A New Look at Alzheimer’s Disease
The Four Horsemen
“Wholly”
Of the Mnestic Apocalypse
Trinity
How many here have ever known anyone
with Alzheimer’s disease?
How many here feel that your memory will be (/was/is)
better in your 50’s than in your 20’s?
THAT is the problem…
p
•
We all know that our memory was better when we were
younger than it is now.
now
•
We all know that Alzheimer’s disease affects the memory
and is very
y common.
•
So, do we all have a little bit of Alzheimer’s disease?
The problem:
•
Memory is such a critical faculty--we carry our lives, our
loves our existence in our memory.
loves,
memory
•
“If a tree falls in the forest…” But what if there is no
recollection--how do we know it happened?
pp
•
“I think, therefore I am.”--Descartes
•
“I remember, therefore I was (and still am!).”
Today, I would like to talk to you about our
studies on neurodegeneration,
neurodegeneration which are asking
what Alzheimer’s disease is all
about,, what memory
y is all about,, and why
y we need
to be able to forget as
well as to remember-this work is really teaching us about one
of the key abilities
that makes us human
human.
Progression of Alzheimer’s
William Utermohlen Self-Portrait
The facts and figures:
•
There are over 5 million people with Alzheimer’s in the
U S ; this number will exceed 13 million by 2050
U.S.;
2050.
•
•
Every 72 seconds someone is diagnosed with AD.
•
By the time symptoms of AD appear, the disease process has
AD costs
t th
the U
U.S.
S over $150 billion
billi annually.
ll
been ongoing for about 20 years.
What Rx is available?
•
Cholinesterase inhibitors: donepizil, rivastigmine,
galantamine tacrine
galantamine,
•
•
•
•
•
•
•
•
NMDA inhibitor: memantine
Vitamin E
Active and passive immunization to beta-amyloid
NSAIDs (Ibuprofen, etc.) and SALAs
BACE inhibitors (future Rx)
Gamma-secretase inhibitors
Statins
Estrogens? (vs. progestins)
Prevention ((and the flaw…))
•
•
3
•
•
•
•
•
•
•
Keeping cholesterol low (including statin use)
Exercise (SAD), Mediterranean diet, normotension, omegaAvoid head trauma
Keep insulin low, avoid type II diabetes mellitus
Education (prevention or negative association?)
Blueberries, raspberries, etc.
Curcumin; vitamin D
NSAIDs and SALAs
Estrogens; testosterone?
THE CURRENT VIEW (over 50,000 papers):
Alzheimer’s is a disease of toxicity.
Chemical and physical effects of Aß peptide:
•Lysosomotropic detergent
•Metal binding peptide
•Reactive
Reactive oxygen species
•Many other theories
PROBLEMS:
•Why make A peptides?
•Recent results from transgenic mice.
Cellular dependence
p
•Rita
Rita Levi-Montalcini
Levi-Montalcini, the 1986 Nobel Prize,
Prize and
the trophic factor hypothesis.
•
It has been generally assumed that trophic factor
withdrawal is associated with the loss of a positive survival
signal.
• However,
Ho e er data acc
accumulated
m lated o
over
er the past 16 years
ears arg
argue
e
that there is a complementary cell death signal mediated by
specific receptors, dubbed dependence receptors, activated
by trophic ligand withdrawal but blocked by ligand binding.
Levi-Montalcini and the classic view
Trophic
factor
Trophic factor
receptor
The old view: p
passive death
No trophic
ligand
Trophic factor
receptor
The Dependence Receptor Concept
Trophic
ligand
Dependence
Receptor
Anti trophic
Anti-trophic
or no
ligand
Programmed
cell
death
Dependence Receptors as Molecular Switches
CLASSICAL SIGNAL TRANSDUCTION
Presence
of Ligand
NEGATIVE SIG
GNAL TRANSDUCTION
Absence of
Trophic Ligand
k1
Complex
• Altered structure
(may be multimeric)
•  Caspase cleavage (AR)
• Anti-apoptotic
A ti
t ti signaling
i
li
ADD
L
Ligand
Dependence
Receptor
(p75NTR, AR, etc.)
k-1
Anti-Apoptotic
Signal
((NFB for p
p75NTR?))
