الفهرس 
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Abstract
Dementia is a progressive disorder leading to cognitive decline involving one or more cognitive abilities as memory, visuospatial abilities and language which is severe enough to interfere with the person’s ability to perform daily activities. The etiology of dementia is complex and multifactorial, where several not fully confirmed theories describe its pathogenesis. Caveolin-1 (cav-1) is an integral membrane protein which is essential for the formation of caveolae. It is involved in caveolae mediated endocytosis, cholesterol homeostasis and signal transduction. Cav-1 could help in the production of amyloid beta (Aβ) as it stimulates the proteolysis of amyloid precursor protein (APP) through activation of β-secretase enzyme. Cellular senescence is a permanent cell cycle arrest occurring in response to various stressful stimuli including telomere attrition, DNA damage and oxidative stress. It leads to a state of chronic inflammation called inflammaging which is the main risk factor of age-related diseases. Senescence associated beta galactosidase (SA-β-gal) is the most used biomarker to detect senescent cells. It catalyzes the hydrolysis of terminal β-linked galactose residues in proteoglycans, glycoproteins, and glycolipids. Nuclear receptor binding SET domain protein 2 (NSD2) is a histone methyltransferase that catalyzes mono and dimethylation of lysine residue 36 on histone H3 (H3K36). It is an epigenetic regulator which leads to active transcription of genes responsible for cell cycle progression, thus preventing cellular senescence. group. Dementia is a progressive disorder leading to cognitive decline involving one or more cognitive abilities as memory, visuospatial abilities and language which is severe enough to interfere with the person’s ability to perform daily activities. The etiology of dementia is complex and multifactorial, where several not fully confirmed theories describe its pathogenesis. Caveolin-1 (cav-1) is an integral membrane protein which is essential for the formation of caveolae. It is involved in caveolae mediated endocytosis, cholesterol homeostasis and signal transduction. Cav-1 could help in the production of amyloid beta (Aβ) as it stimulates the proteolysis of amyloid precursor protein (APP) through activation of β-secretase enzyme. Cellular senescence is a permanent cell cycle arrest occurring in response to various stressful stimuli including telomere attrition, DNA damage and oxidative stress. It leads to a state of chronic inflammation called inflammaging which is the main risk factor of age-related diseases. Senescence associated beta galactosidase (SA-β-gal) is the most used biomarker to detect senescent cells. It catalyzes the hydrolysis of terminal β-linked galactose residues in proteoglycans, glycoproteins, and glycolipids. Nuclear receptor binding SET domain protein 2 (NSD2) is a histone methyltransferase that catalyzes mono and dimethylation of lysine residue 36 on histone H3 (H3K36). It is an epigenetic regulator which leads to active transcription of genes responsible for cell cycle progression, thus preventing cellular senescence. Sialic acids are a family of 9 carbon acidic sugars which are found as the terminal residues in the oligosaccharide chains of glycolipids and glycoproteins. N-acetyl neuraminic acid is the most common sialic acid in humans. Sialic acid plays an essential role in different physiological and pathological processes such as cellular recognition, mediating viral and bacterial infections and tumor growth. Genistein (GE) is an isoflavone found abundantly in soybeans. It is a phytoestrogen with structural similarity to estrogen. It has a multimodal action as an anti-oxidant, anti-inflammatory, anti-cancer and anti-diabetic. It has also a neuroprotective effect to promote brain health through different mechanisms including attenuation of neuroinflammation, reduction of oxidative stress and promotion of growth factor signaling. Aim of the work: The aim of the present study is to investigate the relationship between caveolin-1, NSD2, cellular senescence and scopolamine induced dementia. It also aims to elucidate the neuroprotective and memory enhancement effects of genistein on scopolamine induced dementia. Materials and Methods: The present study was carried out on 40 male mice divided randomly into four equal groups 10 mice each: group I (Control group): Mice received distilled water orally during the experiment period. group II (Scopolamine group): Mice received distilled water orally for 14 days. Then, scopolamine injected intraperitoneally at a dose of (1 mg/kg) for 7 consecutive days. group III (Genistein/Scopolamine group): Mice received oral pretreatment with genistein at a dose of (15 mg/kg) in 0.5 ml dimethyl sulfoxide (DMSO) for 14 days before intraperitoneal injection of scopolamine (1 mg/kg) once daily for 7 consecutive days. The overall period for genistein administration was 21 consecutive days. group IV (Donepezil/Scopolamine group): Mice received oral pretreatment with donepezil at a dose of (1.60 mg/kg) for 14 days before intraperitoneal administration of scopolamine at a dose of (1 mg/kg) once daily for 7 consecutive days. The overall period for donepezil administration was 21 consecutive days. All studied groups were submitted to specific biochemical investigations including: A) Brain tissue homogenates: • Estimation of caveolin-1 level by ELISA (Enzyme Linked Immunosorbent Assay). • Colorimetric assay of beta galactosidase activity. • Estimation of NSD2 level by ELISA. B) Serum samples: • Colorimetric assay of serum level of sialic acid. Behavioral test: object location recognition test (OLR): Before scopolamine injection the OLR test was done, and it revealed that mice were of normal cognitive functions. Then, at the end of the 3rd week, the second, third and fourth groups were submitted to the OLR test half an hour after scopolamine administration. Also, the OLR test was done for the first group at the end of the 3rd week. The OLR test was used to evaluate the short-term, spatial object recognition memory. The attained results revealed the following: Scopolamine group (group II) showed a statistically significant increase of caveolin-1 level, activity of beta galactosidase and serum sialic acid level as compared to the control group. Also, there was a significant decrease in NSD2 level and discrimination index of object location recognition test in scopolamine group (group II) as compared to the control group. On the other hand, there was a statistically significant decrease of caveolin-1 level, activity of beta galactosidase and serum sialic acid level in genistein/scopolamine group (group III) and donepezil/scopolamine group (group IV) when compared to scopolamine group (group II). In addition, there was a significant increase of NSD2 level and discrimination index in genistein/scopolamine group (group III) and donepezil/scopolamine group (group IV) when compared to scopolamine group (group II).