Background Dementia is a leading cause of disability and dependency in elderly people, generating significant physical, psychological, and financial challenges for patients, caregivers, and healthcare systems worldwide. For Alzheimer’s disease (AD), the most common form of dementia, established treatments such as Acetyl-Cholinesterase Inhibitors (AChE) have proven to be marginally beneficial, but side effects remain. Alternatively, a standardized preparation of Ginkgo Biloba Extract (EGb-761) is a popular herbal medicine used globally and widely available in Hong Kong. This paper reviews and synthesizes the effectiveness of EGb-761 in the treatment of AD compared to placebo and AChE treatments. Methods A systematic search was performed using PubMed, ProQuest, and Google Scholar to identify all relevant randomized controlled studies in English that examined the effectiveness of EGb-761 on individuals with AD. The studies, based on expert consensus, had to have a minimum duration of 22 weeks and one of two primary outcome measures: 1. cognitive functioning, 2. functional ability in activities-of-daily-living (ADL). A secondary outcome measure, safety (drop-out rate from adverse events), was also evaluated. Quality was assessed based on indicators derived from the CONSORT 2010 checklist. Findings Ten randomized controlled trials from eight countries, with participants ranging from mild to severe AD were included. Of the ten studies, eight compared EGb-761 with placebo, three compared EGb-761 head-to-head with an AChE (two with Donepezil, one with Rivastigmine), and one compared EGb-761 and AChE stand-alone treatment with combined treatments (EGb-761 + AChE). Overall results on cognitive and functional improvements were mixed. Of the studies that demonstrated a positive association, the clinical significance is questionable. Conclusions Although results were inconsistent, EGb-761’s safety appears to be acceptable. In Hong Kong, given the widespread availability, popularity and perceived safety of EGb-761, the population needs appropriate guidance and support from the government to safeguard quality and increase awareness of potential drug-herb interactions. Concurrently, with AChE becoming an increasingly established treatment for AD, more head-to-head studies on EGb-761 and AChE on the local population are needed to increase understanding and public awareness. / published_or_final_version / Public Health / Master / Master of Public Health

Alzheimer's disease has become one of the most common diseases jeopardizing the health of the human being. The main pathological feature of AD is the accumulation of Aβ in the brain to form senile plaques. Therefore, it is of great significance to develop new and efficient drugs targeting at amyloid-β for the detection, diagnosis and therapeutics for Alzheimer's disease. Xanthohumol (Xn) naturally presents in hops (Humulus lupulus L). Studies have shown that it has anti-lipoperoxidative, anti-inflammatory, anti-proliferative activities, antiangiogenic and antioxidant effects, which further illustrates its potential therapeutic for AD. However, the bio-incompatibility and blood-brain barrier impermeability of Xanthohumol hindered it in vivo efficacy potential for treating Alzheimer's disease. Thus, we designed and prepared a series of Xanthohumol derivatives, namely, Xn-n, (n = 1-9) and its chalcone derivatives C-n, (n = 1-10) to enhance the desirable physical, biological and pharmacological properties, especially the blood-brain barrier permeability for intervention of AD. As an effective technique for in vivo visualization, Near-infrared fluorescence imaging based on organic small molecule probes has a promising application in the diagnosis of Alzheimer's disease. However, most of the reported imaging probes can only visualize Aβ-plaques but do not have therapeutic potential such as neuroprotection against Aβ induced toxicity. Herein, we designed and synthesized a series of oligomeric Aβ targeted near infrared (NIR) fluorescent probes for the diagnosis and therapeutics of Alzheimer's disease, namely DBAN-SLM, DBAN-SLOH, DBAN-OSLM which showed remarkably effective inhibitory effect on Aβ aggregation, significant neuroprotection effect against the Aβ-induced toxicities, and suppression on Aβ-induced ROS generation. indicating its great promise as a useful theragnostic agent for the early diagnosis and therapy of AD. Dual-modal imaging is an important approach to overcome the limitations of single imaging technology in the diagnosis of AD disease. Therefore, based on the dual-modal, we designed and synthesized the NIR/MR dual-modal detection and theragnostic probes namely Dyad-1, Dyad-2, Dyad-3 and NP@SiO2@F-SLOH. More surprising is that the two NIR/MR dual-modal probes show excellent biological properties, including the ability to inhibit Aβ aggregation to a certain extent, neuroprotective effects on cytotoxicity caused by different forms of Aβ species, blood-brain barrier (BBB) permeability, and high stability. All of these newly designed and synthesized molecules were characterized with 1H NMR, 13C NMR, and HRMS and found to show good agreement with the desired structures. The photophysical properties and biological properties of these novel designed and synthesized fluorescent probe such as UV-vis absorption, fluorescence emission, dissociation constant determined by fluorescence titration, cytotoxicity assay, neuroprotection, and inhibition of Aβ aggregation were investigated

Alzheimer's disease is a progressive neurodegenerative disorder, in which there is a marked decline in neurotransmitters, especially those of the cholinergic pathways. One of the approaches to the symptomatic treatment of Alzheimer's disease is the inhibition of the breakdown of the neurotransmitter acetylcholine, using an acetylcholinesterase inhibitor. One such drug tested, is the organophosphate, metrifonate. Any drug used for the treatment of neurodegenerative disorders should preferably not induce further neurological damage. Thus, in the present study, we investigated whether or not metrifonate is neuroprotective. The in vivo and in vitro effect of this drug on free radicals generation shows that metrifonate increases the level ofthese reactive species. Lipid peroxidation induced using quinolinic acid (QA) and iron (II) and show that metrifonate increased the peroxidative damage induced by using quinolinic acid. Metrifonate is also able to induce lipid peroxidation both in vivo and in vitro. This was reduced in vitro in the presence of melatonin. Using iron (II), in vi/ro, there was no significant difference in the level of lipid peroxidation in the presence of this drug. An investigation of the activity of the mitochondrial electron transport chain and complex I of the electron transport chain in the presence of metrifonate revealed that metrifonate reduces the activity of the electron transport chain at the level of complex I. The activity of the mitochondrial electron transport chain was restored in the presence of melatonin. Pineal organ culture showed that metrifonate does not increase melatonin production. Histological and apoptosis studies show that tissue necrosis and apoptosis respectively, occur in the presence of this agent, which is reduced in the presence of melatonin. Metal binding studies were performed USing ultraviolet spectroscopy, and electrochemical analysis to examine the interaction of metrifonate with iron (II) and iron (III). No shift in the peak was observed in the ultraviolet spectrum when iron (ll) was added to metrifonate. Electrochemical studies show that there may be a very weak or no ligand formed between the metal and drug. This study shows that while drugs such as metrifonate may be beneficial in restoring cognitive function in Alzheimer's disease, it could also have the potential to enhance neurodegeneration, thus worsening the condition, in the long term. / KMBT_363 / Adobe Acrobat 9.54 Paper Capture Plug-in

