Your brain evolved to decide:

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Your brain evolved to decide

• Whats for dinner?

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Progress in Alzheimers Disease

• Greg M Cole, Prof. Medicine and Neurology, UCLA
• ASSOC. DIRECTOR, GRECC, Greater LA VAMC
• ASSOC. DIRECTOR, Alzheimers Disease Research
  Center, UCLA

Aristotle taught that the brain exists merely to
cool the blood and is not involved in the
process of thinking. This is true only of certain
persons. - Will Cuppy
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What is Alzheimer's Disease?
Alzheimer's disease is a progressive,
degenerative disease that attacks the brain and
results in impaired memory, thinking, and
behavior. It affects an estimated 4 million
American adults today . Extracellular Amyloid
Plaques and intracellular tangles, NEURON AND
SYNAPSE LOSS.
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"Is Your Brain Really Necessary? R. Lewin
Science 2101232, Dec 1980

• Although the boy had an IQ of 126 and had a first
  class honours degree in mathematics, he had
  "virtually no brain".  A CAT scan showed a thin
  layer of brain cells to a millimeter in
  thickness, the rest was cerebrospinal fluid.  The
  young man continues a normal life with the
  exception of his knowledge that he has no brain
• "I can't say whether the mathematics student has
  a brain weighing 50 grams or 150 grams, but it is
  clear that it is nowhere near the normal 1.5
  kilograms." Dr J. Lorber, Neurologist

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1995-Neuron loss the cause of dementia?
Born with 100 Billion Neurons Living/Learning/Tra
ining/Studying---Neurons form Networks
Neurons loss causes network deficiency leading to
memory loss , other cognitive deficits and
behavior changes.
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Neuron replacement? Where do you get spare
parts? Get Rael or Stem Cell Initiative ?
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NEURONS CONNECTIONS SYNAPSES

• NEUROTRANSMITTERS TRANSDUCE THE ELECTRICAL SIGNAL
  FROM THE PRESYNAPTIC NEURON (AXONAL) ACROSS THE
  GAP TO RECEPTORS ON THE POST-SYNAPTIC
  (SOMATO-DENDRITIC )SIDE OF THE NEXT NEURON AT
  SYNAPSES
• EXAMPLES OF NEUROTRANSMITTERS ACETYLCHOLINE,
  DOPAMINE, NOREPINEPHRINE, SEROTONIN, GLUTAMATE

LOST
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• MR, AD and APP Tg mice have dendritic spine
  defects
• Dendritic spine formation and loss requires
  regulated actin assembly and disassembly which is
  central to synaptic changes during learning
  (plasticity)

Multiple Mental Retardation syndromes and AD
overlap with dendritic spine defects and
cognitive deficits. Downs syndrome epitomizes
this overlap, spine defects
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Dendritic Arbor, Spine Synapse loss
MOOLMAN, SHELANSKI-04
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Where we were 10 years ago

• Disease caused by neuron loss
• Two camps amyloid fibril toxicity and tangles
• No accepted animal models
• Difficulty in diagnosis of AD until autopsy
• confirmation.
• Cholinesterase inhibitor treatments
• Very few clinical trials directed at the causes
  of underlying disease

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Current FDA-approved therapies employ
cholinesterase inhibitors which treat the loss
of cholinergic neurotransmitter activity but
have little affect on causes of underlying
disease leading to synapse and neuron loss

• Donepezil (Aricept)
• 5 mg gradually increasing to 10 mg qd ( half-life
  70 h, hepatic metabolism)
• Galantamine (Reminyl)
• 4 mg bid increasing to 12 mg bid, half-life 6 h,
  hepatic metabolism

• Rivastigmine (Exelon)
• 1.5 mg bid increasing to 6 mg bid half-life 2h
  (8 h in brain), non hepatic metabolism

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Mutations Implicate Abeta
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Genetics of Alzheimers Disease
Genetic Cases
Late Onset (gt90)
Early Onset (lt10)
Unknown Mutations
Chr12 ? Locus
Chr1 PS2
Chr19 APOE
Chr21 A?PP
Chr14 PS1
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Up to 60
lt5
15-60
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70 of AD cases unexplained, likely polygenic and
will require risk assessment chip
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SEARCH FOR WMDTaoists believe in tau protein
-Tangles ßaptists believe in ß-amyloid Protein
Plaques

• or Invisible Aß oligomer toxins in the middle?

