an in vivo MRI Alzheimer’s disease (AD) mouse model.

Summary: Degeneration of cholinergic neurons in the BF contributes to cognitive impairment in AD. A decrease of BF volume measured by structural MRI is thought to represent loss of cholinergic neurons. As there are various types of neurons in the BF, whether this MRI measurement actually reflects the change of cholinergic neurons has not been verified. To test whether specific loss of cholinergic neurons results in BF reduction, the authors ablated cholinergic neurons in the Medial septum.

Usage: Lesions were made via injections of mu-p75-SAP (0.5 mg/ml) or control Rabbit-IgG-SAP (0.5 mg/mL) into ten-week-old female C57Bl/6J mice. However, there was no detectable change in MRI volume between lesioned and unlesioned mice. The results indicate that although loss of cholinergic neurons within the BF likely contribute to volume loss, this change in volume cannot be taken as a direct biomarker of cholinergic neuron number.

Related Products: mu p75-SAP (Cat. #IT-16), Rabbit IgG-SAP (Cat. #IT-35)

Llorente-Ovejero A, Bengoetxea de Tena I, Martínez-Gardeazabal J, Moreno-Rodríguez M, Lombardero L, Manuel I, Rodríguez-Puertas R (2022) Cannabinoid receptors and glial response following a basal forebrain cholinergic lesion. ACS Pharmacol Transl Sci 5(9):791-802. doi: 10.1021/acsptsci.2c00069 PMID: 36110372

Objective: The endocannabinoid system is involved in the control of learning, memory, and neuroinflammatory processes and plays a role in neurodegeneration, such as in Alzheimer’s disease (AD). The objective was to study the roles of cannabinoid receptors in the regulation of neuroinflammation.

Summary: Selective agonists and antagonists to the cannabinoid receptors CB1 and CB2 were studied for their binding to G-proteins after specific lesioning of the basal forebrain cholinergic neurons (BCFN) using 192-IgG-SAP. These neurons are the same cholinergic pathways that are lost in the early stages of Alzheimer’s disease (AD). In their study, an increase of microglia immunoreactivities (GFAP and Iba-1) and decrease of astrocyte immunoreactivities were seen which indicate microglia-mediated neuroinflammation. In cortical BFCN projection areas, CB1 receptor binding to Gi/o-proteins was upregulated and at the injection site, the area that showed the highest increase of microglia, only slight CB2 binding to Gi/o-proteins were detected. Dose: Rats received 135 ng/μLof 192IgG-saporin (1μL/hemisphere; 0.25μL/min).

Related Products: 192-IgG-SAP (Cat. #IT-01)

Liu W, Li J, Yang M, Ke X, Dai Y, Lin H, Wang S, Chen L, Tao J (2022) Chemical genetic activation of the cholinergic basal forebrain hippocampal circuit rescues memory loss in Alzheimer’s disease. Alzheimers Res Ther 14(1):53. doi: 10.1186/s13195-022-00994-w

Related Products: 192-IgG-SAP (Cat. #IT-01)

See Also:

• Tomaszewicz M et al. Changes in cortical acetyl-CoA metabolism after selective basal forebrain cholinergic degeneration by 192IgG-saporin. J Neurochem 87(2):318-324, 2003.

Osterlund Oltmanns JR, Schaeffer EA, Blackwell AA, Pietrucha SA, Yang H, Tasi S, Kartje GL, Wallace D (2021) Effects of age on sexually dimorphic food protection behavior associated with hippocampal cholinergic deafferentation. Neuroscience 2021 Abstracts P210.07. Society for Neuroscience, Virtual.

Summary: Loss of hippocampal cholinergic projection originating from basal forebrain structures has been associated with the progression of Dementia of the Alzheimer’s Type. The role of these fibers in information processing deficits has been debated; however, spontaneous behaviors such as food protection have been observed to dissociate the contributions of hippocampal and cortical cholinergic function. Sexual dimorphism and age are critical factors in the progression of neurodegenerative disorders, yet these factors have not been evaluated in food protection behavior. The current study infused the immunotoxin 192-IgG-Saporin bilaterally into the medial septum to produce selective cholinergic deafferentation of the hippocampal formation. Female and male rats received infusion of the immunotoxin at either three or 18 months of age. Testing in the in the food protection paradigm began six weeks after the surgery. During the five days of testing, rats received two food protection sessions. Each of these sessions involved the rat (dodger) being placed in a transparent cylinder with a same sex conspecific (robber). The dodger was given a one-gram food item to consume, while the robber made multiple attempts to obtain the food item. The number, success rate, and type of food protection behaviors were recorded across all food protection sessions. Rats also received a third session each day in which the latency to consume the food item was recorded in the absence of the conspecific. Preliminary results indicate that sex and age interact with cholinergic hippocampal deafferentation to influence the organization of food protection behaviors. These observations establish a foundation for future work investigating novel therapeutic interventions that target neuroplasticity within spared cholinergic systems.

