alzheimers-disease

Bolshakov AP, Stepanichev MY, Dobryakova YV, Spivak, YS, Markevich, VA (2020) Saporin from Saponaria officinalis as a tool for experimental research, modeling, and therapy in neuroscience. Toxins (Basel) 12(9):546. doi: 10.3390/toxins12090546

Summary: A review of studies where saporin-based conjugates were used to analyze cell mechanisms of sleep, general anesthesia, epilepsy, pain, and development of Parkinson’s and Alzheimer’s diseases.

Related Products: Targeted Toxins

Giannoni P, Fossati S, Claeysen S, Marcello E, eds (2020) Identification of multiple targets in the fight against Alzheimer’s disease. Front Aging Neurosci 12:169. doi: 10.3389/fnagi.2020.00169

Summary: A collection of 20 articles that depict a broad representation of the most impactful advances in Alzheimer’s disease (AD) comprehension and therapeutic openings.

Related Products: 192-IgG-SAP (Cat. #IT-01), mu p75-SAP (Cat. #IT-16)

Qian L, Kasas L, Milne MR, Rawashdeh O, Marks N, Sharma A, Bellingham MC, Coulson EJ (2020) Cholinergic basal forebrain degeneration due to obstructive sleep apnoea increases Alzheimer’s pathology in mice. bioRxiv 2020.03.12.989848. doi: 10.1101/2020.03.12.989848

Usage: bilateral injections of urotensin II-saporin (UII-SAP; 0.07 μg/μL per site – unless stated otherwise; generous gift from Advanced Targeting Systems)

Related Products: Custom Conjugates, Blank-SAP (Cat. #IT-21)

Shin J, Kong C, Lee J, Choi BY, Sim J, Koh CS, Park M, Na YC, Suh SW, Chang WS, Chang JW (2019) 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. doi: 10.1186/s13195-019-0569-x

Objective: To investigate the decrease of adult hippocampal neurogenesis (AHN) in Alzheimer’s disease (AD).

Summary: This work studied the effect of FUS on AHN in a cholinergic degeneration rat model of dementia.

Usage: 192-IgG-SAP was injected bilaterally into the lateral ventricle (4 μl at a concentration of 0.63 μg/μl at a rate of 1 μl/min).

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

Kruashvili L, Beselia G, Chkhikvishvili N (2019) Effect of medial septal selective and non selective lesions on exploratory behavior and recognition memory. Neuroscience 2019 Abstracts 336.01. Society for Neuroscience, Chicago, IL.

Summary: Investigation of cholinergic system and memory interaction has especially become the object of scientific attention due to the clinical and experimental data, in which the severity of dementia in Alzheimer’s disease (AD) was found to have a positive correlation with the extent of the cholinergic loss. The septum is connected to the hippocampus via the fimbria-fomix, which carries projections from the medial septum (MS), and the vertical limb of the diagonal band of Broca. These projections are predominantly cholinergic and GABAergic. Lesions of the fimbria-fomix, or electrolytic lesions of the MS, impair hippocampal- dependent learning and memory. The purpose of this study was to investigate ability to acquire and use spatial (or non-spatial) information as well as to habituate exploratory activity over time in sham-operated, electrolytic, neuro or immunotoxic MS lesioned rats. Methods: A total of 39 male rats were used. For electrolytic lesions a stainless steel was inserted in the MS. All injections were performed stereotaxically. Rats were individually given five 3-min sessions in the open field. All experiments were approved by the Animal Care and Use Committee of the Center and were in accordance with the principles of laboratory animal care. Results: Examination of the AChE stained sections showed that after injections of 192 IgG saporin into the MS, animals exhibited significantly less AChE staining in MS and hippocampus as compared to sections obtained from control animals. The MS electrolytic and ibotenic acid lesioned rats showed an increase in their exploratory activity to the objects and were impaired in habituating to the objects in the repeated spatial environment, rats with immunolesions of the MS did not differ from control rats. Electrolytic lesions of the MS disrupt spatial recognition memory, rats with immuno- or neurotoxic lesions of the MS were normal in detecting spatial novelty. The MS lesioned and control rats clearly reacted to the object novelty by exploring the new object more than familiar ones. Conclusions: MS is sufficient for spatial recognition, but is not sufficient for object recognition memory, the selective loss of septohippocampal cholinergic or noncholinergic projections does not disrupt the function of the hippocampus to a suffi cient extent to impair spatial recognition memory. Therefore, the present study demonstrates dissociation between the two major components (cholinergic and noncholinergic) of the septohippocampal pathway in exploratory behavior assessed in the open field.