The potent analgesic property of acetylsalicylic acid and acetaminophen makes these the most commonly used analgesics in the world. Easy accessibility and cost effectiveness of these agents are attractive to patients seeking pain relief. However, the abuse of nonnarcotic analgesics such as acetaminophen and acetylsalicylic acid by alcoholics and patients seeking to relieve dysphoric moods is well documented. These agents therefore impact on the brain neurotransmitter levels and therefore all processes involved in the synthesis and metabolism of neurotransmitters may be affected. The use of non-narcotic analgesics has been reported to reduce the incidence of neurodegenerative disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). The mode of action by which acetylsalicylic acid and acetaminophen elicit neuroprotection is however unclear as many mechanisms of action have been inconclusively postulated. The first part of this study aims to elucidate the various mechanisms by which acetylsalicylic acid and acetaminophen affect the enzymes responsible for the catabolism of tryptophan, which is a precursor for the mood elevating neurotransmitter serotonin, as well as to investigate whether these agents alter the interplay between serotonin and pineal indole metabolism. The second part of this study focuses on the neuroprotective properties of acetylsalicylic acid and acetaminophen utilizing the neurotoxic metabolite of the kynurenine pathway, quinolinic acid and the potent Parkinsonian neurotoxin, 1-methyl-4-phenylpyridinium (MPP+). The ability of acetylsalicylic acid and acetaminophen to alter TRP metabolism was determined by investigating the effects of these agents on the primary enzymes of the kynurenine pathway i.e. tryptophan 2, 3-dioxygenase and indoleamine 2,3-dioxygenase as well as to investigate whether these agents would have any effects on 3-hydroxyanthranilic acid oxygenase. 3-Hydroxyanthranilic acid oxygenase is the enzyme responsible for the synthesis of quinolinic acid. Acetylsalicylic acid and acetaminophen alter tryptophan metabolism by inhibiting tryptophan 2, 3-dioxygenase and indoleamine 2,3-dioxygenase thus increasing the availability of tryptophan for the production of serotonin. Acetylsalicylic acid and acetaminophen also inhibit 3-hydroxyanthranilic acid oxygenase thus implying that these agents could reduce quinolinic acid production. Acetaminophen administration in rats induces a rise in serotonin and norepinephrine in the forebrain. Acetylsalicylic acid curtails the acetaminophen-induced rise in brain norepinephrine levels as well as enhances serotonin metabolism, indicating that analgesic preparations containing both agents would be advantageous, as this would prevent acetaminophen-induced mood elevation. The results from the pineal indole metabolism study show that acetylsalicylic acid enhances pineal metabolism of serotonin whereas acetaminophen induces an increase in melatonin levels in the pineal gland. Neuronal damage due to oxidative stress has been implicated in several neurodegenerative disorders such as AD and PD. The second part of the study aims to elucidate and characterize the mechanism by which acetylsalicylic acid and acetaminophen afford neuroprotection. The hippocampus is an important region of the brain responsible for memory. Agents such as quinolinic acid that are known to induce stress in this area have detrimental effects and could lead to various types of dementia. The striatum is also a vulnerable region to oxidative stress and hence (MPP+), which is toxic for this particular region of the brain, was also used as a neurotoxin. The results show that ASA and acetaminophen alone and in combination, are potent superoxide anion scavengers. In addition, the results imply that these agents offer protection against oxidative stress and lipid peroxidation induced by several neurotoxins in rat brain particularly, the hippocampus and striatum. Histological studies, using Nissl staining and Acid fuchsin, show that acetylsalicylic acid and acetaminophen are able to protect hippocampal neurons against quinolinic acidinduced necrotic cell death. Immunohistochemical investigations show that QA induces apoptotic cell death in the hippocampus, which is inhibited by ASA and acetaminophen. In addition, ASA and acetaminophen inhibited MPP+ induced apoptotic cell death in the rat striatum. The study also sought to elucidate possible mechanisms by which ASA and acetaminophen exert neuroprotective effects in the presence of MPP+ as these agents are shown to prevent the MPP+-induced reduction in dopamine levels. The results show that acetylsalicylic acid and acetaminophen inhibit the action of this neurotoxin on the mitochondrial electron transport chain, a common source of free radicals in the cell. In addition, these agents were shown to block the neurotoxic effects of MPP+ on the enzymatic defence system of the brain i.e. superoxide dismutase, glutathione peroxidase and catalase. The reduction in glutathione levels induced by MPP+ is significantly inhibited by acetylsalicylic acid and acetaminophen. The results imply that these agents are capable of not only scavenging free radicals but also enhance the cell defence mechanism against toxicity in the presence of MPP+. These agents also block the MPP+-induced inhibition of dopamine uptake into the cell. This would therefore reduce auto-oxidation of dopamine thus implying another mechanism by which these agents exert a neuroprotective role in MPP+-induced neurotoxicity. The discovery of neuroprotective properties of acetylsalicylic acid and acetaminophen is important considering the high usage of these agents and the increased incidence in neurological disorders. The findings of this thesis point to the need for clinical studies to be conducted as the results show acetylsalicylic acid and acetaminophen to have a definite role to play as antioxidants. This study therefore provides novel information regarding the neuroprotective effects of these agents and favours the use of these agents in the treatment of neurodegenerative disorders, such as AD and PD, in which oxidative stress is implicated.

