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
AD Prevalence Age-Dependent 60 Percent Prevalence 50 40 30 20 10 0 65-69 70-74 75-79 80-84 85-89 90-94 95+ Age
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Cellular Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
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
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
AD: Pathology
AD: Pathology
AD: Pathology
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.
AD: Pathology
General Atrophy in Alzheimer s Disease
AD: Pathology Neuritic plaque Neurofibrillary tangles
AD: Pathology Thioflavin S displays a typical plaque & several tangles
AD: Pathology
AD: Pathology Typical plaque with amyloid core & dystrophic neurites
AD: Pathology Plaque amyloid is fibrillar and extracellular
AD: Pathology Plaques are composed of misfolded/ aggregated peptides called β amyloid (Aβ)
AD: Pathology Neurofibrillary tangle
AD: Pathology Tangles are often concentrated in the entorhinal nucleus
AD: Pathology EM shows a band of Paired Helical Filament
AD: Pathology The tangle is made up of paired helical filaments (PHF) composed of hyperphosphorylated Tau
The proportion of synapse loss is greater than that of neuron loss, synapses lost first
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
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)
Alzheimer Amyloid Precursor protein (APP) - processing
APP Processing α-pathway β-pathway
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 Aß40 4042 TGN trans medial cis Golgi 4. Early secretory pathway produces mainly Aß42 42 5. Cells that produce Aß42 in the ER do not secrete this Aß TND 2004 ER
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
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
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
The Alzheimer Amyloid Precursor protein (APP) - processing C99 β α C83 amyloidogenic non amyloidogenic
The Alzheimer Amyloid Precursor protein (APP) - processing β β' hu mo
The Alzheimer Amyloid Precursor protein (APP) - secretases BACE aspartic protease ph 4.5 Schematic structure of BACE
The Alzheimer Amyloid Precursor protein (APP) - processing the remaining C-terminal fragments are cleaved by γ-secretase. β α γ amyloidogenic non amyloidogenic
The Alzheimer Amyloid Precursor protein (APP) - processing and AD relevant Aß42 may be generated β α Aß γ 40 42 p3 amyloidogenic non amyloidogenic
γ-secretase Complex Presenilin Nicastrin APH-1 PEN-2
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
The Pathogenesis of AD Is Multifactorial and Complex
AD: Toxic Mechanisms?
AD: Toxic Mechanisms? Aluminum or other toxins Infectious agents Synaptic abnormalities Vascular/immune abnormalities Lack of growth factor Lipoproteins Protein abnormalities Oxidative stress
Alzheimer s Disease Is Likely Caused by High Levels of Aβ Normal Brain Severe AD Brain Aβ Aβ
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
Genetically Engineered Mice to Study AD and Test Specific Hypotheses AD Brain AD mouse Aβ Amyloid Plaques and Dystrophic Neurites AD Mouse
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
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
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)
AD: Toxic Mechanisms? Aggregates (Amyloid) Cross β-structure
Aβ & α-synuclein Caughey & Lansbury, Ann. Rev. Neurosci., 26:267 (2003)
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
Morris Water Maze
Spatial Learning and Memory Deficits in Six-Month-Old happ Mice
BEHAVIORAL DEFECITS IN TG MICE AT 6 MONTHS
BRAIN FRACTIONATIONS
Aβ*
UREA DOES NOT AFFECT Aβ OLIGOMERS
EFFECT OF HFIP ON Aβ OLIGOMERS
PURIFICATION OF Aβ OLIGOMERS
ANTI-OLIGOMER ANTIBODY ONLY RECOGNIZES 6-12mers
SDS NOT INDUCING Aβ OLIGOMERS
Aβ OLIGOMERS STABLE
Aβ OLIGOMERS STABLE
Aβ OLIGOMERS & MEMORY DEFICITS
Aβ OLIGOMERS & MEMORY DEFICITS
PURIFICATION OF Aβ*
STRUCTURE OF Aβ* Cheng et al., J. Biol. Chem., 282:23,818 (2007)
EFFECTS OF Aβ* ON MEMORY (24h)
EFFECTS OF Aβ* ON MEMORY AFTER 10 DAYS
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
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
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?)
ApoE4 Decreases the Age of Onset of AD Non Alzheimer Cases (% of total) 100 80 60 40 20 0 ApoE4 1 ApoE4 2 ApoE4 60 70 80 90 Age at Onset (years)
ApoE Genotype in Control and AD Populations
The Effects of ApoE genotype on the Evolution of Brain Dysfunction
Plaques and Tangles Contain ApoE
Structure of a Lipoprotein ApoB48 ApoC ApoE Triacylglycerols Phospholipids
OUTLINE I. Clinical manifestations II. Pathology III. Genetics & APP Processing IV. Toxic Mechanisms V. Genetic risk factors (ApoE) VI. Treatments
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
ACETYLCHOLINE Neurotransmission in autonomic NS Neuroendocrine activity Learning and memory Muscarinic & nicotinic receptors
Choline acetyltransferase ACh Acetylcholinesterase + water choline acetate
AD: Treatments NSAIDS Antioxidants (Vitamin E) Estrogen therapy Statins Red wine, exercise, etc. None halt progression, many in development
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.
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...
Some good news? Marijuana may block Alzheimer's The active ingredient in marijuana may stall decline from Alzheimer's disease, research suggests.