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

Nazmuddin M, Rao HA, Van Laar T, Sarter MF (2019) How to stimulate: Basal forebrain DBS parameters to restore the attentional performance of rats with cholinergic losses. Neuroscience 2019 Abstracts 377.10. Society for Neuroscience, Chicago, IL.

Summary: The degeneration of basal forebrain (BF) cholinergic neurons is an index of the severity of cognitive impairment in Alzheimer disease (AD) and Parkinson’s disease (PD). Moreover, in PD patients, gait and balancing deficits, and an increased propensity for falls have been attributed to cholinergic losses. Thus, Deep Brain Stimulation (DBS) of the BF has been considered a potential therapeutic intervention to improve cognition and movement control in these patients. However, efficacy of BF DBS in clinical populations has yet to be conclusively demonstrated. Likewise, the demonstration of beneficial effects of BF DBS in rodent models has been hampered by uncertainties about useful animal models and behavioral tasks and, importantly, a lack of consensus concerning DBS parameters (duration, frequency, current, intermittent versus continuous, prior and/or during task, etc.). Here we assessed various DBS parameters in rats with a partial loss of the cortical cholinergic input system. In rats, such cholinergic losses have been frequently demonstrated to impair the detection of cues during the performance of a Sustained Attention Task (SAT) and to attenuate performance recovery following a distractor challenge (dSAT). In PD patients with cholinergic losses, attentional impairments were also attributed to cortical and thalamic cholinergic losses (Kim et al., 2017). The attribution of SAT impairments to cholinergic losses is consistent with evidence showing that the detection of cues and associated attentional control parameters depend on cortical cholinergic signaling (e.g., Howe et al., 2017). Here, rats acquired the SAT, received infusions of the cholino-specific neurotoxin 192-IgG-saporin into the BF, and were implanted bilaterally with BF unipolar stimulation electrodes. Initial DBS parameters consisted of continuous high (130 Hz) versus low (20 Hz) frequency stimulation, intermittent (20-s ON at 80 Hz and 40-s OFF) stimulation, with pulse width and amplitude kept constant at 100 µs and 100 µA, respectively. We first assessed the effects of these DBS parameters on the behavior of rats in an open field space and then when administered during, or only prior to (for 1 hr), SAT and dSAT performance. Ongoing experiments indicate that these stimulation parameters are well tolerated as indicated by the absence of effects on locomotor and exploratory activity. We predict that BF DBS will be particularly effective in restoring attentional performance in the dSAT condition. If confirmed, this finding will suggest that demonstration of efficacy in patients will require measures indicating their attentional capacities in response to taxing performance challenges.

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

Blumenthal SA, Maness EBL, Fadel JR, Burk JA (2019) Effects of an orexin-2 receptor agonist on attention in rats following loss of cortical cholinergic projections. Neuroscience 2019 Abstracts 418.06. Society for Neuroscience, Chicago, IL.

Summary: Deterioration to the basal forebrain cholinergic system (BFCS) is linked to age-related cognitive impairment, specifically to the pathology of Alzheimer’s disease (AD). Animals with BFCS damage perform poorly on learning, memory, and attention tasks, indicating cognitive deficits. The orexin neuropeptide system, comprised of two neuropeptides (orexin A and orexin B), has also been implicated in the cognitive decline associated with aging, likely due to the role of orexins in promoting attention. Two orexin receptor subtypes exist, orexin 1 (Ox1R) and orexin 2 (Ox2R). Studies have examined the effects of stimulation and blockage of both receptors together and Ox1R alone on attention; but no studies have examined the role of Ox2Rs in attention through the use of Ox2R agonists. Ox2Rs may be implicated in attentional processes and the loss of orexin neurons seen in age-related cognitive decline. In order to examine the role of Ox2Rs in attention following BFCS deterioration, the present study administered the Ox2R agonist, YNT-185, to rats given intrabasalis infusions of either saline (n = 12) or 192 IgG saporin (n=11), an immunotoxin which selectively destroys the BFCS. Animals received infusions of YNT-185 to the lateral ventricle (LV) in doses of 0, 1, 10, and 100nM across four separate sessions and performance was then assessed on a sustained attention task requiring discrimination between signal and non-signal trials through lever presses. The 100nM dose of YNT-185 improved attentional performance, as compared to the 0nM dose, for rats given the immunotoxin, but worsened performance for rats given saline lesions. YNT-185 may be efficacious in aiding attentional function in animals with vulnerable cholinergic systems but may lead to overexcitation for those with intact cholinergic function.

