scholarly journals Evaluation of SAMP8 Mice as a Model for Sleep-Wake and Rhythm Disturbances Associated with Alzheimer’s Disease: Impact of Treatment with the Dual Orexin (Hypocretin) Receptor Antagonist Lemborexant

2021 ◽  
pp. 1-17
Author(s):  
Carsten T. Beuckmann ◽  
Hiroyuki Suzuki ◽  
Erik S. Musiek ◽  
Takashi Ueno ◽  
Toshitaka Sato ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Receptor Antagonist ◽  
Diurnal Rhythm ◽  
Rem Sleep ◽  
Running Wheel ◽  
Wheel Activity ◽  
Samp8 Mice ◽  
Senescence Accelerated Mouse

Background: Many patients with Alzheimer’s disease (AD) display circadian rhythm and sleep-wake disturbances. However, few mouse AD models exhibit these disturbances. Lemborexant, a dual orexin receptor antagonist, is under development for treating circadian rhythm disorders in dementia. Objective: Evaluation of senescence-accelerated mouse prone-8 (SAMP8) mice as a model for sleep-wake and rhythm disturbances in AD and the effect of lemborexant by assessing sleep-wake/diurnal rhythm behavior. Methods: SAMP8 and control senescence-accelerated mouse resistant-1 (SAMR1) mice received vehicle or lemborexant at light onset; plasma lemborexant and diurnal cerebrospinal fluid (CSF) orexin concentrations were assessed. Sleep-wake behavior and running wheel activity were evaluated. Results: Plasma lemborexant concentrations were similar between strains. The peak/nadir timing of CSF orexin concentrations were approximately opposite between strains. During lights-on, SAMP8 mice showed less non-rapid eye movement (non-REM) and REM sleep than SAMR1 mice. Lemborexant treatment normalized wakefulness/non-REM sleep in SAMP8 mice. During lights-off, lemborexant-treated SAMR1 mice showed increased non-REM sleep; lemborexant-treated SAMP8 mice displayed increased wakefulness. SAMP8 mice showed differences in electroencephalogram architecture versus SAMR1 mice. SAMP8 mice exhibited more running wheel activity during lights-on. Lemborexant treatment reduced activity during lights-on and increased activity in the latter half of lights-off, demonstrating a corrective effect on overall diurnal rhythm. Lemborexant delayed the acrophase of activity in both strains by approximately 1 hour. Conclusion: SAMP8 mice display several aspects of sleep-wake and rhythm disturbances in AD, notably mistimed activity. These findings provide some preclinical rationale for evaluating lemborexant in patients with AD who experience sleep-wake and rhythm disturbances.

scholarly journals Trimethylamine N-Oxide (TMAO) links peripheral insulin resistance and cognitive deficiencies in a senescence accelerated mouse model

2021 ◽  
Author(s):  
Manuel H. Janeiro ◽  
Elena Puerta ◽  
Maria Lanz ◽  
Fermin I. Milagro ◽  
Maria J Ramirez ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Insulin Resistance ◽  
Alzheimer's Disease ◽  
Neurodegenerative Diseases ◽  
Insulin Signaling ◽  
Samp8 Mouse ◽  
Cognitive Deficiencies ◽  
Samp8 Mice ◽  
The Brain ◽  
Senescence Accelerated Mouse

