Slide 1

Report
Healthy
Alzheimers
1) Loss of neurons
(cortical degeneration)
3
Prevents tubulin
2
Amyloid Precursor Protein (APP)
• 10 different isoforms (alternative splicing)
• Transmembrane region at the Carboxyl end
allows shorter isoforms to localize to the
neuronal membrane, and in the Golgi bodies
• Longer isoforms are found in non-neuronal
cells
• Normal function = Receptor? Adhesion?
Amyloid Precursor Protein
The enzymes that cut these
are called ‘Secretases’
(specific proteases)
Normally cut
In healthy cells
Figure 14.9
Neuron
Amyloid Precursor Protein
No AD
Normally cut
In healthy cells
Figure 14.9
Neuron
Amyloid Precursor Protein
No AD
No AD
Normally cut
In healthy cells
Figure 14.9
Neuron
Amyloid Precursor Protein
No AD
No AD
AD
Normally cut
In healthy cells
Figure 14.9
Neuron
Amyloid proteins
(40 or 42 amino acid)
cause plaques
to form in the brain
Check out this link to photo from the
brain of a 76 year old with Alzheimers
http://vm.cclcm.ccf.org/slide.jsp?instGUID=90ADFDBE-7CAA-4925-2FE3-6E26EB6B33A6
Plaque
Neurofibrillary Tangles (tau Tangles)
They look like flames (or tadpoles)
tau protein normally helps
microtubule assembly
and stability
Phosphorylation of tau
Microtubules help transfer
vesicles & send signals
down the axon
http://www.uphs.upenn.edu/news/News_Releases/dec04/paclitaxel.htm
< Animation
Two Types of AD:
Early Onset (before 65 years of age) =
less than 10% of AD; caused by dominant
mutations on Chromosomes 1, 14 or 21…
even if one of these genes are inherited > AD
Chromosome 21 = Amyloid Precursor Protein
Early Onset AD:
Phenotype the same as Late Onset AD,
except shows up between ages of 45-60.
Late Onset AD don’t have mutation on APP
Chromosome 21 = Amyloid Precursor Protein
Missense mutations
V717I
V717G
V717F
I716V
K670N
M671L
This somehow encourages
the removal of the
Beta-Amyloid segment
What comes first?
The disease?
The plaques?
The tau Tangles?
Two Types of AD:
Early Onset (before 65 years of age) =
less than 10% of AD; caused by dominant
mutations on Chromosomes 1, 14 or 21…
even if one of these genes are inherited > AD
Chromosome 21 = Amyloid Precursor Protein
Chromosome 14 = Presenilin-1 (helps γ-Secretase)
Chromosome 1 = Presenilin-2 (rare; helps Secretases)
By 1995, researchers knew that there were
three proteases that were cleaving the
β-Amyloid fragment and set about to find the
genes involved.
Most of the searching was done by
pharmaceutical companies….
Finally, in 1999 GlaxoSmithKline announced
they had cloned β-Secretase !
Two Types of AD:
Late Onset (after 65 years) = 90% of cases;
often due to sporadic mutations, but can be
inherited (not one gene in particular,
probably multigenes).
Example = Apolipoprotein E (Chromo. 19)
…called a “risk factor”
The Amyloid Precursor Protein is not mutated
In most cases of Late Onset AD
Two Types of AD:
Late Onset
Apolipoprotein E (Chromo. 19)
Synthesized by Astrocytes (non-neuronal cells)
that control passage of things, like cholesterol,
to the brain…Blood-Brain Barrier)
• Published in February 2006
• Twin Study (done in Sweden)
• 2800 set of twins over the age of 65 were tested for
dementia and AD
Gatz, M. et al. Arch Gen Psychiatry 2006;63:168-174.
Copyright restrictions may apply.
Prevalence of Total Dementia and Alzheimer Disease, Probandwise Concordance Rates, and
Tetrachoric Correlations (With 95% Confidence Intervals) by Zygosity and Sex
See pages 10-11 of our book
Of twins (where one has AD) how often do both have AD?
Gatz, M. et al. Arch Gen Psychiatry 2006;63:168-174.
Copyright restrictions may apply.
They also calculated heritability
Calculated heritability
of AD to be 58%
Prevalence of Total Dementia and Alzheimer Disease, Probandwise Concordance Rates, and
Tetrachoric Correlations (With 95% Confidence Intervals) by Zygosity and Sex
Gatz, M. et al. Arch Gen Psychiatry 2006;63:168-174.
Copyright restrictions may apply.
Canadian Family Physician Feb. 2006
• Controlling menopause with estrogen doesn’t help
• Currently, no great pharmaceutical advances
But, these things help:
• Controlling high blood pressure
• Healthy lifestyle (diet, sleep,
• Ongoing education (‘new learning’)
• Regular physical activity
• Lowering cholesterol (Apolipoprotein E)
• Preventing early head trauma
But drug development is underway
Four million Americans
have Alzheimers.