This qualitative case study investigated the impact of sand tray on individuals diagnosed with Alzheimer’s and other forms of dementia. Four participants successfully completed the creation of sand trays while the researcher observed, interviewed, and documented the individual sand trays. The intervention established that sand tray allows the dementia patient to kinesthetically connect to their inner cognitions through the intentional symbolic expression offered by this unique therapeutic medium. Using a series of eight sand trays of varying thematic concepts, the participants were offered a modality to facilitate a synthesization of their continued individuation, presenting a possible neural pathway to connect and express thoughts, feelings, emotions, concerns, challenges, and fears. The findings of this study include the fact that all trays were classified as “empty” and that the majority of the participants placed objects almost exclusively on the right side of the tray, which is commonly associated with the concreteor conscious side. The use of sand tray allowed each individual the opportunity to create autobiographies in the sand and literally navigate through time – past, present, and future, confronting fears, expressing hope and possibilities. The results of the research study offer insight into the psychotherapeutic effects of using sand tray with dementia patients, as well as a better understanding of the cognitive and expressive abilities and limitations of an individual with impaired memory. The results also offer insight into the difficulties with short-term memory in this population and possibly indicate a potential means for monitoring cognitive decline. Keywords: Neurocognitive disorder, Alzheimer’s, dementia, sand tray, play therapy / Includes bibliography. / Dissertation (Ph.D.)--Florida Atlantic University, 2013.

Hung Shieh-Jung Fanny. / Thesis submitted in: August 2002. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 97-109). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.ii / 摘要 --- p.iv / Content --- p.vi / List of Abbreviations --- p.xiii / List of Figure --- p.xv / List of Tables --- p.xix / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- Alzheimer's Disease (AD) --- p.1 / Chapter 1.1.1 --- Clinical features --- p.2 / Chapter 1.2 --- Histopathological studies of AD --- p.2 / Chapter 1.2.1 --- Neuritic plaques --- p.2 / Chapter 1.2.2 --- Neurofibrillary tangles (NFT) --- p.4 / Chapter 1.2.3 --- Tau --- p.5 / Chapter 1.3 --- Kinases and Alzheimer's Disease --- p.7 / Chapter 1.4 --- Free radical damage --- p.8 / Chapter 1.5 --- Available treatment for AD --- p.7 / Chapter 1.6 --- A Chinese medicinal material 一 Danshen （（Salviae miltiorrhizcie) --- p.11 / Chapter 1.6.1 --- Chemical constituents --- p.11 / Chapter 1.6.1.1 --- Lipophilic Compounds of Danshen --- p.12 / Chapter 1.6.1.2 --- Water-soluble Compounds of Danshen --- p.17 / Chapter 1.6.2 --- Pharmacological usage --- p.20 / Chapter 1.6.2.1 --- Action on Coronary system --- p.20 / Chapter 1.6.2.2 --- Bacteriostatic action --- p.21 / Chapter 1.6.2.3 --- Actions on the immune system --- p.21 / Chapter 1.6.3 --- Biological activity on brain --- p.22 / Chapter 1.7 --- Objectives and scope of the project --- p.23 / Chapter Chapter 2 --- General Materials and Method --- p.24 / Chapter 2.1 --- Recombinant DNA techniques --- p.24 / Chapter 2.1.1 --- Preparation of E. coli strain DH-5a competent cells --- p.24 / Chapter 2.1.2 --- Transformation of plasmid DNA into competent cells --- p.25 / Chapter 2.1.3 --- Preparation of plasmid DNA using QIAGEN Plasmid Maxipreps kit --- p.25 / Chapter 2.1.4 --- Phenol/ choroform extraction of DNA --- p.26 / Chapter 2.1.5 --- Spectrophotometric quantitation of the amount and purity of DNA --- p.27 / Chapter 2.2 --- Drugs preparation --- p.27 / Chapter 2.2.1 --- Preparation of aqueous extracts of Traditional Chinese Medicine (TCM) --- p.27 / Chapter 2.2.2 --- Preparation of ethanol extracts of Traditional Chinese Medicine (TCM) --- p.27 / Chapter 2.3 --- "3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyl-tetrazolium (MTT) assay " --- p.28 / Chapter 2.4 --- Analysis of proteins from culture cells --- p.28 / Chapter 2.4.1 --- Extraction of total proteins from culture cells --- p.28 / Chapter 2.4.2 --- Quantitation of protein by Bradford method --- p.29 / Chapter 2.4.3 --- Protein separation by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) --- p.29 / Chapter 2.4.4 --- Western blot analysis --- p.31 / Chapter 2.5 --- Reagents and buffers --- p.32 / Chapter 2.5.1 --- Reagents for competent cell preparation --- p.32 / Chapter 2.5.2 --- Reagents provided by QIAGEN Plasmid Maxipreps kit --- p.33 / Chapter 2.5.3 --- Reagents for SDS-PAGE --- p.34 / Chapter 2.5.4 --- Reagents and buffers for Western Blotting --- p.35 / Chapter 2.5.5 --- Cell lines --- p.36 / Chapter 2.5.6 --- Antibodies --- p.37 / Chapter 2.5.7 --- Plasmids --- p.37 / Chapter 2.5.8 --- Other Chemicals --- p.38 / Chapter Chapter 3 --- The effect of Danshen on GSK-3 induced hyperposphorylation of tau in Cos7 cells / Chapter 3.1 --- Introduction --- p.39 / Chapter 3.1.1 --- Glycogen synthase kinase-3 (GSK-3) --- p.39 / Chapter 3.1.2 --- Structure of GSK-3 --- p.39 / Chapter 3.1.3 --- The importance of