It has been established that ageing is the major risk factor for cognitive deficiency or neurodegenerative diseases such as Alzheimer's disease (AD) and it is becoming increasingly evident that insulin resistance is another factor. Biological plausibility for a link between insulin resistance and dementia is relevant for understanding disease etiology, and to form bases for prevention efforts to decrease disease burden. The dysfunction of the insulin signaling system and glucose metabolism has been proposed to be responsible for brain aging. Normal insulin signaling in the brain is required to mediate growth, metabolic functions, and the survival of neurons and glia. Insulin receptors are densely expressed in the olfactory bulb, the cerebral cortex and the hippocampus and regulate neurotransmitter release and receptor recruitment. In normal elderly individuals, reduced glucose tolerance and decreased insulin levels in the aged brain are typically observed. Furthermore, insulin signaling is aberrantly activated in the AD brain, leading to non-responsive insulin receptor signaling. The senescence accelerated mouse (SAMP8) mouse was one of the accelerated senescence strains that spontaneously developed from breeding pairs of the AKR/J series. The SAMP8 mouse develops early learning and memory deficits (between 6 and 8 months) together with other characteristics similar to those seen in Alzheimer's disease. The present project proposes the investigation of the missing link between aging, insulin resistance and dementia. Peripheral but not central insulin resistance was found in SAMP8 mice accompanied by cognitive deficiencies. Furthermore, a marked peripheral inflammatory state (i.e. significantly higher adipose tissue TNF-[alpha]; and IL6 levels) were observed in SAMP8 mice, followed by neuroinflammation that could be due to a higher cytokine leaking into the brain across a aging-disrupted BBB. Moreover, aging-induced gut dysbiosis produces higher TMAO that could also contribute to the peripheral and central inflammatory tone as well as to the cognitive deficiencies observed in SAMP8 mice. All those alterations were reversed by DMB, a treatment inhibits the transformation of choline, carnitine and crotonobetaine, decreaseing TMAO levels. The ever-increasing incidence of neurodegenerative diseases not only limits the life quality of the affected individuals and their families but also poses an enormous demand on the societies. Thus, it is instrumental to pursue novel promising approaches to prevent and treat it at the highest possible speed to rapidly translate them to clinical practice. From this point of view, data obtained from this project will be instrumental to validate the principle approach of microbial dysbiosis and increased TMAO secretion as a key link between aging, insulin resistance and dementia. Collectively, the proposed experiments ideally integrate the aim to promote a novel approach to improve the lives of those suffering from cognitive disturbances.

scholarly journals A UPLC-Q-TOF/MS-Based Metabolomics Study on the Effect of Corallodiscus flabellatus (Craib) B. L. Burtt Extract on Alzheimer’s Disease

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Yang-Yang Wang ◽  
Ning Zhou ◽  
Yan-Po Si ◽  
Zhi-Yao Bai ◽  
Meng Li ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Metabolite Profiling ◽  
Huperzine A ◽  
Control Group ◽  
Model Group ◽  
Metabolomics Study ◽  
Samp8 Mice ◽  
Senescence Accelerated Mouse ◽  
Tof Ms

A UPLC-Q-TOF/MS-based metabolomics study was carried out to explore the intervening mechanism of Corallodiscus flabellatus (Craib) B. L. Burtt (CF) extract on Alzheimer’s disease (AD). The AD model group consisted of senescence-accelerated mouse prone 8 (SAMP8) mice, and the control group consisted of senescence-accelerated mouse resistant 1 (SAMR1) mice. UPLC-Q-TOF/MS detection, multivariate statistical analysis, and pathway enrichment were jointly performed to research the change in metabolite profiling in the urine of AD mice. The result suggested that the metabolite profiling of SAMP8 mice significantly changed at the sixth month compared with SAMR1 mice of the same age, and the principal component analysis (PCA) score scatter plots of the CF group closely resembled those of the control and positive drug (huperzine A, HA) group. A total of 28 metabolites were considered potential biomarkers associated with the metabolism of beta-alanine, glycine, serine, threonine, cysteine, methionine, arginine, proline, and purines in AD mice. Furthermore, the CF group was clustered with the control and positive group and was clearly separated from the model group in the heat map. In conclusion, significant anti-AD effects were firstly observed in mice after treatment with the CF extract, and the urinary metabolomics approach assisted with dissecting the underlying mechanism.

