alzheimers-disease

Kucinski AJ, De Jong IEM, Sarter M (2016) Preventing falls in PD in a rat model of impaired cognitive control of complex movements by a pro-cholinergic combination treatment. Neuroscience 2016 Abstracts 835.15 / III34. Society for Neuroscience, San Diego, CA.

Summary: Parkinson’s disease (PD) patients, in addition to primary motor symptoms resulting from extensive losses of striatal dopamine (DA), suffer from an interrelated group of motor-control symptoms including postural instability, gait deficits, and a propensity for falls. These levodopa-insensitive symptoms are associated with losses of cortically-projecting cholinergic neurons of the basal forebrain (BF), as well as cognitive impairments such as poor attention. Given the high prevalence and severe consequences of falls in levodopa-treated patients, alternative treatment options are urgently needed. To assess potential treatments we have developed behavioral models of falls in rats including a test system (Michigan Complex Motor Control Task, MCMCT) that requires persistent control of gait, limb coordination, and carefully timed and placed steps during traversals of dynamic surfaces (rotating square rods). Rats with bilateral cholinergic lesions of the BF using 192 IgG-saporin and 6-OHDA lesions to the dopaminergic dorsomedial striatum (dual lesions, DL) exhibit falls while traversing rotating rods and these falls correlate with impaired performance of a sustained attention task. DL rats’ falls have been hypothesized to result from interactions between disruption of normally cholinergically-driven transfer of extero- and interoceptive cue information from cortex to striatum and impaired striatal action sequencing. Here we tested the hypothesis that falls are reduced by co-treatment with acetylcholinesterase inhibitor donepezil and a 5-HT6 receptor antagonist. This combination treatment was previously reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease. Overall, drug-treated rats fell less frequently from the rotating rods and were particularly more efficient at reinstating forward movement after sudden stoppages of forward movement with a passive (doorframe) distractor task. This treatment combination may benefit fall propensity in PD patients via maintaining planned movement sequences in working memory and improving the vigor of executing such movements following brief periods of freezing of gait. The neuropharmacological interactions of this treatment may involve diverse signaling pathways converging onto striatal output neurons. Results from current experiments using microdialysis and HPLC-mass spectrometry to simultaneously assess release of striatal ACh, animo acids and monoamines during rotating rod traversals will assist in elucidating potential targets for therapeutic prevention of falls. Supported by a grant from H. Lundbeck A/S

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

Wiley RG, Yezierski R, Vierck Jr CJ (2016) Cerebral cholinergic mechanisms in pain: CBF lesions vs systemic scopolamine. Neuroscience 2016 Abstracts 525.15 / SS2. Society for Neuroscience, San Diego, CA.

Summary: Cholinergic inputs to the cerebral cortex and limbic system, originating primarily from the cholinergic basal forebrain (CBF), play an important role in cortical sensory processing, largely through modulation of inhibitory interneurons. Cholinergic agonists given spinally, intracerebroventricularly (ICV) or systemically depress reflex nocifensive responses, but systemic cholinergic antagonists also depress some affective responses to pain and impair attention to aversive stimuli and stress reactions. In the present study, we determined the effects of selective cerebral cholinergic denervation, using ICV microinjection of 4 ug of 192-saporin in 10 μl (Advanced Targeting Systems, San Diego, CA) on operant thermal escape responses to aversive thermal stimuli (10° C, 44.5° C) and hyperalgesic effect of sound stress (ten X 30 sec bursts of 100 dB white noise over a 15 min period, 20 mins prior to thermal escape testing) in normal and CBF-lesioned rats compared to effects of systemic cholinergic antagonism (0.1 mg/kg, i.p., scopolamine, 20 minutes prior to thermal escape testing) in intact, normal rats. All rats were on the thermal escape task prior to either scopolamine, or sound stress testing and prior to ICV 192-saporin. At the conclusion of behavioral testing, choline acetyltransferase immunohistochemistry confirmed that 192-sap produced 62-81% loss of CBF cholinergic neurons. CBF-lesioned rats showed decreased thermal escape responses to both temperatures (10°C and 44.5°C) for >19 weeks. There also was no increase in escape responding (hyperalgesia) after sound stress as seen in normal rats. Scopolamine in normal rats produced decreased thermal escape responses to cold (2° C, 6°C and 10° C) and to heat (44.5° C). These results suggest that systemic scopolamine mimics the effects of CBF destruction on pain and together the overall results are interpreted to indicate an important role for the CBF in cerebral pain processing. These findings may be relevant to clinical pain care in patients with cerebral cholinergic dysfunction, such as Alzheimer’s disease.

