alzheimers-disease

Craig LA, Hong NS, Kopp J, McDonald RJ (2008) Emergence of spatial impairment in rats following specific cholinergic depletion of the medial septum combined with chronic stress. Eur J Neurosci 27:2262-2271. doi: 10.1111/j.1460-9568.2008.06179.x

Summary: Although it is clear that loss of cholinergic neurons in the basal forebrain is intrinsic to Alzheimer’s disease, interaction of this loss with other factors in causing the disease symptoms has not been completely elucidated. Rats received bilateral injections of 192-IgG-SAP (Cat. #IT-01) into the medial septum and vertical limb of the diagonal band of Broca totaling 0.075 µg. Lesioned animals were not impaired in a water maze task, but lesioning combined with stress caused a significant reduction in performance.

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

Aztiria E, Cataudella T, Spampinato S, Leanza G (2009) Septal grafts restore cognitive abilities and amyloid precursor protein metabolism. Neurobiol Aging 30(10):1614-1625. doi: 10.1016/j.neurobiolaging.2007.12.018

Summary: Although cholinergic loss and the presence of ß-amyloid plaques are well documented in Alzheimer’s disease, it is unknown whether restoration of regulatory cholinergic inputs affects in vivo b-amyloid precursor protein (APP). 5 µg of 192-IgG-SAP (Cat. #IT-01) was split between the lateral ventricles of rats. 6 months post-surgery the animals were implanted with cholinergic-rich septal tissue grafts. Grafted animals exhibited normal or near-normal levels of APP. APP levels, as well as improved spatial navigation performance, correlated strongly with graft-induced cholinergic changes.

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

Savage S, Ogren S, Olson L, Mattsson A (2007) Immunotoxin lesion of cholinergic nucleus basalis magnocellularis neurons in Lister hooded rats impair performance in a delayed matching-to-place task. Neuroscience 2007 Abstracts 840.1/TT24. Society for Neuroscience, San Diego, CA.

Summary: Central cholinergic systems play an important role in various aspects of cognition, and deficits in cortical cholinergic function have been implicated in the cognitive impairments associated with normal aging and dementia. Cholinergic dysfunctions have also been implicated in several neuropsychiatric disorders, including schizophrenia. Though cognitive dysfunctions, such as impaired working memory, are observed in Alzheimer, as well as schizophrenic patients, the cholinergic mechanisms behind these dysfunctions are not well characterized in animal models. To investigate whether specific cortical cholinergic deficits will affect spatial learning and memory functions, we lesioned the basalo-cortical cholinergic system by stereotaxic infusion of the immunotoxin 192 IgG-saporin in the nucleus basalis magnocellularis (NBM) of adult male Lister hooded rats. Learning and memory was assessed using a delayed matching-to-place (DMP) paradigm in the water maze. We found that animals with cholinergic denervation of neocortex were impaired in the DMP-task. Thus, while the sham-operated animals rapidly learned the task without prior training, saporin-treated rats showed impairment during the initial three days of testing. By the end of the testing period, the lesioned animals had acquired the task. However, the cholinergically denervated animals showed a performance deficit throughout the duration of the experiment with higher trial latencies and longer distance traveled to find the platform as compared to the controls. They also seemed to employ a different strategy to find the hidden platform as compared to control animals. Whether the deficits after cholinergic lesions to the NBM seen in the present experiment are mnemonic and/or attentional in nature remains to be elucidated.

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

Pang K, Sinha SP, Jiao X, Servatius RJ (2007) Understanding the role of non-cholinergic medial septal neurons in learning and memory: Implications for disease- and aging-related impairments. Neuroscience 2007 Abstracts 932.22/WW17. Society for Neuroscience, San Diego, CA.

Summary: The medial septum-diagonal band of Broca (MS) has an important function in learning and memory. Furthermore, degeneration of the MS may contribute to cognitive impairments associated with Alzheimer’s disease and normal aging. Because the MS contains several types of neurons, the neuronal population(s) involved in learning and memory has been actively investigated. Animal studies have mainly focused on the cholinergic neurons that project to the hippocampus. Although complete lesions of the MS or fimbria-fornix transaction leads to spatial memory impairments, selective damage of cholinergic MS neurons produces no or a mild impairment in spatial memory, suggesting an important role of non-cholinergic neurons. Most of these non-cholinergic neurons are GABAergic. Previously, we used low concentrations of kainic acid to examine the importance of non-cholinergic MS neurons in spatial memory. However, a more selective toxin for GABAergic neurons would facilitate research, as it has done for the cholinergic system. In the present study, we use a new GABAergic immunotoxin that combines an antibody to the GABA transporter GAT1 with saporin. GAT1-saporin was administered into the medial septum of male Sprague Dawley rats. Our preliminary results show that GABAergic septohippocampal neurons as assessed by parvalbumin-immunoreactivity were virtually eliminated, while cholinergic neurons were spared in the medial septum. Current work is focused on further characterizing the cell populations affected by GAT1-saporin. Preliminary behavioral results demonstrate that GABA MS lesions did not impair spatial reference memory in the initial acquisition of a water maze task. However, a deficit was observed in reversal learning. Further testing in a procedure where the escape platform moves to a new location every day showed that rats treated with GAT1-saporin were mildly impaired in within-session learning of the new platform location. These preliminary results demonstrate that intraseptal GAT1-saporin is effective in eliminating at least some populations of GABAergic neurons in the MS. Furthermore, the preliminary behavioral results are consistent with our previous results demonstrating that damage of non-cholinergic MS neurons produces a very specific impairment on reversal learning. In summary, GAT1-saporin may be a useful tool to examine the function of GABA MS neurons in learning and memory and their contribution to cognitive impairments in disease and aging.