GSK-3 in AD --- p.39 / Chapter 3.2 --- Materials and Methods --- p.41 / Chapter 3.2.1 --- Transfection of Gsk-3 and tau into Cos7 monkey kidney cells --- p.43 / Chapter 3.2.2 --- Extraction of total proteins from culture cells --- p.44 / Chapter 3.2.3 --- Quantitation of protein by Bradford method --- p.44 / Chapter 3.2.4 --- Protein separation by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) --- p.44 / Chapter 3.2.5 --- Western blot analysis --- p.44 / Chapter 3.3 --- Results --- p.45 / Chapter 3.3.1 --- Toxicity test on Cos7 cells --- p.45 / Chapter 3.3.2 --- The effect of ethanol extract of Danshen on GSK-3 β induced tau phosphorylation --- p.45 / Chapter 3.3.3 --- The effect of aqueous extract of Danshen on GSK-3 β induced tau phosphorylation --- p.48 / Chapter 3.3.4 --- The effect of Protocatechualdehyde on GSK-3β induced tau phosphorylation --- p.48 / Chapter 3.3.5 --- The effect of Salvianolic acid B on GSK-3β induced tau phosphorylation --- p.49 / Chapter 3.4 --- Discussion --- p.60 / Chapter Chapter 4 --- Cdk5 induced hyperposphorylation of tau in CHO cells / Chapter 4.1 --- Introduction --- p.63 / Chapter 4.1.1 --- Cyclin dependent kinase 5 (Cdk5) --- p.63 / Chapter 4.1.2 --- Structure of Cdk5 --- p.63 / Chapter 4.1.3 --- Neurological functions of Cdk5 --- p.64 / Chapter 4.2 --- Materials and Methods --- p.66 / Chapter 4.2.1 --- Transfection of p35 and tau into CHO cells --- p.66 / Chapter 4.2.2 --- Extraction of total proteins from culture cells --- p.67 / Chapter 4.2.3 --- Quantitation of protein by Bradford method --- p.67 / Chapter 4.2.4 --- Protein separation by sodium dodecylsulphate polyacrylamide gel electrophoresis (SDS-PAGE) --- p.67 / Chapter 4.2.5 --- Western blot analysis --- p.67 / Chapter 4.3 --- Results --- p.68 / Chapter 4.3.1 --- Toxicity test on CHO cells --- p.68 / Chapter 4.3.2 --- Tau transfection in Cdk5/p35 and TauON3R transiently transfected in CHO cells --- p.68 / Chapter 4.3.3 --- Effect of roscovitine treatment on the transiently tau and p35 transfection in CHO cells --- p.74 / Chapter 4.3.4 --- "Effects of aqueous active components of Danshen, PCAH and SAB on the transiently tau and p35 transfection in CHO cells " --- p.74 / Chapter 4.4 --- Discussion --- p.79 / Chapter Chapter 5 --- Antioxidant effect of Danshen and its active components on lipid peroxidation / Chapter 5.1 --- Introduction --- p.81 / Chapter 5.1.1 --- Red-blood-cell hemolysis model --- p.82 / Chapter 5.2 --- Materials and methods --- p.84 / Chapter 5.2.1 --- Red-blood-cell hemolysis model --- p.84 / Chapter 5.2.2 --- Materials --- p.85 / Chapter 5.2.2.1 --- Animals --- p.85 / Chapter 5.2.2.2 --- Chemicals --- p.85 / Chapter 5.3 --- Results --- p.86 / Chapter 5.3.1 --- Aqueous and ethanol extracts of Danshen --- p.86 / Chapter 5.3.2 --- Active components ´ؤ Protocatechualdehyde and Salvianolic acid B --- p.87 / Chapter 5.4 --- Discussion --- p.91 / Chapter Chapter 6 --- General discussion and Outlook / Chapter 6.1 --- General discussion --- p.93 / Chapter 6.2 --- Proposed study in the future --- p.95 / Chapter 6.2.1 --- In vitro kinase assay using gamma32 P ATP and substrate with or without TCM --- p.95 / Chapter 6.2.2 --- Use of neuroblastoma cells (SHSY-5Y) to study the effect of Danshen and its active components on tau phosphorylation --- p.95 / Chapter 6.2.3 --- Thiobarbituric acid-reacting substances (TBARS) assay --- p.96 / Chapter 6.2.4 --- In vitro phosphatase kinase assay --- p.96

by Tsz-Wan Ho. / Thesis submitted in: July 2003. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 107-122). / Abstracts in English and Chinese. / Acknowledgements --- p.i / Abstract --- p.ii / 摘要 --- p.iv / Content --- p.vi / Abbreviations --- p.x / List of Figures --- p.xi / List of tables --- p.xiv / Chapter CHAPTER 1 --- GENERAL INTRODUCTION --- p.1 / Chapter 1.1 --- Alzheimer'sDisease --- p.1 / Chapter 1.2 --- Hallmarks of AD --- p.3 / Chapter 1.2.1 --- The amyloid cascade hypothesis --- p.3 / Chapter 1.2.2 --- The tauopathy hypothesis --- p.4 / Chapter 1.3 --- The Cholinergic Hypothesis --- p.6 / Chapter 1.3.1 --- Cholinergic drug therapy --- p.7 / Chapter 1.3.2 --- Acetylcholinesterase inhibitors --- p.8 / Chapter 1.3.2.1 --- Tacrine --- p.10 / Chapter 1.3.2.2 --- Donepezil --- p.10 / Chapter 1.3.2.3 --- Rivastigimine - ENA-713 --- p.11 / Chapter 1.4 --- AChE inhibitors from plants --- p.12 / Chapter 1.4.1 --- Galanthamine --- p.12 / Chapter 1.4.2 --- Huperzine --- p.14 / Chapter 1.4.3 --- α-onocerin --- p.15 / Chapter 1.4.4 --- (+)-alpha-viniferin --- p.16 / Chapter 1.5 --- My project --- p.17 / Chapter CHAPTER 2 --- MATERIALS AND METHODS --- p.18 / Chapter 2.1 --- Preparation of CMM --- p.18 / Chapter 2.2.1 --- Selecting criteria and sources --- p.18 / Chapter 2.2.2 --- Preparation of aqueous extract --- p.18 / Chapter 2.2.3 --- Preparation of ethanol extract --- p.18 / Chapter 2.3 --- Routine maintenance of cell lines --- p.19 / Chapter 2.4 --- Toxicity test --- p.19 / Chapter 2.5 --- Ellman assay --- p.20 / Chapter 2.6 --- Ellman assay over BuChE --- p.21 / Chapter 2.7 --- Drugs --- p.21 / Chapter CHAPTER 3 --- SCREENING OF ACETYLCHOLINESTERASE INHIBITORS FROM CHINESE MEDICINAL MATERIALS --- p.23 / Chapter 3.1 --- Introduction --- p.23 / Chapter 3.2 --- Materials and Methods --- p.23 / Chapter 3.3 --- Results and discussion --- p.24 / Chapter 3.3.1 --- Preliminary screening of 45 selected TCMs for AChE inhibition --- p.24 / Chapter 3.3.2 --- Rescreening of drugs that show AChE inhibition in both aqueous and organic extracts --- p.25 / Chapter 3.4 --- Discussion --- p.28 / Chapter CHAPTER 4 --- CHARACTERIZATION OF ANTI-ACETYLCHOLINESTERASE ACTIVITY FROM SALVIA MBLTIORRHIZA BGE.