alzheimers-disease

Kong C, Shin J, Lee J, Koh C-S, Yoon M-S, Na Y, Chang J, Chang W (2017) Improvements in memory after focused ultrasound are associated with changes in hippocampal cholinergic activity and neurogenesis. Neuroscience 2017 Abstracts 201.12 / C29. Society for Neuroscience, Washington, DC.

Summary: Abstract Introduction: Alzheimer’s disease is characterized pathologically by neurofibrillary tangles, amyloid plaques, gliosis, synaptic loss and cholinergic deficits. Recently, cell proliferation and neurogenesis was reported to have increased when the blood brain barrier (BBB) was disrupted by Focused ultrasound (FUS) with microbubbles. Previously, we have demonstrated that the cholinergic cell decreases in 192 IgG-saporin rat model, and that decrease in cholinergic cell is associated to decrease in cognitive behavior. The purpose of this study was to determine if the learning and memory abilities of the 192 IgG-saporin rat model are improved by FUS. Materials and Methods: Animals were divided into the four groups: Sham group (PBS injection), Lesion group (saporin injection), FUS-3 and FUS-10 groups (After 3 and 10 days after saporin injection, FUS treatment). Sprague-Dawley rats (200-250g) were injected bilaterally with 192 IgG-saporin into the ventricle. Rats were sonicated using a single-element transducer (frequency 0.5 MHz) with microbubble. The acoustic parameters used for each sonication are: pressure amplitude 0.3 MPa, pulse length 10 ms, burst repetition frequency 1 Hz, and a duration of 120 s. To confirm cell proliferation, BrdU was intraperitoneally injected 2 times per day for 4 consecutive days starting 24 hours after FUS sonication. Two weeks after IgG-saporin administration, spatial memory was tested with the Morris water maze training for 5 days and the final test was performed. Results: In the water maze test, the FUS groups had a higher number of crossing times and staying time in the platform zone than the lesion group. Also, the FUS-3 group was higher than for the FUS-10 group. We confirmed that the amounts of DCX , NeuN , and BrdU were different between the FUS group and the lesion group. Conclusion: Our results suggest that FUS sonication facilitates recovery of memory and learning abilities in cholinergic deficits rat model. Moreover, the results suggest that neurogenesis is correlated with the mechanism of cognitive behavior recovery.

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

Lee S, Cho W, Lee Y, Han J (2018) Impact of chronic stress on the spatial learning and GR-PKAc-NF-κB signaling in the hippocampus and cortex in rats following cholinergic depletion. Mol Neurobiol 55:3976-3989. doi: 10.1007/s12035-017-0620-5

Objective: Examine the effects of chronic stress on cognitive status and GR-PKAc-NF-κB signaling in rats with a loss of cholinergic input to the hippocampus and cortex.

Summary: The activation of NF-κB induced by cholinergic depletion appears to be aggravated by chronic stress, and this might explain the increased susceptibility of patients with Alzheimer’s disease to stress since activation of NF-κB is associated with stress.

Usage: Male Sprague-Dawley rats received injections of 192 IgG-SAP dissolved in sterile 0.01 M PBS) at a concentration of 0.25 μg/μl.

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

Martínez-Gardeazabal J, González de San Román E, Moreno-Rodríguez M, Llorente-Ovejero A, Manuel I, Rodríguez-Puertas R (2017) Lipid mapping of the rat brain for models of disease. Biochim Biophys Acta Biomembr 1859:1548-1557.. doi: 10.1016/j.bbamem.2017.02.011

Objective: To map the spatial distribution of different lipid species in the rat central nervous system (CNS) using IMS to find a possible relationship between anatomical localization and physiology. The data obtained were subsequently applied to a model of neurological disease, the 192IgG-saporin lesion model of memory impairment.

Summary: The specific distribution of different lipids supports their involvement not only in structural and metabolic functions but also as intracellular effectors or specific receptor ligands and/or precursors. Moreover, the specific localization in the CNS described here will enable us to analyze lipid distribution to identify their physiological conditions in rat models of neurodegenerative pathologies, such as Alzheimer’s disease.

Usage: 192 IgG-SAP in aCSF (135 ng/1 μl/hemisphere; 0.25 μl/min) was administered.

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

Gelfo F, Cutuli D, Nobili A, De Bartolo P, D’Amelio M, Petrosini L, Caltagirone C (2017) Chronic lithium treatment in a rat model of basal forebrain cholinergic depletion: Effects on memory impairment and neurodegeneration. J Alzheimers Dis 56:1505-1518. doi: 10.3233/JAD-160892 PMID: 28222508

Objective: To evaluate the potential beneficial effects of a chronic lithium treatment in preventing the damage that a basal forebrain cholinergic neurodegeneration provokes.

Summary: The chronic lithium treatment significantly rescued memory performances but did not modulate ChAT availability and caspase-3 activity. The present findings support the lithium protective effects against the cognitive impairment that characterizes the brain cholinergic depletion.

