Alzheimer′s disease╲t阿尔兹海默病.ppt

1、Neurobiology of Age-related Disorders Alzherimers Disease,Dr. William Ogle, PH. D Assistant Professor Department of Biomedical Engineering Mckinght Brain Institute University of Florida,Overview,Understanding How Your Brain Works,The brain performs an incredible number of tasks: It controls body tem

2、perature, blood pressure, heart rate and breathing. It accepts a flood of information about the world around you from your various senses (eyes, ears, nose, etc.). It handles physical motion when walking, talking, standing or sitting. It lets you think, dream, reason and experience emotions. All of

3、these tasks are coordinated, controlled and regulated by an organ that is about the size of a small head of cauliflower: your brain.,Each cerebral hemisphere can be divided into sections or lobes, each of which specializes in different functions When you plan a schedule, imagine the future, or use r

4、easoned arguments , these two lobes are working. When you enjoy a good meal-the taste, aroma, and texture of the food-two sections behind the frontal lobes called the parietal lobes are works. The forward parts of these lobes, just behind the motor areas, are the primary sensory areas.,The occipital

5、 lobes process images from the eyes and link that information with images stored in memory. Whether you appreciate symphonies or rock music, your brain responds through the activity of the temporal lobes. The cerebellum is responsible for learned rote movements.,Hippocampus: This tiny nub acts as a

6、memory indexer- sending memories out to the appropriate part of the cerebral hemisphere for long-term storage and retrieving them when necessary. Amygdala: The amygdala is a region of the brain that functions in the formation and storage of memories associated with emotional events. It is essential

7、in helping us read the emotions of others, and perhaps facilitated our ability to form relationships and live and work in groups.,Hypothalamus: It wakes you up in the morning, and gets the adrenalin flowing during a test or job interview. It is also an important emotional center, controlling the mol

8、ecules that make you fell exhilarated, angry, or unhappy. Cerebral cortex: Coating the surface of the cerebrum and the cerebellum is a vital layer of tissue the thickness of a stack of two or three dimes. Most of the actual information processing in the brain takes place in the cerebral cortex.,WHO

9、AM I?,where is my key?,HOW MUCH?,?,?,What is dementia?,Dementia symptoms may include asking the same questions repeatedly; becoming lost in familiar places; being unable to follow directions; getting disoriented about time, people, and places; neglecting personal safety, hygiene, and nutrition; Peop

10、le with dementia lose their abilities at different rates.,DEMENTIA,Cerebral atrophy Dementia of Frontal-lobe Type Huntingtons Disease Alcoholic Dementia AIDS- Related Dementia,Multi-Infarct Dementia,Related disorders,Alzheimers Disease,What is Alzheimers?,Alzheimers disease (AD) is the progressive b

11、rain disorder that occurs gradually and results in memory loss, unusual behavior, personality changes, and a decline in thinking abilities that cannot be reversed.,Multi-infarct Dementia,In multi-infarct dementia, a series of small strokes or changes in the brains blood supply may result in the deat

12、h of brain tissue. The location in the brain where the small strokes occur determines the seriousness of the problem and the symptoms that arise.,Background of Alzheimers disease,AD is the most common form of dementia in the elderly. Estimates of numbers affected worldwide are said to be approximate

13、ly 18 million. Looking at two Western countries as examples, the UK with a reported estimate of 420,000 AD sufferers in a population of approximately 60.6 million(0.7%) and the USA with reportedly 4.5 million sufferers in a total population of 298 million（1.5%）,we have an insight into the possible n

14、umber of cases in worldwide population of 6.5 billion.,Alzheimers four distinct clinical stages,Early stages of Alzheimers disease Intermediate stages of Alzheimers disease Severe stage of Alzheimers disease Final stages of Alzheimers,AD pathogenesis-Clues from the scene of the crime,Neurofibrilling

15、 Tangels Abeta (A) amyloid Senile plaques,Brain Atrophy,AD Etiology,Age- is the most important known risk factor for AD. The rates of the disease increase markedly with advancing age, with 25 percent of people over 85 suffering from Alzheimers or other severe dementia. The number of people with the

16、disease doubles every 5 years beyond age 65. Geneticsfamily history of AD is also one of the most consistent risk factors. Several risk factor genes may interact with each other and with non-genetic factors to cause the disease. The only risk factor gene identified so far for late-onset AD is a gene

17、 that makes one form of a protein called apolipoprotein E (ApoE).,Oxidative stress - is a feature of AD, and it localizes in areas specifically affected by the disease . Toxins- abnormal accumulation of iron participates in the induction of oxidative stress promoting neurodegeneration in AD. Vascula

18、r disease-It per se are now considered to be significant contributing risk factors.,Therapeutic Targets,Cholinergic strategies: Cholinesterase inhibitors Aricept Exelon Reminy (these inhibitors have been licensed for the treatment of mild to moderate AD) Other neurotransmitter approaches: Block the

19、release of excess glutamate -Ebixa MAO inhibitor-Selegiline (L-deprenyl),Neuroprotective strategies: estrogen replacement therapy Anti-inflammatory drugs Antioxidants Ginkgo biloba extract Alpha-tocopherol Glial cell modulation Calcium-channel blockers Immunotherapy for AD,Treatment for Mild to Mode

20、rate AD Medications called cholinesterase inhibitors are prescribed for mild to moderate AD. These drugs may help delay or prevent symptoms from becoming worse for a limited time and may help control some behavioral symptoms. The medications include: Razadyne (galantamine) Exelon (rivastigmine) Aric