Related Products: GAT1-SAP (Cat. #IT-32)

ATS Poster of the Year Winner

Rennie KE, Frechette M, Pappas BA (2007) Behavioural consequences of combined cholinergic lesion and chronic cerebral hypoperfusion in rats. Neuroscience 2007 Abstracts 698.16/R26. Society for Neuroscience, San Diego, CA.

Summary: Chronic cerebral hypoperfusion compromises the health of hippocampal neurons, leading to a slowly emerging loss of pyramidal cells accompanied by spatial memory impairments in rats. Recent research suggests that vascular abnormalities resulting in insufficient cerebral blood flow or impaired nutrient delivery to the brain represent a significant risk factor for Alzheimer’s disease (AD) and may contribute to its pathogenesis. AD is also characterized by dysfunction of the forebrain cholinergic system. Since there is evidence that this system is involved in the control of local cerebral blood flow, we hypothesized that there would be synergistic effects of chronic cerebral hypoperfusion and cholinergic dysfunction. Hence, the aim of this study was to determine whether cholinergic dysfunction exacerbates the effects of cerebral hypoperfusion. Female rats were subjected to forebrain cholinergic lesion or control surgery by intraventricular infusion of the immunotoxin 192-IgG-saporin (192S) or phosphate buffered saline (PBS) on postnatal day 7. Six months later the rats underwent permanent bilateral occlusion of the carotid arteries (2VO), which causes moderate, chronic cerebral hypoperfusion, or sham surgery. When exposed to an open field 48, 72 and 96 hours after 2VO or sham surgery, the groups did not differ on measures of overall activity. However, the cholinergic lesion increased the latency to enter the centre area, and reduced both the number of centre entries and the percentage of total distance that was traveled in the inner squares. The lesion effects were mainly seen in the combined 192S/2VO group while 192S or 2VO alone produced only minor behavioural changes. Elevated plus testing 2 weeks after surgery revealed a reduction in open but not closed arm entries due to the cholinergic lesion. Interestingly, the effects of 2VO were dependent on the status of the cholinergic system. 2VO increased open arm entries in the PBS group, but decreased this behaviour in the 192S group. Thus on both the open field and elevated plus maze, the cholinergic lesioned rats displayed more anxious behaviour, particularly after 2VO. Finally, cholinergic lesion produced impairments on the working memory version of the Morris water maze. Again, this effect was most pronounced in the combined 192S/2VO group. This effect is unlikely to be due to motivational or sensorimotor deficits as all groups performed similarly on a cued platform version of the maze. Cholinergic lesion and 2VO appear to act synergistically to produce behavioural alterations, even at relatively early time points after 2VO. Their combined effects on CA1 pyramidal cell viability are currently under examination.

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

Browning PG, Gaffan D, Baxter MG (2007) Severe visual learning impairments in monkeys with combined but not separate lesions of the temporal cortical cholinergic system and the fornix. Neuroscience 2007 Abstracts 341.7. Society for Neuroscience, San Diego, CA.

Summary: A dense amnesia can be produced in the monkey by sectioning the anterior temporal stem, amygdala and fornix, a procedure which deafferents temporal cortex from modulatory inputs from the midbrain and basal forebrain. The present experiment investigated the neurochemical specificity of these severe learning impairments by selectively destroying cholinergic projections to the entire inferior temporal cortex by making multiple injections of the immunotoxin ME20.4-saporin into the inferior temporal cortex bilaterally. Six male macaque monkeys were preoperatively trained to learn new object-in-place discrimination problems each day until they could rapidly learn many such problems within a testing session. The monkeys then underwent surgery and received either injections of immunotoxin (n=3) or injections of saline (n=3). Both groups of monkeys were unimpaired when postoperative and preoperative performance were compared. Each monkey then underwent a second surgery to transect the fornix. After this surgery monkeys who had previously received injections of immunotoxin into temporal cortex showed a severe learning impairment, whereas monkeys who had previously received injections of saline showed a mild impairment. Monkeys with the combined immunotoxin plus fornix lesion were also severely impaired at concurrent object discrimination learning. These results suggest that different neuromodulatory inputs to inferior temporal cortex may act in concert to support cortical plasticity in visual learning such that the loss of acetylcholine only is not sufficient to disrupt normal learning behavior. The results also suggest that in monkeys, as in humans with Alzheimer’s disease, severe memory impairments occur only when a loss of acetylcholine projections to cortex is accompanied by organic tissue damage.

