ALZHEIMER S DISEASE FACTOIDS & STATISTICS

Transcription

1 ALZHEIMER S DISEASE FACTOIDS & STATISTICS ~ 4 million affected in US alone 6-8% if 65+ years old, 30-50% if 80+ By 2030, in US >65 million people >65+ (---> ~14 million with AD) AD is one of the top 10 leading causes of death in Americans over 65 years of age 3rd most expensive disease after heart disease, cancer ($61 billion in 2002 in US alone) Federal funding 4-7X lower than for heart disease, cancer, AIDS

2 AD Prevalence Age-Dependent 60 Percent Prevalence Age

3 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Cellular Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

4 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

5 CLINICAL MILESTONES IN AD Emergence of cognitive symptoms Conversion from MCI to dementia Emergence of neuropsychiatric symptoms Nursing home placement Loss of self-care Death

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7 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

8 AD: Pathology

9 AD: Pathology

10 AD: Pathology

11 AD: Pathology Normal AD PET (positron emission tomography) scans show differences in brain activity between a normal brain and a brain affected by Alzheimer s disease. Blue and black in the images above denote inactive areas.

12 AD: Pathology

13 General Atrophy in Alzheimer s Disease

14 AD: Pathology Neuritic plaque Neurofibrillary tangles

15 AD: Pathology Thioflavin S displays a typical plaque & several tangles

16 AD: Pathology

17 AD: Pathology Typical plaque with amyloid core & dystrophic neurites

18 AD: Pathology Plaque amyloid is fibrillar and extracellular

19 AD: Pathology Plaques are composed of misfolded/ aggregated peptides called β amyloid (Aβ)

20 AD: Pathology Neurofibrillary tangle

21 AD: Pathology Tangles are often concentrated in the entorhinal nucleus

22 AD: Pathology EM shows a band of Paired Helical Filament

23 AD: Pathology The tangle is made up of paired helical filaments (PHF) composed of hyperphosphorylated Tau

24 The proportion of synapse loss is greater than that of neuron loss, synapses lost first

25 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

26 AD: Genetics Tauist, or Baptist? First mutations (5), amyloid precursor protein (APP) Next set of mutations, Presenilin 1 and 2 (PS1, PS2) Down s syndrome (trisomy 21) Late onset not truly mendelian (yet 25-50% first relative rate vs. 10% in controls) Tau mutations cause Frontotemporal dementia with parkinsonism linked to chromosome 17 (FTDP)

27 Alzheimer Amyloid Precursor protein (APP) - processing

28 APP Processing α-pathway β-pathway

29 Aβ sub-cellular localization and organelles of production 4042 PM Endosomes SV 1. Cells with neuronal phenotype produce more intracellular Aß 2. Other cell types produce mainly secretory Aß 3. Late secretory pathway produces mainly Aß TGN trans medial cis Golgi 4. Early secretory pathway produces mainly Aß Cells that produce Aß42 in the ER do not secrete this Aß TND 2004 ER

30 The Alzheimer Amyloid Precursor protein (APP) - processing One of the most important aspects of APP are the different steps of its degradation Commonly these processing steps have been grouped into the amyloidogenic (Aβ producing) and the nonamyloidogenic pathway amyloidogenic APP There are multiple proteases involved and the specifics of how they are used in this process largely defines the cellular and the pathological role of APP. Aβ-related region extracellular or cytosolic domains non amyloidogenic

31 The Alzheimer Amyloid Precursor protein (APP) - processing APP TACE / ADAM10 Most APP molecules are first cleaved by α-secretase α (a disintegrin and metalloprotease family) amyloidogenic non amyloidogenic

32 The Alzheimer Amyloid Precursor protein (APP) - processing APPsß if not cleaved by α-secretase APP will be cleaved by β-secretase APPsα β α amyloidogenic non amyloidogenic

33 The Alzheimer Amyloid Precursor protein (APP) - processing C99 β α C83 amyloidogenic non amyloidogenic

34 The Alzheimer Amyloid Precursor protein (APP) - processing β β' hu mo

35 The Alzheimer Amyloid Precursor protein (APP) - secretases BACE aspartic protease ph 4.5 Schematic structure of BACE

36 The Alzheimer Amyloid Precursor protein (APP) - processing the remaining C-terminal fragments are cleaved by γ-secretase. β α γ amyloidogenic non amyloidogenic

37 The Alzheimer Amyloid Precursor protein (APP) - processing and AD relevant Aß42 may be generated β α Aß γ p3 amyloidogenic non amyloidogenic

38 γ-secretase Complex Presenilin Nicastrin APH-1 PEN-2

39 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

40 The Pathogenesis of AD Is Multifactorial and Complex

41 AD: Toxic Mechanisms?

42 AD: Toxic Mechanisms? Aluminum or other toxins Infectious agents Synaptic abnormalities Vascular/immune abnormalities Lack of growth factor Lipoproteins Protein abnormalities Oxidative stress

43 Alzheimer s Disease Is Likely Caused by High Levels of Aβ Normal Brain Severe AD Brain Aβ Aβ

44 Alzheimer s Disease Is Likely Caused by High Levels of Aβ Normal Brain Severe AD Brain Aβ Aβ learning and memory centers: hippocampus and dentate gyrus