(丹參) --- p.33 / Chapter 4.1 --- Introduction --- p.33 / Chapter 4.1.1 --- Clinical application of Danshen --- p.34 / Chapter 4.1.2 --- Pharmacological properties of Danshen and Salvia species --- p.34 / Chapter 4.1.2.1. --- Antiinflammatory and antibacterial responses --- p.35 / Chapter 4.1.2.2 --- Diabetes --- p.35 / Chapter 4.1.2.3 --- Alcoholism --- p.35 / Chapter 4.1.2.4 --- Apoptosis --- p.36 / Chapter 4.1.2.5 --- The effect of Salvia extracts on neuro-receptors --- p.36 / Chapter 4.1.3 --- Anti-cholinesterase activity by the Salvia species --- p.37 / Chapter 4.1.4 --- Active components from Salvia miltiorrhiza Bge --- p.38 / Chapter 4.2 --- Effects of tanshinone derivatives on AChE --- p.39 / Chapter 4.2.1 --- Materials and Methods --- p.39 / Chapter 4.2.2. --- Results --- p.39 / Chapter 4.3 --- Discussion --- p.50 / Chapter CHAPTER 5 --- EXTRACTION OF CRYPTOTANSHINONE FROM SALVIA MILTIORRHIZA --- p.54 / Chapter 5.1 --- Introduction --- p.54 / Chapter 5.1.1 --- Reverse phase high performance liquid chromatography (RP-HPLC) --- p.55 / Chapter 5.2 --- Materials and Methods --- p.56 / Chapter 5.2.1 --- Extracts of Danshen from different sources for obtaining the chemical profile --- p.55 / Chapter 5.2.2 --- Reverse phase high performance liquid chromatography (RP-HPLC) --- p.57 / Chapter 5.2.2.1 --- Analytical RP-HPLC --- p.57 / Chapter 5.2.2.2 --- Preparative RP-HPLC --- p.58 / Chapter 5.3 --- Results --- p.60 / Chapter 5.3.1 --- Identification of Peaks that contain the proposed active components --- p.60 / Chapter 5.3.2 --- Different samples of Danshen contain different amount of active components that can exert inhibitory effect on hAChE --- p.66 / Chapter 5.4 --- Discussion --- p.75 / Chapter CHAPTER 6 --- EFFECT OF CRYPTOTANSHINONE ON CALCIUM MOVEMENT in SH-SY5Y Cell --- p.80 / Chapter 6.1 --- Introduction --- p.80 / Chapter 6.2 --- Materials and Methods --- p.82 / Chapter 6.2.1 --- Reagents and drugs --- p.82 / Chapter 6.2.2 --- Calcium fluorimetry --- p.82 / Chapter 6.3 --- Results --- p.85 / Chapter 6.4 --- Discussion --- p.96 / Chapter CHAPTER 7 --- GENERAL DISCUSSION --- p.98 / Chapter 7.1 --- Structure-function relationship of crytotanshinone and dihydrotanshinone I --- p.98 / Chapter 7.2 --- Further study on cryptotanshinone and dihydrotanshinone I --- p.100 / Chapter 7.2.1 --- Modulation on nictonic receptor --- p.100 / Chapter 7.2.2 --- Behavioral study on mice --- p.101 / Chapter 7.2.3 --- Large scale production of the desired active components --- p.102 / Chapter 7.3 --- Study on other candidate herbs --- p.102 / References --- p.107

Alzheimer's disease (AD) is associated with decreased brain energy metabolism. Hypometabolism in the posterior cingulate cortex (PCC) occurs before the onset of memory deficits in subjects at genetic risk for AD who are not yet cognitively impaired. There is a specific inhibition in cytochrome oxidase (C.O.) in the PCC, an area involved in spatial navigation. Creating an animal model that exhibits the early pathophysiology of AD is important for developing and testing drugs that could reverse memory problems associated with such deficits. Methylene blue (MB) is a compound that improves C.O. activity and memory retention in rats. This dissertation had three specific aims: 1) to examine if isolated PCC hypometabolism causes spatial memory deficits in rats; 2) to find a dose of MB that improves memory without nonspecific behavioral effects; and 3) to prevent memory deficits from PCC hypometabolism with low dose MB. PCC hypometabolism was produced by focal administration of sodium azide, an inhibitor of C.O. activity. PCC hypometabolism resulted in impaired spatial memory in a hole board food-search task, increased oxidative damage, and neurotoxicity in the PCC. In addition, PCC hypometabolism resulted in reduced inter-regional correlations in brain activity. Our second set of studies examined the dose-response effects of MB. Our findings demonstrated that a low dose of MB: 1) enhanced memory in open field habituation and object recognition tasks; 2) did not affect general locomotor activity, exploration, motivation, or anxiety; and 3) increased brain oxygen consumption 24 hr after in vivo administration. Finally, our last study found that low dose MB prevented the deficits caused by PCC hypometabolism. MB did not prevent PCC inhibition or cell loss caused by sodium azide. Inter-regional correlations of brain metabolic activity suggested that rats treated with MB were using a different, but equally efficient, strategy for memory retrieval. This animal model of C.O. hypometabolism in the PCC can provide information to understand the mechanisms that regulate early pathological degeneration and reveal new therapeutic strategies aimed at reducing or preventing cognitive decline. Studies of low dose MB in humans are needed to examine its effects in AD patients.