A ti caspase
Active
(or possibly other protease)
k2
CP1
?
ADD
Pro-Apoptopic
Signal
CP2
Anti-Apoptotic
Anti
Apoptotic
Signal
Mitochondria?
Nuclei?
Other intermediates?
Pro-caspase
(or possibly other pro-protease)
Diversity of Dependence Receptors
DCC
UNC5Hs
p75NTR
p
Chopper
(D1185)
D1290
D412
ZU-5
Breast Cancer (from The Thermogram Center)
Immunoglobin-like domain
Thrombospondin type I-like domain
Fibronectin-like domain
D th d
Death
domain
i
Cysteine-rich domain
Tyrosine kinase domain
Alzheimer’s Disease (and Newsweek)
Neuroanatomy 101
Amyloid Precursor Protein (APP)
-secretase
-secretase
secretase
cleavage
cleavage
26D6
COOH
NH2
-secretase
cleavage
D664A
A “D664A”
CT15 antibody
KKKQYTSIHHGVVEVDAAVTPEERHLSKMQQNGYENPTYKFFEQMQN
664 antibody
“C31”
What happens to Mouzheimer’s if C31 is
p
prevented?
Non-lethal cell death signaling events
-synaptophysin
P idi
Propidium
iiodide
did
Synaptic density normalized by D664A Tg
The Mouse That Remembered to Roar:
Alzheimer’s Electrophysiology Normalized by Blocking C31
Normal mice can learn
“Mouzheimer’s”
Mouzheimer’s no more
Epileptiform EEGs in AD models
Alzheimer’s Phenotype Dissection
APP Dependent
p
APP Independent
p
•
Asp 664 Dependent
•
•
•
•
•
•
•
•
Synapse Loss
A
Atrophy
Memory Loss
Neophobia
EPSP, LTP
Neural Precursors
P-PAK
GSK--3
GSK
Asp 664 Independent
•
•
•
•
•
•
Senile Plaques
A1-40
A1-42
Nitro--Tyr
Nitro
Protein
P t i C=O
C O
4HNE
???
What mediates selective neuronal vulnerability in
Alzheimer’s disease?
Molecular Switch
For Neural Survival and Degeneration
Th 4 Horsemen
The
H
…
APP
sAPP
A
Jcasp
C31
…of the Mnestic Apocalypse
Molecular Switch
APP
sAPP
“Wholly”
p3
AICD
T i it
Trinity
Remembering and Forgetting With APP
Novel prions and anti-prions?
APP + A  2A + sAPP + Jcasp + C31
(“4 Horsemen”)
APP + Netrin-1
Netrin 1  sAPP
sAPP + p3 + AICD
(“Wholly Trinity”)
Theories of Prion-nativity
X
Special Theory: PrPSc + PrPC  2PrPSc
(Conformational mechanism)
Z (Z’)
General Theory: X + Y  2X
(Multiple mechanisms?)
Negative Feedback
(Homeostatic)
Prionic System
y
Metastable
Screening for Novel Therapeutics
A New Treatment
Synaptic element interdependence
and the most important
p
event…
Thank you, thank you, thank you
Veronica Galvan
Varghese
g
John
Alexander Patent
Clare Peters-Libeu
Alexei Kurakin
Daniel Lu ((UCSF))
Patrick Mehlen (now at CNRS)
David Madden
Kayvan Niazi (DTU)
Olivia Gorostiza
Joachim Angerer
Andrzej Swistowski
Karen Poksay
Shahrooz Rabizadeh ((ABBI))
Ram Rao
Joanna Fombonne
Veronique Corset
Patricia Spilman
p
Matthew Hart
Olivier Descamps
Sylvia Chen
Qiang
g Zhang
g
Thuy-Vi Nguyen
Mark Orcholski
Collaborators: Patrick Mehlen, Ed Koo, Lennart Mucke, John Reed,
Guy Salvesen,
Salvesen Doug Green,
Green Michael Hayden,
Hayden Jamal Nasir,
Nasir David
Greenberg, Brad Gibson, David Nicholls
Thanks for support: NINDS, NIA, NCI, ABI, ISOA, Drown Fdn.,
Hillblom, Rosenberg Foundation
The Buck Institute For Age
g Research
Extending the healthy years of life