Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

Alzheimer’s disease is a progressive cognitive dysfunction. However, pharmacological treatments are symptomatic and have many side effects, opening the opportunity to alternative medicine. This study investigated the antiamnesic effect of the aqueous extract of Ziziphus jujuba on D-galactose-induced working memory impairment in rats. Impairment of working memory was induced by subcutaneous (s.c.) injection of D-galactose (350 mg/kg/day) to rats for 21 days. These animals were then subjected to object recognition and Y-maze tests. Rats with confirmed memory impairment were treated per os (p.o.) with tacrine (10 mg/kg), aspirin (20 mg/kg, p.o.), extract (41.5, 83, and 166 mg/kg, p.o.), and distilled water (10 mL/kg, p.o.) daily for 14 days. At the end of the treatments, alteration in working memory was assessed using the above paradigms. Afterward, these animals were euthanized, and cholinergic, proinflammatory, and neuronal damage markers were analyzed in the prefrontal cortex. Rats administered D-galactose and treated with distilled water had impaired working memory (evidenced by decreased time spent on the novel object and discrimination index) and decreased spontaneous alternation in the Y-maze. D-galactose also decreased the levels of acetylcholinesterase and acetylcholine and increased the level of glial fibrillary acidic protein, ionized calcium-binding adapter molecule 1, tumor necrosis factor-alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and interferon-gamma (IFN-γ). Treatment with the extract (166 mg/kg) reversed the time spent on the novel object and the discrimination index. It equally increased the percentage of spontaneous alternation. Neurochemical analysis revealed that the extract markedly alleviated acetylcholinesterase activity and neuroinflammation. These observations were corroborated by the reduction in neuronal loss. Taken together, these results suggest that Ziziphus jujuba aqueous extract possesses an antiamnesic effect. This effect seems to involve cholinergic and anti-inflammatory modulations. This, therefore, claims using this plant in the treatment of dementia in Cameroon subject to further studies and trials.

show abstract

“…In AD patients, the activity of AchE is significantly decreased [62]. Similar patterns were found in aged rodents [62].…”

Section: Discussionsupporting

confidence: 58%

“…In AD patients, the activity of AchE is significantly decreased [ 62 ]. Similar patterns were found in aged rodents [ 62 ]. AchE causes the degradation of Ach which produces cholinergic deficits.…”

Section: Discussionmentioning

confidence: 99%

Ziziphus jujuba (Rhamnaceae) Alleviates Working Memory Impairment and Restores Neurochemical Alterations in the Prefrontal Cortex of D-Galactose-Treated Rats

Kandeda

Nguedia

Ayissi

et al. 2021

Evidence-Based Complementary and Alternative Medicine

View full text Add to dashboard Cite

show abstract

“…Additional approaches suggested the cholinergic projection from medial septum had increased activity and increased expression of the rate-limiting enzyme for acetylcholine synthesis, the acetylcholinesterase (Kam et al, 2016). The data suggested it was timely to reconsider the well-established idea that the medial septal cholinergic neurons play a critical role in AD (Davies and Maloney, 1976; Ferreira-Vieira et al, 2016; Mufson et al, 2008; Parent et al, 2013; Shiozaki et al, 2001; Stepanichev, 2017; Sultzer, 2018). That is, early in life in Tg2576 mice there was increased excitability manifested by IIS, and cholinergic dysfunction contributes (Kam et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

Alcantara‐Gonzalez

Chartampila

Scharfman

2020

Preprint

View full text Add to dashboard Cite

It has been reported that hyperexcitability occurs in a subset of patients with Alzheimer's disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD mouse models.

show abstract

“…The strong involvement of the cholinergic circuits in age-related brain functional deterioration has led to the development of cholinergic hypothesis of geriatric cognitive impairments [18,[70][71][72][73]. In normal aged brains, loss of cholinergic neurons, depletion of ACh, reduced ChAT activity, and declines in the densities of muscarinic and nicotinic ACh receptors have been reported [12,13,18,19,58,72,73]. Based on positron emission tomography, Albin et al [74] reported region-specific declines in VAChT binding sites in the cortex and striatum in the aged brain.…”

Section: Discussionmentioning

confidence: 99%

Preventive effects of bone marrow-derived mesenchymal stem cell transplantation in a D-galactose-induced brain aging in rats

et al. 2022

View full text Add to dashboard Cite

Aging is a complex process accompanied by numerous morphological, functional, and metabolic impairments in the brain, and a critical risk factor involved in the increasing incidence of neurodegenerative diseases. Few studies have evaluated the efficacy of different sources of mesenchymal stem cells (MSCs) in ameliorating the early morphological and functional alterations in the aging brain. This study, for the first time, evaluated the potential efficacy of intravenous injection of bone marrow-derived mesenchymal stem cells (BMMSCs) in a D-galactose-induced rat model of brain aging.BMMSCs (1 × 10 6 ) were intravenously injected into brain aging model rats once every two weeks for 8 weeks. The transplanted cells survived and migrated to the brain, and differentiated into astrocytes and neurons, including choline acetyltransferase neurons.BMMSC transplantation improved locomotor activity and cognitive functions, restored cholinergic system function, protected atrophic cholinergic neurons in the basal forebrain, induced antioxidative effects and restored neurotrophic factors, and modulated 1 hippocampal synaptic plasticity by upregulating PSD95 and Egr1 expression. Our findings demonstrated the efficacy of BMMSC injection in an aging rat model and suggest that these cells may be developed into an effective cell therapy for the aging brain.

show abstract

Cholinergic degeneration in early stages of Alzheimer’s disease: Loss of cholinergic phenotype or loss of cells?

Cited by 5 publications

References 65 publications

Ziziphus jujuba (Rhamnaceae) Alleviates Working Memory Impairment and Restores Neurochemical Alterations in the Prefrontal Cortex of D-Galactose-Treated Rats

Ziziphus jujuba (Rhamnaceae) Alleviates Working Memory Impairment and Restores Neurochemical Alterations in the Prefrontal Cortex of D-Galactose-Treated Rats

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer’s disease neuropathology and atypical effects of the cholinergic antagonist atropine

Preventive effects of bone marrow-derived mesenchymal stem cell transplantation in a D-galactose-induced brain aging in rats

Contact Info

Product

Resources

About