What sort of medicines
might be designed to
fight Alzheimers
Disease?
What doesn’t help:
Megadoses of antioxidants
Vitamin E and Vitamin C…..
…they actually appear to hurt!
Auburn University, 2005
1) Acetylcholine is a neurotransmitter that is
important in the parasympathetic nervous
system (autonomous system that is responsible
for returning body functions back to normal after
stimulation).
Neurotransmitters released into ‘cleft’
Examples:
• Glutamate (most common in brain)
• Gamma-aminobutyric acid (GABA)
• Dopamine
• Acetylcholine
• Epinephrine
• Histamine
• Serotonin
• Neurotensin
• Nitric Oxide
• Neuropeptide Y
Acetylcholinesterase is the enzyme
that breaks down Acetylcholine.
Acetylcholinesterase Inhibitors
increase the amount of Acetylcholine.
This seems to help AD patients.
Acetylcholinesterase Inhibitors:
Tacrine (Tetrahydroaminoacridine) was the
1st treatment approved for Alzheimers (1995).
Now, have several other drugs that act the
same way…..basically increasing the levels
of Acetylcholine.
2) High levels of the neurotransmitter, Glutamate
occur in AD patients. This overstimulates
the Calcium channels to let in too much Ca+.
What if you could block the Glutamate
Receptor? Memantine (a drug used in
Germany for 20 years to treat brain disease)
does just that. Approved in U.S. in 2003.
Really helps patient with severe AD…..
doesn’t help as much in early stages
Hyperlink >
3) Is exposure to Aluminum associated with AD?
Controversial…but it is increasingly looking
to be true!
Β-Amyloid shape is affected by Iron,
Zinc, Copper, Iron & Aluminum
Aluminum also causes accumulation
of tau protein
Kyushu University of Health and Welfare, Japan, 2005
Clioquinol
Originally used against skin infections
Chelates Zinc & Copper and
reduces tau tangles & plaques
in mice…
…but contains an impurity so
has been taken off the market.
Insert Joke Here
4) Voyager Pharmaceutical Corp. observed an AD
patient with unusual levels of a hormone
called “Gonadotropin”….
…….which regulates
estrogen and testosterone level.
They are investigating ways to modify levels of this
hormone in AD patients.
North Carolina, 2006
5)
Lipitor
(the anti-cholesterol
drug) appears to
help AD patients
6) Anti-Psychotic Drug to treat
Schizophrenia and Bipolar Disease
Used for AD in nursing homes.
Actually makes AD worse.
King’s College, London, February, 2005
7)
γ-Secretase
Developing drugs to inhibit
gamma-Secretase.
But finding that this enzyme has roles
in healthy tissue. For instance:
embryonic development (Notch),
T-cell development, intestines.
University of Tokyo, 2006
γ-Secretase
Some anti-inflammatory medicines (like Ibuprofen)
reduce γ-Secretase activity.
But others (like Naproxen, Celebrex, Vioxx) don’t.
University of Tokyo, 2006
8)
β-Secretase
Developing drugs to inhibit
beta-Secretase.
Has fewer side effects in animals.
2006
9)
Alzhemed
Binds to ß-amyloid protein after it is made
but prevents it from aggregating into
plaques.
Clinical trials in Canada & Europe right now
10) Amyloid Plaques
first form inside
Acetylcholine-responsive
neurons.
So researchers are
looking for ways to
block the movement of
Amyloid protein into these
Neurons.
11)
Vaccination
against
Alzheimers
Injecting people with
small amounts of
β-amyloid protein to
raise an immunity to it.
But 6% of test patients got
seriously ill.
12)
Isolate skin cells and insert the gene for
Nerve Growth Factor (linked to a promoter
that induces high levels of transcription).
Then these cells are implanted in the brain.
Seems to be working.
At a recent meeting of AD researchers and
M.D.s at John Hopkins University there were
vigorous questions from physicians about what
they should actually prescribe for AD.
One researcher estimated that the current
treatments on the market might be 10% effective.
Another expert gave better odds…..
“All you can do is look into your soul and do
the best you can” said one expert.
Heritability of Lung Cancer = 25%
The seven warning signs of Alzheimer's Disease:
1. Asking the same question over and over.
2. Repeating the same story, word for word.
3. Forgetting how to do activities that were previously easy (like
cooking, playing cards, etc.).
4. Losing one's ability to pay bills or balance one's checkbook.
5. Getting lost in familiar surroundings, or misplacing common
objects.
6. Neglecting to bathe, or wearing the same clothes over and over.
7. Relying on someone else, such as a spouse, to make decisions
or answer questions.
http://www.nia.nih.gov/Alzheimers/Publications/sevensigns.htm

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