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Insoluble Toxic Deposit
Amyloid Protein Folding and Self Aggregation
Soluble, NonToxic
Monomer
Dimer
Trimer
Oligmer/Protofilbril
Amyloid filbril
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Aß Oligomers
(Courtesy Dr. Jeffery Cummings, UCLA)
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Pathogenesis Of AD Amyloidosis
Secretion
Aggregation
Fibrillogenesis
B
Microglial Cell
Neuron
F
D
A
I
N
H
C
E
G
Reactive Astrocyte
Clearance
Clearance
Clearance
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Transgenic Tests for Risk Factors- 1Tg 2576
(Hsiao) Mice Transgenic for human Amyloid
Precursor with AD mutation lots of amyloid but
little or no synapse or neuron loss
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Candidate Risk Factors for AD Yellow -tested in
APP Tg mice

• Increase risk
• Aging
• ApoE E4
• Head injury
• Inflammation-CRP
• High cholesterol,low HDL
• High fat diet/Type II diabetes
• Low fish/DHA
• High blood pressure
• High homocysteine
• Low exercise?
• NOSE PICKIING??

• Decrease risk
• Die young
• ApoE E2
• Education enriched environ
• NSAIDs-ibuprofen, flurizan
• Statins
• High Fish/DHA
• ? Red wine modest alcohol
• Fruits Veggies- blueberries
• Vit E/VitC
• Folate?
• Exercise? enriched environ

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23 studies show NSAIDs reduce AD risk-McGeer
meta-analysis
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Effect of ibuprofen in TG mouse modelLim et
al., 2000, J. Neuroscience. 20579814

• Chronic (10-16 mo) ibuprofen reduced
• plaque burden and Aß levels 40-50
• Interleukin 1ß levels
• Microgliosis
• Astrocytosis
• Neuritic plaques
• Caspase activation per plaque

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Evidence that NSAIDs directly effect g-secretase
and Aß42

• No involvement of multiple other NSAID targets
  COX NFkB lipoxygenases peroxisome
  proliferator-activated receptor (PPAR) signaling
• Weggen Nature 2001 JBC 2003, Morihara J Neurochem
  2002,
• Sagi JBC 2003, Eriksen JCI 2003
• Aß42 reduction was preserved in cell-free systems
• -Takahashi,Tomita, Iwatsubo et al JBC 2003,
• Sagi JBC 2003, Eriksen JCI 2003
• PS-1 mutations APPmut around g-sec site (V717)
  influence efficiency of Aß42 suppression by
  NSAIDs
• Weggen JBC 2003

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Problems with NSAID Approach

• Dosing? Are chronic high doses needed?
• Chronic NSAIDs have GI CVD toxicity issues
• NSAID primary prevention trial with COX-2
  inhibitor and naproxen-Breitner
• Dec 2004, Trial stopped due to questions about
  chronic safety and CVD with Vioxx, Celebrex,
  naproxen etc
• Alternative R-enantiomers (R-flurbi in trials )
• ALTERNATIVE NSAIDs?
• What about diet?

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Myriad R-flurbiprofen (flurizan) phase II trial--
800 mg BID, 48 patientsG. Wilcock (Bristol)
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Mc D DAY- McDonalds Invades Japan
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DHA (C226, n-3) and brain

• Essential fatty acids-
• linoleic acid (182 n-6 gtgtgtarachidonic (ARA, n-6
  series)
• Linolenic acid (183 n-3) gtgtgtdocosahexanoic acid
  (DHA, n-3)
• n-6 pro-inflammatory, n-3 are anti-inflammatory
• Ratio of n-6/n-3 is optimal near 41.
• DHA ( fish, algae) is crucial in brain/retina
  development and CNS maintenance in adults
• DHA is very high in brain (31 of FA in PE in
  cortex)
• Six double bonds make it most susceptible to
  oxidative attack.

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Mouse chow has abundant DHA, C226, n-3) (from
fish).

• Fish and DHA intake reduce AD risk, (Kalmijn,
  Grant, Kyle, Morris and others)
• Low n-6/n-3 PUFA ratio diets have less risk of AD
  with an optimum protection from 41 ratio
• DHA or derivatives like neuroprotectins are
  neuroprotective in multiple systems
• NIH-31 based chow has an 41 n-6/n-3 ratio . Is
  the diet protective?