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

Cunningham C, Lowry JP (2019) In vivo monitoring of cholinergic neurotransmission with a microelectrochemical choline biosensor. Neuroscience 2019 Abstracts 614.03. Society for Neuroscience, Chicago, IL.

Summary: Acetylcholine acts as a key neuromodulator within the central nervous system, capable of altering neuronal excitability and coordinating neuronal firing patterns. Conversely, cholinergic neurotransmission plays a crucial role in a variety of cognitive functions, including the encoding of new memories. Cholinergic neuronal loss, and the resulting drop in cholinergic neurotransmission (collectively referred to as hypocholinergia), is closely associated with cognitive dysfunction in a number of chronic neurodegenerative disorders including Alzheimer’s disease. However, conventional analytical techniques for monitoring in vivo cholinergic neurotransmission lack the spatiotemporal resolution required to accurately detect endogenous cholinergic dynamics. Here we validate in mice a Pt-based electrochemical biosensor for selective monitoring of choline, a verified marker of cholinergic transmission. Enzymatic choline biosensors (modified with choline oxidase) were sterotaxically implanted in the medial prefrontal cortex (mPFC) and contralateral dorsal hippocampus (dHPC) of female C57Bl6J mice. Real-time choline current recordings over a period of several days revealed circadian fluctuations in both regions, with extracellular choline levels highest during light phases. Administration of pharmacological compounds known to induce central acetylcholine release, scopolamine (1mg/kg) and amphetamine (4mg/kg), evoked a robust increase in choline current. In contrast, peripheral injection of the reversible acetylcholinesterase inhibitor, donepezil (3mg/kg), produced a marked decrease in recorded choline current. The induction of systemic infammation with bacterial lipopolysaccharide (LPS; 500µg/kg) produced characteristic ‘sickness behaviour’ in mice and evoked a tonic rise in central choline levels in both the mPFC and dHPC. Furthermore, the induction of hypocholinergia in selected mice was preformed via intracerebroventricular injections of murine-p75-saporin immunotoxin (1.2µg). Evoked cholinergic neurotransmission was dramatically attenuated in lesioned (hypocholinergic) mice. Collectively, the data suggests that microelectrochemical choline biosensors may serve as a powerful tool for monitoring cholinergic neurotransmission across a number of behavioural and disease states.

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Verkhratsky A, Parpura V, Rodriguez-Arellano J, Zorec R (2019) Astroglia in Alzheimer’s Disease. (eds. Verkhratsky A, Ho M, Zorec R, Parpura V). In: Advances in Experimental Medicine and Biology: Neuroglia in Neurodegenerative Diseases. 1175:273-324. Springer, Singapore. doi: 10.1007/978-981-13-9913-8_11

Summary: A review of the tools for creating animal models of Alzheimer’s Disease. 192-IgG-SAP binds selectively and irreversibly to low-affinity nerve growth factor receptor interrupting cholinergic neuronal protein synthesis was employed. Anti-DBH-SAP binds dopamine-β-hydroxylase, which is not only localized mainly in the cytosol, but also at the plasma membrane surface of noradrenergic neurons. Anti-DBH-SAP produced specific and dose-dependent depletions of locus coeruleus neurons, with no effects on other cholinergic, dopaminergic or serotonergic neuronal populations. The possibility to induce a partial or total noradrenergic loss (by varying the injected dose) makes this immunotoxic approach an ideal model to study events within the noradrenergic projection system, as they occur during age-related demise of locus coeruleus in humans.

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

Veening-Griffioen DH, Ferreira GS, van Meer PJK, Boon WPC, Gispen-de Wied CC, Moors EHM, Schellekens H (2019) Are some animal models more equal than others? A case study on the translational value of animal models of efficacy for Alzheimer’s disease. Eur J Pharmacol 859:172524. doi: 10.1016/j.ejphar.2019.172524 PMID: 31291566

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