Related Products: 192-IgG-SAP (Cat. #IT-01)

Shramm PA, Ancheta LR, Bouajram R, Lappi DA (2021) A brief history of saporin and its contributions to neuroscience. Neuroscience 2021 Abstracts J002.11. Society for Neuroscience, Virtual.

Summary: When investigating the origins of targeted toxins (a drug, therapy, or scientific tool directed to a unique extracellular target), an appropriate place to begin is with the Nobel Prize-winning work of Paul Ehrlich and his concept of the “magic bullet.” Over 100 years later, the use of targeted toxins to perform molecular neurosurgery has become a vital practice that allows researchers to observe changes in organisms after eliminating a neuronal population. A prime example of this practice is the specific targeting of cholinergic neurons in the basal forebrain to mimic Alzheimer’s disease (AD). The research tool designed for this purpose is 192-IgG-Saporin, an antibody conjugated to the ribosome-inactivating protein (RIP) Saporin. Researchers have used this targeted toxin for over 30 years. A 2019 publication by Verkhratsky et al. reviews AD models and states this is the only lesion model that specifically targets cholinergic neurons. In 1983, during a quest to find the optimal payload for a targeted toxin, Fiorenzo Stirpe and colleagues discovered Saporin, a plant protein isolated from the common soapwort plant Saponaria officinalis. Unlike ricin and abrin, Saporin does not have a binding chain and cannot enter a cell on its own. Scientists have devised new ways to use Saporin to advance their research and drug development activities. Just a few examples include: 1. A novel suicide gene therapy approach that uses a vector encoding a double-stranded DNA aptamer to deliver the gene encoding Saporin, 2. Delivery of Saporin encapsulated in a nanotechnology system for development of cancer treatments, 3. A deeper understanding of the difference between pain and itch and the relevant pathways, and 4. Development of a stable epilepsy animal model that is used for screening specific treatments that will lead to micro-methods to eliminate the disease. This review will focus on Saporin as the payload delivered to cells. Targeted toxins (typically targeted by an antibody or peptide chemically linked or genetically fused) provide robust tools for neuroscience where ablation of specific neuronal populations is used to study behavior and function. Saporin is an ideal molecule because of its extreme resistance to high temperatures and denaturation, retention of catalytic activity after conjugation, and lack of a binding chain to allow entrance to the cytoplasm of cells on its own. As a result, it is one of the most studied RIPs used for its vigorousness, potency, safety, and ease of use in the laboratory. The information presented will shed light on the history of Saporin, current applications, and what the future holds for this protein in the neuroscience field.

Related Products: Saporin (Cat. #PR-01)

View the complete poster.

Nurmasitoh T, Sari DCR, Susilowati R (2021) Toxic substance-induced hippocampal neurodegeneration in rodents as model of Alzheimer’s dementia. Open Access Maced J Med Sci [Internet] 9(F):523.

Summary: In this review, the authors discussed hippocampal neurodegeneration rodent animal models of Alzheimer’s Dementia and their induction via a toxic substance. Between 2016-2021, 80 studies were reported with 17 different modeling techniques mentioned.

Usage: 192-IgG-Saporin was referenced using intracerebroventricular injection (ICV) as the route of administration where the parameters studied included, neurotrophic factors, cholinergic activity and neuro-degeneration markers.

Related Products: 192-IgG-SAP (Cat. #IT-01)

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See Also:

• Gelfo F et al. Chronic lithium treatment in a rat model of basal forebrain cholinergic depletion: Effects on memory impairment and neurodegeneration. J Alzheimers Dis 56:1505-1518, 2017.
• Volobueva MN et al. Intracerebroventricular administration of 192IgG-saporin alters the state of microglia in the neocortex. Neurochem J 14(1):37-42, 2020.
• Shin J et al. Focused ultrasound-induced blood-brain barrier opening improves adult hippocampal neurogenesis and cognitive function in a cholinergic degeneration dementia rat model. Alzheimers Res Ther 11(1):110, 2019.