Related Products: ME20.4-SAP (Cat. #IT-15)

Baxter MG, Kyriazis DA, Croxson PL (2007) Cholinergic depletion of prefrontal cortex does not impair episodic memory or strategy implementation in rhesus monkeys. Neuroscience 2007 Abstracts 341.9. Society for Neuroscience, San Diego, CA.

Summary: The prefrontal cortex is involved in regulating multiple aspects of memory, decision-making, and cognitive control. Cholinergic input to prefrontal cortex is thought to be involved in supporting its functions. To examine this hypothesis we tested 4 rhesus monkeys (3 male) with cholinergic depletion of ventrolateral prefrontal cortex (N=2) or the entire prefrontal cortex, excluding its medial aspect (N=2). Selective cholinergic depletion was produced by multiple injections of the immunotoxin ME20.4-saporin (0.02 ug/ul) into the prefrontal cortex. These monkeys were tested on two tasks that each require frontal-inferotemporal interaction, as well as an intact ventrolateral prefrontal cortex. The first, strategy implementation, requires monkeys to apply different choice strategies to different categories of objects in order to maximize the rate of reward delivery, and engages decision-making and cognitive control. The second, scene memory, is a test of episodic memory in which monkeys rapidly learn 20 new object-in-place scene discrimination problems within a single test session. Cholinergic depletions of prefrontal cortex, whether they were limited to ventrolateral prefrontal cortex or included the whole of lateral and orbital prefrontal cortex, were without effect on either strategy implementation or new scene learning relative to each monkey’s preoperative performance. Thus, episodic memory and strategy implementation can proceed normally even with severely disrupted cholinergic input, so loss of cholinergic input on its own cannot explain impaired prefrontal function in conditions such as Alzheimer’s disease. Acetylcholine may work in tandem with other neuromodulators to affect prefrontal cortex function; alternatively, it may only be involved in very specific aspects of cortical function, for example representational plasticity.

Related Products: ME20.4-SAP (Cat. #IT-15)

Severino M, Pedersen AF, Trajkovska V, Christensen E, Lohals R, Veng LM, Knudsen GM, Aznar S (2007) Selective immunolesion of cholinergic neurons leads to long-term changes in 5-HT2A receptor levels in hippocampus and frontal cortex. Neurosci Lett 428:47-51. doi: 10.1016/j.neulet.2007.09.026

Summary: Changes in several neurotransmitter systems, including serotonin and 5HT2A receptors, are associated with early Alzheimer’s disease (AD). The authors gave rats intracerebroventricular injections of either 2.5 or 5 µg of 192-IgG-SAP (Cat. #IT-01) then examined both of these systems. 5HT2A receptor levels were markedly decreased in the frontal cortex and markedly increased in the hippocampus of animals lesioned with 5 µg of 192-IgG-SAP. The change in 5HT2A receptor number suggests that the AD effect stems from interaction with the cholinergic system.

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

Chin JH, Ma L, MacTavish D, Jhamandas JH (2007) Amyloid beta protein modulates glutamate-mediated neurotransmission in the rat basal forebrain: involvement of presynaptic neuronal nicotinic acetylcholine and metabotropic glutamate receptors. J Neurosci 27:9262-9269. doi: 10.1523/JNEUROSCI.1843-07.2007 PMID: 17728440

Summary: This work focused on the effect of amyloid beta on glutamate-mediated neurotransmission in the diagonal band of Broca. Using neurons identified by staining with Cy3-labeled 192-IgG (Cat. #FL-01, 5 µl of 1:1 diluted antibody injected into the left and right ventricle) the authors monitored the response to amyloid beta by measuring excitatory postsynaptic currents via whole-cell patch-clamp recordings. The results suggest that glutamate neurotransmission might be vulnerable to Alzheimer’s disease, and may also be a therapeutic target.

Related Products: 192-IgG Mouse Monoclonal, Cy3-labeled (Cat. #AB-N43FL3)

Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ (2007) A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28(3):286-292. doi: 10.1016/j.nbd.2007.07.019

Summary: Microglia are thought to play a key role in the clearance of amyloid-b (Ab) in Alzheimer’s disease. To examine this role the authors applied 30 µl of 0.5 mg/ml Mac-1-SAP (Cat. #IT-06) to the brain surface of mice for 20 minutes. The number of microglia and plaques was determined by counting of immunohistochemical samples. Results indicate that microglia play a minor role in clearing Ab plaques, although the interaction of microglia-mediated inflammation and anti-Ab antibodies appears to be vital in this process.

Related Products: Mac-1-SAP mouse/human (Cat. #IT-06)