45 Genetically Engineered Mice to Study AD and Test Specific Hypotheses AD Brain AD mouse Aβ Amyloid Plaques and Dystrophic Neurites AD Mouse

46 High Levels of Aβ Induce Learning and Memory Deficits in Humans and in Mouse Models AD Brain Aβ happ FAD AD mouse models Healthy mouse (NTG) Aβ

47 High Levels of Aβ Induce Learning and Memory Deficits in Humans and in Mouse Models AD Brain Aβ happ FAD AD mouse models AD Mouse (TG) Aβ

48 AMYLOID HYPOTHESIS Aggregation of proteins into an ordered fibrillar structure is causally related to aberrant protein interactions that culminate in neuronal dysfunction and cell death Hardy and Selkoe, Science 297, 353 (2002)

49 AD: Toxic Mechanisms? Aggregates (Amyloid) Cross β-structure

50 Aβ & α-synuclein Caughey & Lansbury, Ann. Rev. Neurosci., 26:267 (2003)

51 A SIMPLIFIED MODEL FOR AMYLOID ASSEMBLY KEY QUESTION: WHAT IS THE TOXIC CONFORMATION? OR ASSEMBLY THAT MEDIATES NEURONAL DYSFUNCTION? NATIVE CONFORMATION ABNORMAL MONOMERIC CONFORMATIONS SPHERICAL OLIGOMERS FIBRILS ANNULAR OLIGOMERS? AMORPHOUS AGGREGATES

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54 Morris Water Maze

55 Spatial Learning and Memory Deficits in Six-Month-Old happ Mice

56 BEHAVIORAL DEFECITS IN TG MICE AT 6 MONTHS

57 BRAIN FRACTIONATIONS

58 Aβ*

59 UREA DOES NOT AFFECT Aβ OLIGOMERS

60 EFFECT OF HFIP ON Aβ OLIGOMERS

61 PURIFICATION OF Aβ OLIGOMERS

62 ANTI-OLIGOMER ANTIBODY ONLY RECOGNIZES 6-12mers

63 SDS NOT INDUCING Aβ OLIGOMERS

64 Aβ OLIGOMERS STABLE

65 Aβ OLIGOMERS STABLE

66 Aβ OLIGOMERS & MEMORY DEFICITS

67 Aβ OLIGOMERS & MEMORY DEFICITS

68 PURIFICATION OF Aβ*

69 STRUCTURE OF Aβ* Cheng et al., J. Biol. Chem., 282:23,818 (2007)

70 EFFECTS OF Aβ* ON MEMORY (24h)

71 EFFECTS OF Aβ* ON MEMORY AFTER 10 DAYS

72 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

73 AD & ApoE Late onset AD ~95% of cases All mutations lead to early onset 3 dozen putative genetic risk factors/ modifiers identified for late onset AD Only ε4 allele of APOE validated

74 AD & ApoE & Cholesterol ApoE major apolipoprotein in plasma (VLDL), main cholesterol carrier in brain 3 common alleles of APOE (ε2, ε3, ε4) Homozygosity at ε4 allele --> 8X AD risk (2%) APOE knockout in APP mice inhibits Aβ amyloid deposition, not synthesis Cholesterol linked to increased AD risk; statins may protect against AD (lipid affects?)

75 ApoE4 Decreases the Age of Onset of AD Non Alzheimer Cases (% of total) ApoE4 1 ApoE4 2 ApoE Age at Onset (years)

76 ApoE Genotype in Control and AD Populations

77 The Effects of ApoE genotype on the Evolution of Brain Dysfunction

78 Plaques and Tangles Contain ApoE

79 Structure of a Lipoprotein ApoB48 ApoC ApoE Triacylglycerols Phospholipids

80 OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments

81 AD: Treatments Loss of cholinergic neurons is believed to account for much of the learning and memory deficit Anticholinesterase inhibitors (Aricept, Tacrine, Reminyl, Exelon) are approved though limited in benefit

82 ACETYLCHOLINE Neurotransmission in autonomic NS Neuroendocrine activity Learning and memory Muscarinic & nicotinic receptors

83 Choline acetyltransferase ACh Acetylcholinesterase + water choline acetate

84 AD: Treatments NSAIDS Antioxidants (Vitamin E) Estrogen therapy Statins Red wine, exercise, etc. None halt progression, many in development

85 NSAIDS: Celebrex FDA 12/17/04, NCI polyp study Patients in the clinical trial taking 400mg of Celebrex twice daily had a 3.4 TIMES (emph) greater risk of CV events compared to placebo. For patients in the trial taking 200mg of Celebrex twice daily, the risk was 2.5 TIMES (emph) greater. The average duration of treatment in the trial was 33 months.

86 NSAIDS: Celebrex February 03, 2005 Pfizer Denies It "Never Revealed" Alzheimer's Disease Findings In today's Boston Herald: "...Pfizer Inc. denied a consumer group's accusation that the company never revealed findings in a 1999 study linking its painkiller Celebrex to a higher risk of heart attack... Pfizer, which posted the dangers on an industry Web site last month, insisted it had submitted the results to the U.S. Food and Drug Administration four years ago." Read more...

87 Some good news? Marijuana may block Alzheimer's The active ingredient in marijuana may stall decline from Alzheimer's disease, research suggests.