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

Coradazzi M, Gulino R, Fieramosca F, Falzacappa L, Riggi M, Leanza G (2016) Selective noradrenaline depletion impairs working memory and hippocampal neurogenesis. Neurobiol Aging 48:93-102. doi: 10.1016/j.neurobiolaging.2016.08.012

Summary: Neuronal loss in the locus coeruleus (LC) of Alzheimer’s patients is well known, but the contribution of LC-derived noradrenergic afferents to learning and memory function is unknown. To model noradrenergic neuron degeneration in the LC, rats were bilaterally injected directly into the LC with 0.2 ug of Anti-DBH-SAP (Cat. #IT-03). Lesioned and sham-lesioned animals were tested behaviorally and exhibited robust working memory deficits but lesioning did not affect reference memory. They concluded that ascending noradrenergic afferents might be involved in more complex aspects of working memory, possibly via newly generated progenitors in the hippocampus.

Related Products: Anti-DBH-SAP (Cat. #IT-03)

Kucinski A, de Jong IEM, Sarter M (2017) Reducing falls in Parkinson’s disease: interactions between donepezil and the 5‐HT6 receptor antagonist idalopirdine on falls in a rat model of impaired cognitive control of complex movements. Eur J Neurosci 45:217-231.. doi: 10.1111/ejn.13354

Objective: To assess the effects of treatment on MCMCT performance and attention in DL rats. The combined treatment of the acetylcholinesterase inhibitor donepezil and the 5-HT6 receptor antagonist idalopirdine (Lu AE58054) was use because it has been reported to exhibit synergistic pro-cholinergic activity in rats and improved cognition in patients with moderate Alzheimer’s disease.

Summary: This treatment may reduce fall propensity in patients.

Usage: 192-IgG-SAP aCSF infused bilaterally (120 ng/uL; 0.5 uL/hemisphere).

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

Köppen J, Stuebing S, Sieg M, Blackwell A, Blankenship P, Cheatwood J, Wallace D (2016) Cholinergic deafferentation of the hippocampus causes non-temporally graded retrograde amnesia in an odor discrimination task. Behav Brain Res 299:97-104. doi: 10.1016/j.bbr.2015.11.021

Summary: The memory impairments experienced in neurodegenerative disorders such as Alzheimer’s disease have been well documented. One theory attributes these impairments to the loss of cholinergic basal forebrain neurons, a hallmark of Alzheimer’s disease. Some patients experience a retrograde amnesia, in which older memories are relatively stable and more recent memories are frequently lost. The temporal relationship of memories to disease onset has not been definitively established. In this work the authors administered either 150 ng or 200 ng of 192-IgG-SAP (Cat. #IT-01) into the medial septum of rats. Using a string-pulling task, a model for temporal learning was established. The results indicate that cholinergic projections originating in the medial septum are involved in long-term memory retrieval, and that loss of these neurons does not create a temporal type of amnesia.

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

Jeong D, Oh J, Lee J, Lee J, Cho Z, Chang J, Chang W (2016) Basal forebrain cholinergic deficits reduce glucose metabolism and function of cholinergic and gabaergic systems in the cingulate cortex. Yonsei Med J 57:165-172. doi: 10.3349/ymj.2016.57.1.165

Summary: A common result of cholinergic neuron loss in the hippocampus and cortical regions due to Alzheimer’s disease is a reduction in glucose metabolism. The authors examine the interaction between the cell loss and metabolic changes. Rats received 5-μg bilateral cortical injections of 192-IgG-SAP (Cat. #IT-01), were subject to water maze testing, and analyzed by 18F-2-fluoro-2-deoxyglucose positron emission tomography. Lesioned animals displayed decreased learning performance and reduced metabolic activity in the cingulate cortex.