Usage: Neurodegeneration was induced by injecting the immunotoxin 192 IgG-SAP in the medial septum (0.5 ug/side) and nucleus basalis magnocellularis (0.4 ug/side).

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

Joly S, Lamoureux S, Pernet V (2017) Nonamyloidogenic processing of amyloid beta precursor protein is associated with retinal function improvement in aging male APP. Neurobiol Aging 53:181-191. doi: 10.1016/j.neurobiolaging.2017.02.004 PMID: 28262325

Objective: To determine amyloid beta role in the aging retina in Alzheimer’s Disease

Summary: Retinal-specific processing of amyloid may confer protection against AD and selectively preserve cone-dependent vision during aging.

Usage: Immunohistochemistry 1:1000

Related Products: Melanopsin Rabbit Polyclonal (Cat. #AB-N38)

Kelly SC, Nelson PT, Counts SE (2017) Featured Article: The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Targeting Trends 18

Related Products: Anti-DBH-SAP (Cat. #IT-03), Mouse IgG-SAP (Cat. #IT-18)

Read the featured article in Targeting Trends.

See Also:

• Kelly SC et al. The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Neuroscience 2016 Abstracts 786.11 / H7, 2016. Society for Neuroscience, San Diego, CA

Turnbull M, Coulson E (2017) Cholinergic basal forebrain lesion decreases neurotrophin signaling without affecting tau hyperphosphorylation in genetically susceptible mice. J Alzheimers Dis 55:1141-1154.. doi: 10.3233/JAD-160805

Summary: Alzheimer’s disease(AD) is a progressive, irreversible neurodegenerative disease that destroys memory and cognitive function. Aggregates of hyperphosphorylated tau protein are a prominent feature in the brain of patients with AD, and area major contributor to neuronal toxicity and disease progression. However, the factors that initiate the toxic cascade that results in tau hyperphosphorylation in AD are unknown. The authors investigated whether degeneration of basal forebrain cholinergic neurons (BFCNs) and/or resultant decrease in neurotrophin signaling cause aberrant tau hyperphosphorylation. Two-month-old male and female pR5 mice were infused with murine p75-SAP (Cat. #IT-16) at a concentration of 0.4 mg/ml or 0.4 mg/ml of control Rabbit IgG-SAP (Cat. #IT-35) using a 30G needle attached to a 5 ml Hamilton syringe and pump. The needle was lowered into the medial septum according to coordinates in a mouse brain atlas, and the toxin was infused at a rate of 0.4 ul/min (1.5 u total volume). The results reveal that the loss of BFCNs in pre-symptomatic pR5 tau transgenic mice results in a decrease in hippocampal brain-derived neurotrophic factor levels and reduced TrkB receptor activation. However, there was no exacerbation of the levels of phosphorylated tau or its aggregation in the hippocampus of susceptible mice. Furthermore the animals’ performance in a hippocampal-dependent learning and memory task was unaltered, and no changes in hippocampal synaptic markers were observed. This suggests that tau pathology is likely to be regulated independently of BFCN degeneration and the corresponding decrease in hippocampal neurotrophin levels, although these features may still contribute to disease etiology.

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

Kelly SC, Nelson PT, Counts SE (2016) The locus coeruleus: a potential link between cerebrovascular and neuronal pathology in Alzheimer’s disease. Neuroscience 2016 Abstracts 786.11 / H7. Society for Neuroscience, San Diego, CA.

Summary: Noradrenergic locus coeruleus (LC) neuron loss is a major feature of Alzheimer’s disease (AD). The LC is the primary source of norepinephrine (NE) in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex and hippocampus. Furthermore, LC-mediated NE signaling is thought to play a role in blood brain barrier maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease (CVD) and AD. However, the extent to which LC projection system degeneration occurs in the earliest stages of AD is not fully characterized to date. To address these issues, we analyzed LC tissue samples from University of Kentucky AD Center subjects who died with a premortem diagnosis of no cognitive impairment (NCI) and Braak stages 0-II at autopsy, NCI subjects with Braak stages III-V thought to be in a preclinical AD (PCAD) stage, and subjects with mild cognitive impairment (MCI) or mild AD (n = 5-6 cases/group). Paraffin-embedded pontine tissue blocks containing the LC were cut at 20µm, immunostained with tyrosine hydroxylase (TH, a marker for NE synthesis), and analyzed by stereology to estimate total LC neuron number (total number of neuromelanin-containing LC neurons) and the percentage of TH+ LC neurons. Preliminary analysis reveal a ~20% loss of both total and TH+ LC neurons in PCAD (p = 0.08), a ~30-35% loss of these neurons in MCI (p < 0.05), and a ~45-50% loss of total and TH+ neurons in AD (p < 0.01) compared to NCI. Studies were also performed to compare additional LC neuronal pathologies (phospho-tau, TDP-43, and 8dOHG) in the diagnostic groups. A substantial increase in 8dOHG and phospho-tau is observed in PCAD compared to NCI. The morphometric data will be correlated with postmortem neuropathologic and CVD variables (e.g., microinfarcts and cerebral amyloid angiopathy) to gauge the relationship between LC neurodegeneration and cerebral AD and vascular pathology. To model these relationships in vivo, we stereotactically lesioned LC projection neurons innervating the PFC, a major LC projection zone, in the TgF344-19 rat model of AD (6 months old) using the noradrenergic immunotoxin, dopamine-β-hydroxylase-saporin, or a control lesion (n = 8/group). Prior to sacrifice at 9 months, immunotoxin- and control-lesioned rats will be tested behaviorally on the Barnes maze task. Postmortem PFC will be analyzed for LC fiber innervation, NE and NE metabolite levels, CVD pathology and AD-like pathology. Taken together, these data will shed light on the multifactorial noradrenergic pathways contributing to neuronal and vascular pathologies during the onset of AD.

