الفهرس 
INTRODUCTIONOnly 14 pages are availabe for public view
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Abstract
Alzheimer’s disease (AD) is the most common cause of dementia among neurodegenerative diseases. It is an irreversible, progressive brain disease that slowly destroys memory and thinking skills, and even¬tually even the ability to carry out the simplest tasks. In most people with Alzheimer’s, symptoms first appear after age 60 .
The neuropathological hallmarks of AD are the presence in the brain of extracellular senile plaques and intracellular neurofibrillary tangles, along with neuronal loss. As more and more plaques and tangles form in particular brain areas, healthy neurons begin to work less efficiently. Then, they lose their ability to function and communicate with each other, and even¬tually they die. This damaging process spreads to a nearby structure, called the hippocampus, which is essential in forming memories.
Senile plaques mainly consist of fibrils of 39-42 (43) amino acid amyloid β-peptide (Aβ) that are surrounded by dystrophic neurites and reactive glial cells. The Aβ peptide itself is derived from the processing of a larger precursor protein known as the amyloid precursor protein (APP).
Three secretases, α, β, and γ, are involved in APP processing. There are two APP processing pathways; α- and γ-secretase (non–amyloidogenic) and β- and γ-secretase (amyloidogenic) pathways. Sequential cleavage of APP by β-and γ-secretases yields either Aβ1–40 or Aβ1–42 peptide; whereas sequential α- and γ- secretase cleavage of APP does not generate Aβ. It is unknown which factor(s) determines the switch between the two APP processing pathways .
There is a large body of evidence suggesting that increased levels of plasma membrane cholesterol promote the amyloidogenic processing of the APP and thereby contribute to the key series of molecular (proteolytic) events widely believed to underlay with the etiology of AD.
Long-chain omega-3 fatty acids are important building blocks for neuronal cell membranes, and they have key roles in brain development, neurotransmission and possessing neuroprotective properties.
The PUFAs incorporated into the neuronal membrane also increase synaptic protein expression, strengthening the hippocampal synaptic plasticity. This is modulated by transcription factors such as peroxisome proliferator activated receptors (PPARs). The role of PPARs in the CNS is mainly been related to lipid metabolism, however, these receptors, especially PPAR-γ, have been implicated in neural cell differentiation and death as well as in inflammation and neurodegeneration, including AD.
The present study aimed to elucidate whether omega -3 fatty acids supplementation had a protective and ameliorative effect in enhancing cognitive ability and elucidate the role of PPAR -γ in sporadic AD conducted on a modified animal model of AD.
To achieve this forty adult male Spargue Dawley rats weighting (150-200 gm) were used in the present study. Rats were randomly divided into three groups ;
1. Group I: Normal control group (n =10).
2. Group II: An Alzheimer’s disease positive control (AD group) (n =10).
The rats were maintained on a high cholesterol diet and supplemented with trace levels of copper sulphate (6 mg/L) in their drinking water for 2 months until development of Aβ deposits in the hippocampal region of the brain, as confirmed by histopathological studies .
3. Group III: Rats were supplemented with omega-3 fatty acids, 40 mg/ kg daily (n=20).
This group were randomly subdivided into 2 subgroups, each 10 rats ;
Subgroup A: Rats were supplemented with omega -3 fatty acids for 6 weeks pre AD induction.
Subgroup B: Rats were supplemented with omega -3 fatty acids for 6 weeks post AD induction.
At the end of the experiment rats underwent object recognition test (ORT) to asses cognitive function of the rats .After behavioral procedures ,histopathological studies were performed to establish the development of Aβ deposits in the hippocampal region of the brain. Serum and hippocampal tissue samples were taken for determination of : serum lipid profile (Triglycerides, total cholesterol, Low density lipoprotein-cholesterol (LDL-cholesterol), and High density lipoprotein- cholesterol (HDL- cholesterol)), Brain tissue Lipid content ,serum α- and γ-secretases , hippocampal tissue α- and γ-secretases and PPAR-γ.
The results of the ORT indicated that the cognitive functions were disrubted in response to AD induction as discrimination index (DI) was significantly decreased compared to normal control group. Omega-3 fatty acids supplementation pre and post AD induction improved learning and memory as the DI was increased compared to AD control group. Moreover, the results of the present study reported that the effect of supplementation with omega -3 fatty acids was more pronounced in the rats supplemented with omega -3 fatty acids pre AD induction indicating a protective role against development of AD.
Also, the present study revealed that all parameters of serum lipid profile were disturbed in response to induction of AD. AD induction significantly increased the levels of serum triglycerides and total cholesterol. On the other hand supplementation with omega -3 fatty acids pre AD induction significantly decreased the levels of cholesterol and triglycerides, but the effect was more pronounced in the rats supplemented with omega -3 fatty acids pre AD induction.
Additionally , the results demonstrated that serum and hippocampal α-secretase levels were slightly decreased in response to AD. Omega-3 fatty acids pre and post AD induction showed a slightly improvement in serum and hippocampal α-secretase levels.
Moreover, the results demonstrated that serum and hippocampal γ-secretase levels were significantly increased in response to AD induction. Omega-3 fatty acids pre and post AD induction reduced the activity of serum and hippocampal γ-secretase.
Furthermore, the results reported that the hippocampal PPAR-γ levels were significantly increased in response to AD induction. Omega-3 fatty acids pre and post AD induction significantly reduced the levels ,this indicates that the effect of omega-3 fatty acids supplementation with was more pronounced in the rats supplemented with omega-3 fatty acids pre AD induction.
from the results of the present study we can conclude that:
1) DHA has a typical pleiotropic effect; DHA-mediated Aβ reduction is not the consequence of a single major mechanism, but is the result of combined multiple effects:
• DHA directs amyloidogenic processing of APP toward nonamyloidogenic processing, effectively reducing Aβ release.
• Increases protein stability of α-secretase resulting in increased nonamyloidogenic processing.
• Decreases γ-secretase activity
• Alters the cholesterol distribution in plasma. In the presence of DHA, cholesterol shifts from raft to non-raft domains..
2) The PUFAs incorporated into the neuronal membrane also increase synaptic protein expression, strengthening the hippocampal synaptic plasticity .This is modulated by transcription factors such as peroxisome proliferator activated receptors (PPARs) .
3) There is a relationship between gene expression of PPARs and supplementation with omega-3 fatty acids. The increase in omega-3 PUFAs of the brain may lead to increased PPAR gene expression.
4) PPAR-γ is expressed in the brain at the low levels under physiological conditions.
5) PPAR-γ has a prominent role in the regulation of central nervous system inflammation and neuroprotection leading to improvement in cognitive performance.
6) The anti-inflammatory and anti-apoptotic role of PPARs could play important functions in the improvement of the mental ability of the brain.