Alzheimer’s disease (AD) is a gradually progressing neurodegenerative disorder characterized by alterations in brain structure and functions. The characteristic symptoms observed in AD include a progressive decline in cognitive functions and behavioral alterations such as difficulties in learning and memory, anxiety and depression. In some cases increase life span may produce various age-related disorders and brain aging is a threat for many neurodegenerative disorders. AD has been considered as a consequence of an accelerated aging process in the CNS because the underlying pathological mechanism of AD highly resembles with aged brain. Many environmental, genetic and physiological factors have been implicated in the pathology of AD. A close association between aluminium (Al) and etiology of various neurodegenerative diseases has been well established. Epidemiological studies have connected elevated levels of Al in brain with AD development. Previous studies have strongly linked Al accumulation in the brain and progression of AD like symptoms such as aggregation of tau protein in the form of neurofibrillary tangles and accumulation of insoluble amyloid-β (Aβ) proteins as Aβ plaques. Currently available medication for the treatment of AD such as acetylcholinesterase (AChE) inhibitors can only offer symptomatic relief with various side effects. Such medications can only work on intact neurons, but cannot stop the ongoing neurodegenerative process. Hence, there is an intense need for development of therapeutic strategy that can not only improve brain functions but can also prevent neurodegeneration. Therefore, the main goal of current work is to determine the beneficial and effective strategy that can work against the neurodegenerative process associated with AD. Apart from determining the safe and effective therapeutic strategy, the present thesis aimed at gaining insight into the underlying neurodegenerative mechanism of AD. To understand the pathological mechanism of AD, AD-like animal model was developed by combined administration of aluminium chloride (AlCl3) and D-galactose (D-gal). Initially the compounds were administered separately and their effects were investigated, then their combined effects were determined. Various behavioral, biochemical, neurochemical and histopathological analysis were done to understand the pathological mechanism associated with AD. D-gal induced accelerated senescence was used to develop aging model for brain. It was found that administration of D-gal significantly altered behavioral, biochemical and neurochemical responses in rats that were found to be similar to those reported earlier in normal aged brain, and brain oxidative stress was found to be the main causative factor of observed alterations. Al has been considered as a potential cause of AD since, when it was first observed that specific regions of AD xvii brain contain high levels of Al than age-matched controls. The thesis was then focused on determining the neurotoxic effect Al on brain and associated functions mainly cognitive functions. Acute administration of AlCl3 resulted in noticeable behavioral deficits. Cognitive deficits and neuropsychiatric disturbances were evident in AlCl3 injected rats. Marked antioxidant enzymes, cholinergic, serotonergic and dopaminergic dysfunctions were significantly observed following Al administration. Degenerated neurons were evident in hippocampus and cortex in brain treated with AlCl3.The observed effects may be due to pro-oxidant nature of Al and its participation in free radical mediated oxidative stress and cellular injury. D-gal mimics natural aging process while Al promotes neurodegeneration by acting as a neurotoxin.With the aim of gaining better understanding of neurodegenerative mechanism of AD combined effects of AlCl3 and D-gal were then investigated and it was found that AlCl3+D-gal significantly induced AD-like behavioral alterations. Rats cognitive abilities were significantly impaired in AD-like model rats and various neuropsychiatric symptoms were also found. AlCl3+D-gal significantly altered brain neurochemistry and redox status, indicating oxidative stress as a potential contributing factor in the underlying neuronal degenerative process in AD. Oxidative stress is one of the main causative factors of AD and AD associated characteristics such as behavioral, neurochemical and biochemical alterations are believed to be originated from free radical mediated oxidative stress. Extensive evidence supports the fact that oxidative stress and alteration in antioxidant enzyme activities in brain is highly involved in the neurodegenerative mechanism of AD and together with other causative factors age associated cognitive problems have been strongly linked to oxidative stress. Considering oxidative stress as a pathological factor in AD, it can be hypothesized that supplementation of antioxidant might be protective strategy against the neurodegenerative mechanism. Reactive oxygen species (ROS) produced during metabolic pathways cause progressive damage over a lifetime. Free radicals have harmful effects on biological system, induce damage to important biomolecules, accelerate disease progression and shorten lifespan, whereas antioxidant therapy is supposed to attenuate these effects. Even under normal physiological conditions a certain amount of oxidative damage takes place. However, it is suggested that the rate of oxidative damage increases with aging process as the functions of repairing mechanisms and antioxidant defense system decreases. Free radical mediated neurotoxicity is a leading cause of neurodegenerative disorders and neurodegeneration due to oxidative stress can produce cognitive dysfunctions. In neurodegenerative disorders the brain regions that are more susceptible to neurodegenerative mechanism are also reported to have xviii increased oxidative stress and lowered activity of antioxidant defense system showing a strong link between oxidative stress and neuronal death. Polyphenols are characteristic compounds from medicinal plants play an imperative part in maintaining the chemical balance of brain. Polyphenols can potentially ameliorate the adverse effects of aging on brain. They are natural antioxidants that are beneficial against neurodegenerative mechanism by providing a variety of important biological functions including suppression of free radicals, inactivation of inflammatory pathways, modulation in enzyme activities and beneficial effects on gene expression and intracellular signaling mechanisms. Flavonoids and curcuminoids are naturally occurring polyphenols that display a variety of therapeutic importance against oxidative stress. In order to evaluate potential role of polyphenols in neurocognitive functions and prevention against oxidative stress, a comparative investigation was designed. Young rats were orally treated with naringenin (NAR), curcumin (CUR) and quercetin (QUE) to determine their effects on brain functions. Treatment of NAR, CUR and QUE significantly enhanced cognitive functions in terms of learning acquisition, memory retention and reconsolidation and prevented memory extinction, they also prevented the oxidative stress by increasing brain antioxidant defense system. Among the tested flavonoids the memory improving and retaining effects of NAR was more potent. To test the main hypothesis, rats were orally pre-treated with NAR and were then exposed to AlCl3+ D-gal to develop AD-like animal model. On the basis of the cholinergic hypothesis of AD, scopolamine (SCO) and donepezil (DPZ) were used as standard drugs to further strengthen the hypothesis. Results showed that NAR pre-treatment significantly protected behavioral disturbances in rats. Observed effects might be due to improved neurotransmission, prevention against histopathological alteration and antioxidant defense system. In DPZ group, rats showed improved cognitive and cholinergic functions but neuropsychiatric functions were remained impaired and marked histopathological alterations were observed. NAR not only prevented AlCl3+D-gal induced AD-like symptoms but also significantly prevented SCO induced cholinergic dysfunctions in rats. Findings from this study strongly suggested neuroprotective and cognitive enhancing functions of NAR. NAR may be considered as a neuroprotective compound in the future for therapeutic management of AD. This work provides biological evidence supporting the usefulness of these polyphenols in daily life for the improvement of cognitive abilities and hence may have a potential role in the management of dementia and related disorders. These polyphenols are naturally available in many fruits and vegetables. Consumption of polyphenols such as NAR may delay or even prevent the neurodegenerative mechanism and associated disorders." xml:lang="en_US