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

ATS Poster of the Year Winner. Read the featured article in Targeting Trends.

Leong CS, Maness EB, Baraki DI, Burk JA (2016) Effects of protein kinase C activation on attention deficits following loss of corticopetal cholinergic neurons. Neuroscience 2016 Abstracts 833.03 / HHH22 . Society for Neuroscience, San Diego, CA.

Summary: Alzheimer’s disease (AD) is a neurodegenerative dementia characterized by memory loss, cognitive impairment, and attention deficits. Damage to corticopetal cholinergic neurons originating in the basal forebrain is thought to contribute to the attention deficits. Recent evidence had identified G-protein decoupling at the M1 muscarinic acetylcholine receptor as well as decreased levels of protein kinase C (PKC) in rat AD models and the human AD brain. PKC is a signaling kinase that can affect neurite outgrowth, synaptic formation, and neurotransmitter release. PKC activation additionally may affect voltage-gated calcium currents. Previous research in this lab has shown that inhibition of PKC by chelerythrine chloride decreased signal detection in a sustained attention task. The present experiment evaluates the effect of PKC activation on sustained attention following loss of cortical cholinergic projections induced by infusions of 192 IgG-saporin into the basal forebrain. Male and female Sprague-Dawley rats were trained to discriminate between signals (illumination of a central panel light) and nonsignals (no panel light illumination) in a two-lever sustained attention task. Each rat received intraventricular infusions of the PKC activator bryostatin-1 (0, 0.5, 2.0, and 4.0pM) prior to testing. In the middle block of trials, a flashing houselight distracter was included to increase attentional demands. Compared to sham-lesioned animals, lesioned animals showed poorer signal detection in the distracter block of the task, but no differential effects of lesion on nonsignal trials. Distracter scores (initial block of trials with no distracter – distracter block) were calculated for each behavioral measure. For signal detection, there was a dose × group interaction (F(3,30) = 3.069, p = 0.043). Bryostatin-1 attenuated signal detection deficits in lesioned animals. Sham-treated animals showed decreased performance with increased bryostatin-1 dosage. Following the highest bryostatin-1 dose, there were no difference in signal detection between the sham and lesioned animals. The present results support the hypothesis that Bryostatin-1 can improve performance in a visual attention task following damage to corticopetal cholinergic neurons.

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

Maness EBL, Leong CS, Burk JA (2016) Effects of N-desmethylclozapine on attentional performance following loss of basal forebrain corticopetal cholinergic inputs. Neuroscience 2016 Abstracts 833.15 / HHH34. Society for Neuroscience, San Diego, CA.

Summary: Corticopetal cholinergic neurons play a vital role in attentional processing, and dysregulation of this system contributes to central nervous system disorders whose main attributes include an inability to engage in sustained attention, such as Alzheimer’s disease. The cholinergic muscarinic-1 (M1) receptor is known to be necessary for normal attentional processing. In general, there has been a trend towards supporting drugs that provide allosteric agonism of cholinergic receptors as an approach that may yield greater benefits than drugs that act at orthosteric receptor sites. There exists contention in the literature regarding the action of N-desmethylclozapine (NDMC), a partial M1-preferring agonist, that is thought to act at an allosteric site on the M1 receptor. The goal of the present experiment is to further evaluate NDMC’s activity at these sites in a lesion model of cholinergic dysfunction using an operant task assessing attentional capacity. After training in an attention-demanding task requiring differentiation between signal trials (500, 100, and 25ms illumination of a central panel light) and non-signal trials (no light illumination), Sprague Dawley rats received intrabasalis infusions of either saline or the cholinergic neurotoxin 192 IgG-saporin, and attentional performance was later measured following intracerebroventricular infusions of NDMC. In general, NDMC impaired attentional performance, particularly for lesioned animals. These findings suggest that NDMC may functionally decrease acetylcholine stimulation of M1 receptors or that the actions of NDMC at other receptor sites disrupt any beneficial effects of NDMC at the M1 receptor.

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