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

Gulino R (2016) Neuroplasticity and repair in rodent neurotoxic models of spinal motoneuron disease. Neural Plast 2016:2769735. doi: 10.1155/2016/2769735

Summary: TDP-43 (Transactive response DNA-binding protein) is a highly conserved nuclear protein that binds both DNA and RNA. It has been found in cytoplasmic protein aggregates of patients with conditions such as amyotrophic lateral sclerosis and Alzheimer’s disease. In this work the authors examine the role of TDP-43 in spinal cord plasticity. Mice received bilateral 3-μg injections of CTB-SAP (Cat. #IT-14) into the lateral and medial gastrocnemius muscles. The results indicate that motor performance is dependent on expression of synapsin-I, which in turn may be dependent on TDP-43.

Related Products: CTB-SAP (Cat. #IT-14)

Chen Y, Pan C, Xuan A, Xu L, Bao G, Liu F, Fang J, Long D (2015) Treatment efficacy of NGF nanoparticles combining neural stem cell transplantation on Alzheimer’s Disease model rats. Med Sci Monit 21:3608-3615. doi: 10.12659/msm.894567

Summary: NSC (neural stem cell) transplants into animals have been shown to compensate for the loss of cholinergic cells in the basal forebrain, a hallmark of Alzheimer’s disease. One hurdle to overcome is the actuation of NSC differentiation into the specific replacement cells needed. NGF has been shown to induce this differentiation, but it has a very short half-life and does not permeate tissue very effectively. In this work the authors administered 5 mcl of icv 192-IgG-SAP (Cat. #IT-01) to rats, followed by a graft of NCSs in the presence of NGF nanoparticles with a polymer coating. Rats receiving both NCSs and NGF nanoparticles showed significantly improved memory and learning functions as compared to control animals.

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

Li T, Yu Y, Cai H (2015) Effects of brain-derived neurotrophic factor-pretreated neuron stem cell transplantation on Alzheimer’s disease model mice. Int J Clin Exp Med 8:21947-21955.

Summary: In order to generate the AD mouse model, mu p75-SAP (1-1.2 μg/μL)  was injected to the bilateral icv areas.

Related Products: mu p75-SAP (Cat. #IT-16)

Carnes B, DeLacalle S (2015) Compensatory cortical sprouting across the lifespan of the rat. Neuroscience 2015 Abstracts 391.10/C34. Society for Neuroscience, Chicago IL.

Summary: To investigate the plastic capacity of the cholinergic system in a partial animal model of Alzheimer’s disease, adult and aged rats received unilateral lesions of the horizontal diagonal band of Broca (HDB) using the cholinergic-specific toxin 192-IgG-saporin. The rats were sacrificed at 2, 4, 8, 12, or 24 weeks post lesion. Immuno- and histochemical techniques were used to quantify the effects of the lesion. Tissues were stained using an acetylcholinesterase technique. A 230µm by 200µm grid was used to indirectly measure the density of cholinergic fibers in the Entorhinal Cortex (EC). We compared our data to a young (3 month old) control group (Hartonian, 2005) in which the maximal loss of fiber density occurred by 8 weeks post-lesion and recovered to 75% of the intact contralateral EC by 12 weeks. All groups (young adult: 12-15; adult: 18; aged: 24-27 month old rats at the start of the experiment) exhibited a decrease in cortical fiber density after the lesion, which was more pronounced in the young adult group. All groups showed a recovery in fiber density to 60-80% of the intact side by 24 weeks post lesion. Interestingly, the loss occurred faster and more intense in the young adult group (to 25% of the intact side at 8 weeks post-lesion) than in the older ones (to 60% of the intact side by week 12 post lesion). Twenty four weeks after the lesion, the young adult group had recovered fiber density to 70%. The adult group also reached 70%, and the aged group reached 80% of the contralateral intact side. We conclude that following a cholinergic specific lesion, a compensatory mechanism is activated in the basal forebrain such that surviving neurons, projecting to the same target, are able to extend terminals and occupy the denervated area. It remains to be investigated whether the sprouts are able to establish proper synaptic connections and make a functional recovery.

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