21、ept (donepezil) Cognex (tacrine). Treatment for Moderate to Severe AD N-methyl D-aspartate (NMDA) antagonist: Namenda (memantine),Focus on distinct clinical stages,Oxidative Stress in the Development of Alzheimers Disease,The brain has one of the highest mass-specific oxygen consumption rates in the

22、 body. Oxidative stress contributes to pathology in AD and can be induced by chronic stress. The complexity of the disease makes it difficult to uncover unknown mechanisms involved in memory impairment, which may be targeted with novel treatments. Curcumin is extract form curcuma longa. This study i

23、nvestigated the effect of curcumin on impaired spatial memory and neuronal plasticity induced by chronic stress.,Background,Fig. 1. Learning curve in the water maze task of restraint-stressed rats treated with vehicle or curcumin. Trials were conducted after stressed animals were administered curcum

24、in for 21 days.,A,B,Fig. 2. Latency to reach the platform and the number of platform crossings during the immediate (A, B) probe trials of the water maze after 21 days of treatment with curcumin.,C,D,Fig. 3. Latency to reach the platform and the number of platform crossings during 24h (C, D) probe t

25、rials of the water maze after 21 days of treatment with curcumin.,Fig. 4. Effect of curcumin on serum corticosterone levels in restraint-stressed rats.,A,B,Fig. 6. Effect of curcumin on hippocampal dendritic remodeling in restraint-stressed rats. The number of apical branch points (A) and dendritic

26、length (B) for 50400 m segments from the soma of stressed rats treated with vehicle or curcumin.,C,D,Fig. 7. Effect of curcumin on hippocampal dendritic remodeling in restraint-stressed rats. The number of basal branch points (C) and dendritic length (D) for 50400 m segments from the soma of stresse

27、d rats treated with vehicle or curcumin.,C,D,E,F,B,A,Fig. 9. Effect of curcumin on Cu/Zn SOD immunoreactivity in the dentate gyrus of each of the treatment groups. F: Percentage difference in optical density (OD) of Cu/Zn SOD immunoreactivity in the dentate gyrus of stressed rats (n=6).,Fig. 10. Eff

28、ect of curcumin on corticosterone-induced cell death in hippocampal neurons.,A,G,B,C,D,E,F,Fig. 11. Effect of curcumin on corticosterone-induced ROS production in hippocampal neurons.,A. NMDA-R2A,B. Grik2,Fig. 12. Effect of curcumin on NMDA-R2A (A) and Grik2 (B) mRNA expression in corticosterone-tre

29、ated hippocampal neurons.,Summary & Conclusion,Curcumin may be effective in treating cognitive difficulties and the neuronal structural abnormalities that accompany chronic stress. The neuroprotective effect of curcumin is possibly mediated by its modulatory effect on LHPA axis function and oxidativ

30、e stress response as well as its ability to decrease in glutamate receptors in hippocampal neurons. 3. Curcumin may be an effective therapeutic for the cognitive dysfunction related to chronic stress and may also be beneficial in other related disorders such as AD.,AD Research Enters the Molecular A

31、ge,ER gene,ER/GR,Corticosterone,11HSD,GR,GR genes,MR,MR genes,dn GR,Figure: Representation of the glucocorticoid circuit with enhancement to ER/GR,Glucocorticoid Receptor,Nuclear Steroid Receptor Domains for ligand binding, dimerization, nuclear translocation, and DNA binding Modular in structure -

32、fusions may be created Located cytosolic (Inactive) Activated by ligand binding Homodimerization Nuclear translocation Bind appropriate hormone response element,Engineered Proteins - GR,Alternative splicing generates wild type (GR) and transdominant GR (GR) GR transdominant effects,1,795,1,757,rGRa,

33、rh-dnGRb,Transcriptional Activity,Antagonist/Agonist Activity,A/B,C,D,E,F,F,E,D,A/B,C,Engineered Proteins - ER/GR,ER/GR fusion Estrogen Receptor DNA binding domain Glucorticoid Receptor ligand binding domain Estrogen binding is neuroprotective Transdominant heterodimer formation,DNA Binding,DNA Bind

34、ing,DNA Binding,Ligand Binding,Ligand Binding,Ligand Binding,Hinge,Hinge,Hinge,hERa,rGRa,ER/GR,1,595,C,D,E,F,A/B,1,795,C,D,E,F,A/B,1,535,Dimerization,A/B,C,D,E,F,Gene Therapy,Exploits viruses for transfer of genes into host cells Remove viral genes not involved in packaging and replace with desired

35、transgenes Required genes may be delivered in trans for appropriate function Different vectors for different applications Achievable titers Tissue specificity Immune response Carrying capacity,Genes of Interest,Glucocorticoid cascade of gene expression (Ogle, et al. unpublished),Vector Design,Induci

36、ble promoter Activated by glucocorticoids Variable promoter strength (GRE number) Clinically important,Intron,Intron,Intron,Herpes Simplex Virus-1,Deletion of immediate early genes lead to latent infection and reduces immunogenicity Can be prepared to high purity Prevents reactivation of latent viru

37、s Amplicon vector allows for large packaging capacity,Plasmids,Helper Virus Da4,Amplicons,+ a4,Figure 1. Construction and expression of viral vectors.,Figure 2 .Transgenes alter corticosterone (cort)-induced nuclear translocation of GR in hippocampal neurons.,Figure 3. Transgene expression modulates corticosterone-induced gene expression.,Figure 4 .Transgene expression protects against the del