In 2015, an estimated 46.8 million people were living with dementia, a number predicted to increase to 74.7 million by 2030 and 131.5 million by 2050. Whilst there are numerous causes for the development of dementia, Alzheimer's disease is by far the most common, accounting for approximately 50-70% of all cases. Current therapeutic agents against Alzheimer's disease are palliative in nature, managing symptoms without addressing the underlying cause and thus disease progression and patient death remain a certainty. Whilst the main underlying cause for the development of Alzheimer's disease was originally thought to be an abnormal deposition of insoluble amyloid-β peptide derived plaques within the brain, the failure of several high-profile therapeutic agents, which were shown to reduce the plaque burden without improving cognition, has recently prompted a shift in focus to soluble oligomeric forms of amyloid-β peptide. Such soluble oligomers have been shown to be toxic in their own right and to precede plaque deposition. Soluble amyloid-β oligomers have been identified in various subcellular compartments, including the mitochondria, where they form a complex with the 17β-HSD10 enzyme resulting in cytotoxicity. Interestingly, hallmarks of this toxicity have been shown to be dependent on the catalytic activity of the 17β-HSD10 enzyme, suggesting two therapeutic approaches may hold merit in treating Alzheimer's disease: disrupting the interaction between the 17β-HSD10 enzyme and amyloid-β peptide, or directly inhibiting the catalytic activity of the 17β-HSD10 enzyme. In 2006, Frentizole was identified as a small molecule capable of disrupting the 17β-HSD10/amyloid interaction. The work described herein details the generation of a robust screening assay allowing the catalytic activity of the 17β-HSD10 enzyme to be measured in vitro. This assay was subsequently employed for small molecule screening using two methodologies; first in a targeted approach using compounds derived from the Frentizole core scaffold, and second in an explorative manner using a diverse library of compounds supplied by the National Cancer Institute. As a result, a range of novel small molecule inhibitors of the 17β-HSD10 enzyme have been identified and the most promising characterised in terms of potency and mechanism of action. De-selection assays were developed to allow the efficient triage of hit compounds and work was begun on a cellular based assay which would allow the ability of compounds of interest to reverse a disease relevant phenotype to be assessed in a cellular environment. As such, we now have a number of hit compounds which will form the basis for the generation of subsequent series of derivatives with improved potency and specificity, as well as the robust assays required to measure such criteria, potentially leading to the generation of novel therapeutic agents against Alzheimer's disease.

阻塞性睡眠呼吸暂停（OSA）是一种常见的睡眠障碍，睡眠过程中反复发作的气道阻塞，导致间歇性低氧血症。OSA 中的間歇性缺氧（IH）一直被视為一個主要致病因素。會影響神經認知功能，包括記憶障礙，遲鈍的反應和其它。以前的研究提示氧化应激产物（ROS）和细胞凋亡是間歇性缺氧引起的认知功能障碍的主要機制之一。然而，确切的机制仍然知之甚少，并没有得到解决。我们基于間隙性缺氧 （IH）的动物模型的实验结果首次发现，即在IH 模型中海馬長時程增強（LTP）的降低，以及腦源性神經營養因子（BDNF）的表达减少。同時我們發現，大脑内注射BDNF 可以有效地恢复LTP 的幅度。因此，我们的研究提供了一种新的可能机制，即在缺乏脑源性神经营养因子可能是阻塞性睡眠呼吸暂停導致的伴有脑功能障碍一个关键因素。 / Ampakine 是一種AMPA 受體調節劑，更重要的是可以增加腦內BDNF 的表達。在这项研究中，我們在不同缺氧時間處理的動物模型中通过腹部注射ampakine 來觀察其效應。我們使用了四组成年雄性小鼠，其中組接受7 天IH处理，另外两组接受14 天缺氧处理。所有四组均分别接受腹腔ampakine 和对照生理盐水注射。 IH 模式仍然是氧含量在90 秒内从21 降到10%，再回复到21%。缺氧时间是每天8 小時周期。从整个IH /正常氧环境的第一天开始，八臂放射迷宮被用来研究参考记忆和工作记忆的表现。然后，我们对脑源性神经营养因子，活性氧和细胞凋亡的分子标记和海马的树突棘形态的表达进行了检查， 海馬突触可塑性的表現，包括E-LTP，L-LTP 也都被檢測。 / Western blot 分析显示，ampakine 注射有效恢复了IH 導致的海马BDNF 水平下降。同时， 我們也發現在ampakine 注射組中ROS 的表达减少，细胞凋亡的减轻，其中包括内质网应激诱导的细胞凋亡。树突棘被認為是海马突触可塑性的结构基础之一。高尔基体染色也表明， ampakine 注射IH 成功回復了7 天IH 導致的較大的，成熟树突棘的減少。 / 此外，八臂放射迷宮的结果表明，无论是参考记忆和工作记忆在7 天IH和14 天IH 均有受損表現。但是，ampkine 的使用同樣挽救了IH 引起的這些记忆障碍。 / 最後，通過研究AMPA 受體調節劑（ampakines）對IH-誘導的神經認知功能障礙及長時程增強障礙影響，我們發現進一步的闡明BDNF 在OSA 所起的重要作用。這些結果也將探索新的藥物治療的OSA 了新的思路。 / 阿爾茨海默病（AD），也叫老年癡呆癥，在65 歲的人的失憶症中，是最常見的原因，也是最常見的神經退行性疾病。 AD 的原因並不清楚，其起病也並不明顯。它的特點是逐漸喪失記憶，語言障礙及其他認知功能障礙，這些症狀可能會變得明顯。在AD 中，兩種蛋白質聚集體的參與和特點的AD 病理澱粉樣斑塊，由澱粉樣蛋白-β 肽，並導致細胞外病變和tau 蛋白纏結，這是由過度磷酸化的絲微管相關蛋白tau，並導致細胞內的病變。 / 鐵是最豐富的微量金屬，在大腦中參與範圍廣泛的細胞過程的運作。然而，鐵臭名昭著的另一方面是其強大的氧化催化性能。事實上，失調的鐵已被發現與細胞老化和各種各樣的神經退行性疾病有牽連。鐵在突觸功能的重要性是對突觸的影響，例如其可以順行軸突運輸突觸功能區域，這也是阿爾茨海默病中的澱粉樣蛋白斑的沉積的起始部位。然而，到現在，鐵的積累是如何影響突觸功能以及更普及的大腦功能很少被研究。 / 為了調查是否高鐵食有任何正常或阿爾茨海默氏病的影響，我們在實驗中引入了APPswe/ps1 轉基因小鼠，這是一個經典的老年癡呆症的疾病的動物模型。研究中，我們使用四組動物模型，即野生型（WT）和APPswe/ps1 小鼠（TG），每組給予至少10 個月正常（ctrl）的食和高鐵（HI）食。 / 海馬LTP 記錄表明，野生小鼠與正常食（WT-HI）的海馬長時程增強下降。 Tg-ctrl 組也相比wt-ctrl 組顯示LTP 水準下降，包括E-LTP 和L-LTP。引人注目的是，高鐵食下的APPswe/ps1 下顯示了被提高和恢復的海馬長時程突觸可塑性。 / 八臂放射迷宮的結果還表明，與高鐵食的野生型以及正常食的APPswe/ps1，無論是在參考記憶體或工作記憶，比野生型與正常食組有較差的記憶水準。同樣，我們驚訝地發現，和APPswe/ps1 正常食的小鼠相比，給予高鐵食的APPswe/ps1 組的迷宮成績要好得多,几乎回复到和野生型对照组一样的水平。 / 這些結果表明，鐵在阿爾茨海默病的功能是非常複雜的，可能會對其神經可塑性顯示雙相調節作用特性。詳細機制有待進一步探討。 / Obstructive sleep apnea (OSA) is a common sleep disorder, characterized by repeated episodes of airway obstruction during sleep resulting in intermittent hypoxemia. Previous studies proposed that reactive oxygen species (ROS) and apoptosis caused by intermittent hypoxia (IH) contributed to cognitive deficits. However, the exact mechanism is still poorly understood and not settled. Our recent studies, for the first time, showed that there is decreased expression of brain-derived neurotrophic factor (BDNF) in the hippocampus and impairment in long-term potentiation (LTP). Intra-brain injection of BDNF can effectively restore the magnitude of LTP. Thus, our study provides a novel mechanism and insight in the etiology of OSA-induced brain dysfunction in that lacking BDNF could be a critical factor. / In this study, ampakine application was used as “BDNF raiser“ during 7-day IH and 14-day IH treatment by intraperitoneal (i.p.) injection. Four groups of adult male mice were used, two of them exposed to 7-day IH and two of them exposed to 14-day IH, each received either vehicle or ampakine i.p. injection. The paradigm of IH consisted of cycles of oxygen levels between 10% and 21% every 90s during the daytime for 8 hrs. Radial arm maze was used to investigate the performance of reference memory and working memory during the whole IH/ normoxia treatment from the first day. After that, expression of BDNF, ROS and molecular markers of apoptosis and morphology of hippocampal dendritic spines were examined, together with the investigation of both hippocamal synaptic plasticity, including early phase LTP (E-LTP) and late phase L-LTP (L-LTP). / Ampakine treatment restored the decreased level of hippocampal BDNF in the IH-treated group, as revealed by Western blot. Meanwhile, decreased ROS expression and alleviated cell death, including ER stress induced-apoptosis are all found in those ampakine injected groups. Golgi staining also showed that ampakine injection IH treatment rescued the decrease of mature dendritc spines, which is the structural basis of hippocampal synaptic plasticity, under 7-day IH treatment. Hippocampal long-term synaptic plasticity, which underlies the proposed mechanism of memory, was also found reversed in those ampakine injected groups, compared with groups under IH treatment. / Furthermore, results of radial arm maze showed that both the reference memory and working memory are impaired by 7-day IH treatment or 14-day IH treatment. However, the application of ampakine rescued IH-induced memory deficits. / Finally, by studying the effects of the ampakines on IH-induced neurocognitive dysfunction and LTP impairment, the role played by BDNF in OSA was further elucidated. These results were shed new lights on the exploration of novel pharmacological treatments in the OSA. / Alzheimer’s disease is the most common cause of dementia among aged people. The causes of AD are not clear and onset of the disease is also not obvious. Iron is the most abundant trace metal in the brain and dysregulation of iron has been implicated in cell aging and a wide variety of neurodegenerative diseases including Alzheimer disease. However, up to now, very little is known about how iron accumulation is involved in Alzheimer disease. / To investigate whether high iron diet has any effects on normal or Alzheimer’s disease, we introduced APPswe/ps1 transgenic mice, an Alzheimer’s disease animal model, and used four groups in our study, namely wild type (wt) and APPswe/ps1 mice (tg), each with normal (ctrl) diets and high iron (HI) diet for at least 10 months. / Hippocampal LTP recording showed that wild type with high iron diet (wt-HI) decreased than that of wt-ctrl group. Tg-ctrl group also displayed decreased LTP level, including E-LTP and L-LTP, than that of wt-ctrl group. Strikingly, that of APPswe/ps1 under HI diets rescued the impaired hippocampal long-term synaptic plasticity than that of APPswe/ps1 mice under normal diets. / Results from radial arm maze also showed that both APPswe/ps1 with normal diet and wild type with HI diet had worse performance, either in reference memory or working memory, than those of wild type with normal diets. Again, it is surprised to find that performances of tg-HI group were much better than APPswe/ps1 mice under normal diet. / These results showed that the function of iron are very complicated, may have different effects on neural function of normal and AD objects. The detailed mechanisms needs to be further explored. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Xie, Hui. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 200-225). / Abstracts also in Chinese. / Declaration --- p.II / ABSTRACT OF THESIS ENTITLED --- p.III / 中文摘要 --- p.VII / Acknowledgements --- p.XI / List of abbreviations --- p.XIII / List of publications --- p.XVI / Chapter CHAPTER 1 --- INTRODUCTION --- p.4 / Chapter 1.1 --- Overview of the study --- p.4 / Chapter 1.2 --- Obstructive sleep apnea --- p.7 / Chapter 1.2.1 --- Epidemiology --- p.8 / Chapter 1.2.2 --- Pathogenesis --- p.10 / Chapter 1.2.3 --- Pathophysiologic Consequences --- p.11 / Chapter 1.2.4 --- Diagnosis --- p.14 / Chapter 1.2.5 --- Treatment --- p.15 / Chapter 1.3 --- Memory and long-term potentiation --- p.17 / Chapter 1.3.1 --- Memory --- p.17 / Chapter 1.3.2 --- Hippocampal Synaptic plasticity --- p.19 / Chapter 1.3.3 --- Dendritic Spines --- p.23 / Chapter 1.4 --- Brain-derived neurotrophic factor --- p.35 / Chapter 1.4.1 --- Introduction of BDNF --- p.35 / Chapter 1.4.2 --- BDNF and synaptic plasticity --- p.36 / Chapter 1.5 --- Intermittent hypoxia impaired memory and neuroplasticity --- p.38 / Chapter 1.5.1 --- Clinical and basic studies on IH-induced neurological