الفهرس 
Review of literatureOnly 14 pages are availabe for public view
 |  | from | 190 |  |  |
| | | from | 190 | | |
Abstract
Alzheimer’s disease (AD) is a complex progressive neurodegenerative and dementing disorder that is only clinically diagnosed at the end stage. AD is a leading cause of dementia, causing progressive loss of memory and cognition and affecting 46.8 million people globally.
The hallmarks of this disorder are the extracellular aggregation of amyloid β (Aβ) peptides (Aβ plaques) in senile plaques (SP) and the intracellular deposition of hyperphosphorylated tau protein (NFT) in the hippocampus and neocortex . Many risk factors have been associated with AD including those related to aging, genes, metals, traumatic brain injury, diet, vascular factors, the immune system, and exposure to infectious agents.
Aluminum is a widespread chronic neurotoxin thus exposure to aluminum chloride leads to the accumulation of intermediary toxic compounds such as hydrogen peroxide and hydroxyl radicals, which may mediate the toxicity of aluminum. Also the activities of antioxidant enzymes such as superoxide dismutase, catalase, and glutathione peroxidase are decreased, whereas xanthine oxidase is increased following exposure to aluminum chloride .It is stated that aluminum, a well-established neurotoxicant, owing to its simple entry and retention in the central nervous system, is implicated in the etiology of (AD).
Quercetin is one of the most potent plant origin antioxidants and is one of the most prevalent flavonoids found in edible plants. Numerous biochemical and pharmacological activities, such as free-radical scavenging, have been reported to Q as well as it affects the immune and inflammatory cell activities, it may have benefits in AD by alleviating age associated cell damage caused by metabolic production of reactive oxygen species (ROS). Quercetin may use multiple neuroprotection mechanistic targets for AD, including the downstream regulation of oxidative stress and neuroinflammation, contributing to the direct protection of neurons, AChE enzymes inhibition and increasing the level of acetylcholine and decreasing the phosphorylation of Tau and Aβ aggregation, tumor necrosis factor-α (TNFα), interleukin-1β (IL-1β), and interleukin-6 (IL-6). .Moreover, it has inhibitory effects on the pathways of the JNK, PI3K/Akt, and betasecretase1 (BACE1) enzyme activity.
This work aimed to investigate the role of Q in the treatment and protection of AlCl3-induced AD rats through exploring the molecular mechanisms underlying its therapeutic and neuroprotective properties. Therefore, this study was conducted in two independent experiments; experiment I (effect of post treatment with quercetin) and experiment II (Coadministration of AlCl3 with quercetin).
In this study, 96 male Wistar rats were subjected to two experiments; experiment I in which the rats were distributed into; a normal control group which was induced with saline for 56 days , two quercetin doses groups that is orally administrated with Q (25 and 50 mg/kg) for 28 days after induction with saline for 28 days, AD group, that is IP administrated with AlCl3(50 mg/kg) for 28 days followed by saline for 28 days, and the treated groups :AlCl3 followed by Q25, and AlCl3 followed by Q50 that is orally administrated with Q (25 and 50 mg/kg) for 28 days after induction with AlCl3 for 28 days, as well as, experiment II that divided into normal control (NC) group , two quercetin doses (both 25 and 50 mg/ kg) groups which are orally administrated with Q by gastric intubation, AlCl3 (AD) group that IP administrated with AlCl3 , co-administration with AlCl3 + Q25 group, and co-administration with AlCl3 + Q50 group that are IP administrated with AlCl3 followed by (after 1-15 min) oral administration with Q for 56 successive days. Behavioral tests, histopathology study, gene expression assessmentcontain, and biochemical studies were used to assess the efficacy of quercetin.
The results of experiment 1 showed that Administration of Q especially the high dose (Q50) to AlCl3-induced AD rat model attenuated behavioral deficits, improved cholinergic and dopaminergic dysfunctions, and diminished insoluble amyloid β (Aβ) plaques aggregation in the hippocampus. These ameliorative effects of Q were associated with down-regulation of APP, BACE1, APH1, and PSEN1 and up-regulation of ADAM10 and ADAM17 gene expression levels in the hippocampus. Moreover, experiment 2 resulted in; the co-administration of quercetin (50 mg /kg) with AlCl3 having a significant effect on learning and memory deficits via decreased eosinophilic plaques and β-amyloid plaques deposits and restore the activity of Acetylcholine esterase (AchE) and dopamine (DA). Furthermore, AlCl3 + Q50 group resulted in significantly decreased levels of amyloid precursor protein (APP), β-amyloid converting enzyme 1 (BACE1), and Presenilin I (PSEN1) and increased the expression of ADAM17 in the hippocampus tissue compared to the AlCl3 group. In conclusion, the current study may explain the mechanism of Q by two separate experiments to diminish Aβ aggregation in the hippocampus based on the stage of Alzheimer’s disease as well as the dose and duration of Q in the AlCl3-induced AD rat model. The first one, the treatment experiment, in the mild AD, Q can target both the non-amyloidogenic and amyloidogenic pathways by up-regulating the expression of alpha secretase genes(ADAM 10 and ADAM 17) as well as down-regulating beta and gamma secretases (APP, BACE-1, PSEN1, and APH1) gene expression leading to protection of the hippocampus from the accumulation of Aβ plaques. The second, the experiment of protection, in late AD, Q could inhibit the amyloidogenic pathway via down-regulating APP, BACE-1, PSEN1, and APH1 gene expression along with increased the expression level of ADAM 17 that is involved in many pathways such as Notch pathway that can affect Aβ plaques aggregation. We suggest that ADAM10 and ADAM17 activation could be potential therapeutic targets for Alzheimer’s disease in order to slow disease progression and improve cognitive impairment. Additionally, future clinical trials using quercetin as a neuroprotective medicine should be conducted to investigate its ability to prevent the onset of AD.
6. Recommendations
We recommended that
• Integrative studies should be carried out to explore the molecular mechanism of quercetin against AD via regulation of the amyloidogenic and non-amyloidogenic pathway
• Future clinical trials of quercetin as therapeutic and neuroprotective agents could be evaluated as potentially preventing the development of early-stage Alzheimer’s disease, which has been cited as the main concern related to Alzheimer’s disease.
• Individuals should increase the amount of quercetin in daily food sources, because it has proven its effectiveness as a protective and therapeutic agent against Alzheimer’s disease.