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BAD Diet depleted of DHA(w3)

• Tg2576 and Tg- Mice aged to 17 months on
  standard (Purina 5015 ) breeder chow diet
  (w-6/w-371)
• From 17 to 22.5 months, groups placed on 3
  different diets
• 1. Standard diet (w-6/w-3 71)-soy
• 2. BAD diet ( w-6/w-3 851)- safflower
• 3. BAD diet DHA (w-6/w-3 81).

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APP Transgenics on DHA depleting Bad diet -
Calon et al Neuron Sept 2004

• Major loss of dendritic spine protein, drebrin,
  PSD-95 PI3-K p85 in model AD
• Increased oxidative damage and focal postsynaptic
  caspase activation , but no neuron loss.
• Increased cognitive deficits
• CaMKIIa, but not NR2B loss restored by DHA -in
  press, Calon et al 2005 EJN

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DHA lowers plaque burden
Low DHA
High DHA
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DHA treatment causes reduction in insoluble Ab42
and Ab40 levels of APPSw mice-
Insoluble Ab42
Insoluble Ab40
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DHA protects against diet-induced increase of
oxidative damage
Carbonyls
Tg

40 30 20 10 0

Optical density
p lt 0.001 vs. Standard diet p lt 0.01
vs. Low DHA diet
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TG mice (but not Tg- mice) had significant CNS
DHA depletion. Consistent with increased
oxidative damage in Tg2576.
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Diet X Tg Interaction
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DHA Inhibits GSK3ß a major tau kinase in Ent
Cortex

• GSK3ß (tau kinase 1)
• can
• Mediate Aß toxicity
• Cause apoptosis
• Drive tangles
• GSK3a can
• regulate g-secretase

GSK inhibitory ser9 phosphorylation is increased
by DHA in vivo.
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Vit E (10-16 mos) failed to protect
Oxidative damage (carbonyls)
Insoluble amyloid
And Vit E failed to protect against

• Atherosclerosis, lung cancer
• Lipoprotein oxidation in AD CSF
• Transition from MCI to AD

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What is Curcumin?
A group of polyphenolic plant pigments,
responsible for currys yellow color.

• Extracted from the roots of Curcuma Longa plant
• Ground into a powder used in Asian cuisine
• Marketed OTC as a mixture of three related
  compounds
• curcumin, (being the most active)
• demethoxycurcumin
• bisdemethoxycurcumin
• collectively termed "curcuminoids"

Roots
Powder
Wild Flower
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Incidence of Dementia in India Compared to the US
Incidence Per 1000 Person- Years
(Chandra et al, Neurology 2001 57 985-989)
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Curcumin from Turmeric .

• diferulomethane, M.W. 368.4
• Cancer chemoprevention, Phase II inducer
• Antioxidant (OH, O2-, NO), inhibits brain lipid
  peroxidation 5-10x better than vit E
• Anti-inflammatory ( inhibits induction of iNOS,
  Cox-2, cytokines etc)
• Lowers total cholesterol, raises HDL
• Metal (iron) chelator
• Favorable toxicity profile (animals/people)
• Life extension in mice

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Curcumin resembles known amyloid and oligomer
inhibitors

• Curc inhibits prion assembly-B Caughey
• Curc inhibits fibril assembly
• Curc inhibits oligomer assembly
• Other aggregates in neurodegenerative diseases???

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Curcumin inhibits Aß aggregation in vitro- Yang
et al JBC 2004
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In brain sections, Curcumin (left) labels amyloid
plaques just like thioflavin (right)
curcumin
Thioflavin S
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Curcumin in diet (B) or injected iv (C,D) labels
CNS plaques in vivo demonstrating brain
penetration and avidity for amyloid
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Curcumin prevented fibril formation,
disassociated pre-formed fibrils (In vitro- Ono
et al. 2004 (IC50lt 1µM)) , and reduced plaques
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In vitro, with rat microglia on AD sections,
Curcumin increases µglia in high plaque but not
low plaque areas compared to vehicle-treated
adjacent sections
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Curcumin stimulates murine microglial
phagocytosis of plaques in human AD sections
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Curcumin reduces total Aß (by ELISA) from human
AD sections incubated with murine microglia
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Curcumin induces amyloid phagocytosis in vivo?