Double-Blind, Controlled Phase II Study of a 5-HT6 Receptor Antagonist, SB-742457, in Alzheimer's Disease

2010 ◽  
Vol 999 (999) ◽  
pp. 1-12 ◽  
Author(s):  
Gareth Maher-Edwards ◽  
Marina Zvartau-Hind ◽  
A. Jacqueline Hunter ◽  
Michael Gold ◽  
Gillian Hopton ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Receptor Antagonist ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Double Blind

Circadian Rhythm Disturbance in Agitation of Alzheimer's Disease

2021 ◽  
Vol 29 (4) ◽  
pp. S111-S113
Author(s):  
John Outen ◽  
Adam Spira ◽  
Sarah Wanigatunga ◽  
Vadim Zipunnikov ◽  
Mark Wu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Rhythm Disturbance

scholarly journals Unique Sleep and Circadian Rhythm Dysfunction Neuroinflammatory and Immune Profiles in Alzheimer’s Disease with Mild Cognitive Impairment

2021 ◽  
pp. 1-6
Author(s):  
Jagan A. Pillai ◽  
James Bena ◽  
Lynn M. Bekris ◽  
Nancy Foldvary-Schaefer ◽  
Catherine Heinzinger ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Circadian Rhythm ◽  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Cerebrospinal Fluid Biomarkers ◽  
Circulating Markers

Sleep dysfunction has been identified in the pathophysiology of Alzheimer’s disease (AD); however, the role and mechanism of circadian rhythm dysfunction is less well understood. In a well-characterized cohort of patients with AD at the mild cognitive impairment stage (MCI-AD), we identify that circadian rhythm irregularities were accompanied by altered humoral immune responses detected in both the cerebrospinal fluid and plasma as well as alterations of cerebrospinal fluid biomarkers of neurodegeneration. On the other hand, sleep disruption was more so associated with abnormalities in circulating markers of immunity and inflammation and decrements in cognition.

24 hour cortisol circadian rhythm in Alzheimer's disease: Comparison with normal subjects

1994 ◽  
Vol 15 ◽  
pp. S10
Author(s):  
C.E. Rosenberg ◽  
J. Lee ◽  
D. Rowland ◽  
P.J. Whitehouse
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Circadian Rhythm ◽  
Normal Subjects

scholarly journals Musical Electroacupuncture May Be a Better Choice than Electroacupuncture in a Mouse Model of Alzheimer’s Disease

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Jing Jiang ◽  
Gang Liu ◽  
Suhua Shi ◽  
Zhigang Li
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Frontal Lobe ◽  
Morris Water Maze ◽  
Water Maze ◽  
Morris Water Maze Test ◽  
Maze Test ◽  
Model Of Alzheimer’S Disease ◽  
Samp8 Mice

Objectives. To compare musical electroacupuncture and electroacupuncture in a mouse model of Alzheimer’s disease.Methods. In this study, 7.5-month-old male senescence-accelerated mouse prone 8 (SAMP8) mice were used as an Alzheimer’s disease animal model. In the normal control paradigm, 7.5-month-old male SAMR1 mice were used as the blank control group (N group). After 15 days of treatment, using Morris water maze test, micro-PET, and immunohistochemistry, the differences among the musical electroacupuncture (MEA), electroacupuncture (EA), Alzheimer’s disease (AD), and normal (N) groups were assessed.Results. The Morris water maze test, micro-PET, and immunohistochemistry revealed that MEA and EA therapies could improve spatial learning and memory ability, glucose metabolism level in the brain, and Aβamyloid content in the frontal lobe, compared with the AD group (P<0.05). Moreover, MEA therapy performed better than EA treatment in decreasing amyloid-beta levels in the frontal lobe of mice with AD.Conclusion. MEA therapy may be superior to EA in treating Alzheimer’s disease as demonstrated in SAMP8 mice.

P4-387: 5-HT6 receptor antagonist SB-742457 as a novel cognitive enhancing agent for Alzheimer's disease

2006 ◽  
Vol 2 ◽  
pp. S631-S632 ◽  
Author(s):  
Aaron T.T. Chuang ◽  
Andrew Foley ◽  
Perdita L. Pugh ◽  
David Sunter ◽  
Xin Tong ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Receptor Antagonist
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