dysfunction --- p.38 / Chapter 1.5.2 --- Current mechanisms of IH-induced neurological dysfunction --- p.39 / Chapter 1.5.3 --- ROS generation and intermittent hypoxia --- p.41 / Chapter 1.5.4 --- Critical role of decreased BDNF expression in chronic intermittent hypoxia --- p..46 / Chapter 1.6 --- Ampakine --- p.48 / Chapter 1.6.1 --- Effects of ampakine on receptor activities --- p.49 / Chapter 1.6.2 --- Effects of ampakine on synaptic transmission --- p.50 / Chapter 1.6.3 --- Effects of ampakine on long-term potentiation --- p.52 / Chapter 1.6.4 --- Ampakine, BDNF and neurological disease --- p.53 / Chapter CHAPTER 2 --- METHODS --- p.61 / Chapter 2.1 --- Experimental procedure --- p.61 / Chapter 2.1 --- Animal model of Obstructive Sleep Apnea --- p.62 / Chapter 2.1.1 --- Chronic Intermittent Hypoxia --- p.62 / Chapter 2.1.2 --- Oxygen saturation measurement under normoxia and intermittent hypoxia --- p.64 / Chapter 2.1.3 --- Body weight during hypoxia treatment --- p.64 / Chapter 2.2 --- Western Blot Analysis --- p.65 / Chapter 2.3 --- ROS measurement --- p.67 / Chapter 2.4 --- Golgi staining --- p.67 / Chapter 2.4.1 --- Analysis of spine density --- p.68 / Chapter 2.4.2 --- Measurement of dendritic spines --- p.68 / Chapter 2.5 --- Electrophysiological Experiments --- p.69 / Chapter 2.5.1 --- Brain Slice Preparation --- p.69 / Chapter 2.5.2 --- Multi-electrode Recording Setup (MED64) --- p.70 / Chapter 2.5.3 --- Slice Superfusion --- p.72 / Chapter 2.5.4 --- Field Potential Recordings --- p.73 / Chapter 2.5.5 --- LTP Induction Protocol --- p.74 / Chapter 2.6 --- Radial arm maze --- p.76 / Chapter CHAPTER 3 --- RESULTS --- p.91 / Chapter 3.1 --- Molecular detection under IH treatment and ampakine injection --- p.91 / Chapter 3.1.1 --- BDNF expression under IH treatment and ampakine injection --- p.91 / Chapter 3.1.2 --- ROS measurement under IH treatment and ampakine injection --- p.92 / Chapter 3.1.3 --- Involvement of ER stress during IH treatment --- p.93 / Chapter 3.2 --- Changes of dendritic spines under IH treatment and ampakine injection --- p.100 / Chapter 3.2.1 --- Changes of total dendritic spine density under IH treatment and ampakine injection --- p.100 / Chapter 3.2.2 --- Changes of different dendritic spine density under IH treatment and ampakine injection --- p.101 / Chapter 3.2.3 --- Changes of dendritic spine morphology under IH treatment and ampakine injection --- p.103 / Chapter 3.3 --- IH-induced impairment in hippocampal synaptic plasticity --- p.110 / Chapter 3.3.1 --- E-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.110 / Chapter 3.3.2 --- L-LTP measurement of 7-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.111 / Chapter 3.3.3 --- E-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.112 / Chapter 3.3.4 --- L-LTP measurement of 14-day intermittent hypoxia treatment in long-term synaptic plasticity --- p.113 / Chapter 3.4 --- Behavioral studies under IH treatment and ampakine injection --- p.119 / Chapter 3.4.1 --- Reference memory test under IH treatment and ampakine injection --- p.119 / Chapter 3.4.2 --- Working memory measurement under IH treatment and ampakine injection --- p..122 / Chapter CHAPTER 4 --- DISCUSSION --- p.140 / Chapter 4.1 --- Molecular changes under IH treatment and ampakine application --- p.140 / Chapter 4.1.1 --- Intermittent hypoxia down regulate BDNF expression in hippocampus while ampakine injection rescued IH-induced decreased BDNF level --- p.140 / Chapter 4.1.2 --- Ampakine injection against ROS and apoptosis --- p.143 / Chapter 4.1.3 --- Involvement of ER stress-induced apoptosis during IH treatment --- p.145 / Chapter 4.2 --- Changes of spine morphology and density under IH treatment and ampakine injection --- p.146 / Chapter 4.3 --- Ampakine rescued hippocampal synaptic plasticity --- p.152 / Chapter 4.4 --- IH impaired reference memory and working memory --- p.156 / Chapter 4.5 --- Summary --- p.160 / Chapter Chapter 5 --- Effects of High-iron diet in Alzheimer’s Disease --- p..164 / Chapter 5.1 --- Overview of the study --- p.164 / Chapter 5.2 --- Introduction --- p.166 / Chapter 5.2.1 --- Alzheimer's disease --- p.166 / Chapter 5.2.2 --- Function of iron in brain --- p.167 / Chapter 5.2.3 --- Involvement of iron in oxidative damage --- p.168 / Chapter 5.2.4 --- Role of iron in neurodegeneration diseases --- p.168 / Chapter 5.2.5 --- Role of iron in Alzheimer's disease --- p.169 / Chapter 5.2.6 --- Deleterious effects of iron in memory function --- p.171 / Chapter 5.3 --- Methods --- p.172 / Chapter 5.3.1 --- Experimental design --- p.172 / Chapter 5.3.2 --- T-maze --- p.172 / Chapter 5.4 --- Results --- p.174 / Chapter 5.4.1 --- Validation of animal model of Alzheimer's disease --- p.174 / Chapter 5.4.2 --- Examination of normal and high iron diet on body weight --- p.174 / Chapter 5.4.3 --- Effects of Aβ accumulation and high-iron diet on hippocampal synaptic plasticity --- p.175 / Chapter 5.4.4 --- Effects of Aβ accumulation and high-iron diet on spatial memory measured by T-maze --- p.177 / Chapter 5.4.5 --- Effects of Aβ accumulation and high-iron diet on reference memory and working memory measured by radial arm maze --- p.178 / Chapter 5.5 --- Discussion --- p.180 / Chapter Chapter 6 --- General discussion --- p.195 / Reference --- p.200