• RED -Aß
• GREEN -microglia
• Yellow overlap
• 6 mos curcumin in APPsw mice

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Some NSAIDS reduce amyloid
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Curcumin Inhibition of Oligomer Formation as
Compared with CR

• 22 mer
• 11 mer
• 5 mer
• 4 mer
• 1 mer
• 1 mer

Oligomer -
-
Monomer


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Curcumin (NSAID/AO) reduces drebrin
postsynaptic marker loss
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Pilot Curcumin Clinical TrialJ. Ringman J.
Cummings (UCLA Alzheimer Center)

• 40 patients with 0, 2000 and 4000 mg
• before and after 6 months drug examining CSF
  biomarkers (oxidative damage, inflammation, tau,
  amyloid ) cholesterol
• PET imaging of amyloid and energy metabolism
• Cognitive function out to 12 months.

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Conclusions

• NSAIDS like ibuprofen reduce amyloid pathogenesis
  and AD risk, but may have safety issues with
  chronic high dose use
• The curry spice curcumin is a safe and intriguing
  alternative polyphenolic antioxidant/ NSAID with
  multiple anti-amyloid activities
• The omega 3 fatty acid DHA reduces AD risk,
  effectively limits AD pathogenesis and has an
  outstanding safety profile

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Developing Tools for Early Detection of
Alzheimers Disease
Amyloid and Tau Imaging
SS
FDG-PET
Cognitive Stress Test
5-HT1A
Genetic Risk
Onset
Current Clinical Approach
Cognitive Function
Silent Period
Early stage
AD
Time
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Cerebral Metabolism in Alzheimers Disease
Progression and in Normal Brains-an index of
synaptic activity?
Normal
Early Alzheimer's
Late Alzheimer's
infant
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AD Tangles/Plaques, Metabolism and 5-HT1A
Receptors
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PET -F-18FDDNP Logan plot parametric images
- In vivo (Barrio, Kepe, Small)
wild-type control rat
AD Tg rat
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K. Hsiao Ashe, Science 2005
Images courtesy of Karen H. Ashe, University of
Minnesota
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FDDNP In vivo Labeling of Tau Aggregates in Tau
TG
Collaboration with Karen Ashe, U.Minn
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Where we are today

• Better diagnosis through imaging and much better
  imaging at research tool stage
• Multiple valuable animal models
• Some treatments with limited efficacy
• Suggestive positive trials that appear to slow
  progression (Vaccine, aggregation inhibitor,
  Flurizan,)
• More than 53 Clinical Trials to find out the ways
  to treat or prevent AD, most based on amyloid
  hypothesis.

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Conclusion Control Risk Factors for Dementia to
Prevent

• Increase risk
• Low exercise
• High cholesterol,low HDL
• Type II diabetes
• High saturated fat
• Inflammation-CRP
• Low fish/DHA
• High blood pressure
• High homocysteine

• Protection
• Exercise (walk gt2 miles/day)
• Statins-Lipitor trial positive
• folate
• High Fish/DHA, low sat fat
• Vit E/Vit C ibuprofen
• Curcumin
• polyphenolsHigh Fruits Veggies, Juices
• ? Red wine modest alcohol

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In the next 10 yrs

• Early (pre-MCI) diagnosis combining imaging with
  better probes and blood tests
• Effective prevention strategies, but no proof
• Anti-amyloid therapeutics will slow progression
• Attempts at stem cell therapy to treat?

• Successful tau therapies in new animal models
• Clinical trials with anti-tau therapies will
  improve cognitive function
• Combination therapy to restore dendritic spines
  and synaptic function of remaining neurons will
  be a remarkably effective treatment?

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Where we are going IF NOTHING IS DONE- Expect 14
Million US Cases
High
Median
Millions
Low
Year
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Whole World Dementing?

• The world's population is ageing.
• 18 million people in the world with
  dementia.
• 66 of people with dementia live in developing
• countries.
• Dementia numbers will increase, especially in
  rapidly
• developing and heavily populated regions
  such
• as China, India and Latin America
• EXPECT DOUBLING AND DOUBLING AGAIN

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Salmon for dinner

• Yellow Curry for lunch

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UCLA, Sepulveda VA Medical Center Alzheimers
Disease Research Laboratory, 2002
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Lab Collaborators
Collaborators Sally Frautschy K. Hsiao Ashe A.
Triller B. Teter N. Salem T. Montine
Lab Takashi Morihara MD, PhD Sheldon Ball,
MD,PhD
Frederic Calon, PhD Giselle Lim, PhD Lixia Zhao,
PhD Fusheng Yang, MD Oliver Ubeda P.P.
Chen Walter Beech Jonathan Yao
Support NIH, Alz Assoc, VA, Siegel Life
Project