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Alzheimers. Healthy . 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

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PowerPoint Slideshow about 'Alzheimers' - MikeCarlo


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slide2

Alzheimers

Healthy

1) Loss of neurons

(cortical degeneration)

slide3

3

Prevents tubulin

2

slide4

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?
slide5

Neuron

Amyloid Precursor Protein

The enzymes that cut these

are called ‘Secretases’

(specific proteases)

Normally cut

In healthy cells

Figure 14.9

slide6

Neuron

Amyloid Precursor Protein

No AD

Normally cut

In healthy cells

Figure 14.9

slide7

Neuron

Amyloid Precursor Protein

No AD

No AD

Normally cut

In healthy cells

Figure 14.9

slide8

Neuron

Amyloid Precursor Protein

No AD

No AD

AD

Normally cut

In healthy cells

Figure 14.9

slide9

Amyloid proteins

(40 or 42 amino acid)

cause plaques

to form in the brain

slide10

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

slide11

Neurofibrillary Tangles (tau Tangles)

They look like flames (or tadpoles)

slide12

tau protein normally helps

microtubule assembly

and stability

Microtubules help transfer

vesicles & send signals

down the axon

Phosphorylation of tau

http://www.uphs.upenn.edu/news/News_Releases/dec04/paclitaxel.htm

slide15

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

slide16

Phenotype the same as Late Onset AD,

except shows up between ages of 45-60.

Late Onset AD don’t have mutation on APP

Early Onset AD:

Chromosome 21 = Amyloid Precursor Protein

Missense mutations

This somehow encourages

the removal of the

Beta-Amyloid segment

V717I

V717G

V717F

I716V

K670N

M671L

slide17

What comes first?

The disease?

The plaques?

The tau Tangles?

slide19

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)

slide20

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 !

slide21

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

slide22

Two Types of AD:

Late OnsetApolipoprotein E (Chromo. 19)

Synthesized by Astrocytes (non-neuronal cells)

that control passage of things, like cholesterol,

to the brain…Blood-Brain Barrier)

slide23

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.

slide24

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.

slide26

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.

slide27

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
slide28

But drug development is underway

Four million Americans

have Alzheimers.

What sort of medicines

might be designed to

fight Alzheimers

Disease?

slide29

What doesn’t help:

Megadoses of antioxidants

Vitamin E and Vitamin C…..

…they actually appear to hurt!

Auburn University, 2005

slide30

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).

slide31

Neurotransmitters released into ‘cleft’

  • Examples:
  • Glutamate (most common in brain)
  • Gamma-aminobutyric acid (GABA)
  • Dopamine
  • Acetylcholine
  • Epinephrine
  • Histamine
  • Serotonin
  • Neurotensin
  • Nitric Oxide
  • Neuropeptide Y
slide32

Acetylcholinesterase is the enzyme

that breaks down Acetylcholine.

Acetylcholinesterase Inhibitors

increase the amount of Acetylcholine.

This seems to help AD patients.

slide33

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.

slide34

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 >

slide35

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

slide36

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.

slide38

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

slide39

5) Lipitor

(the anti-cholesterol

drug) appears to

help AD patients

slide40

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

slide41

γ-Secretase

7)

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

slide42

γ-Secretase

Some anti-inflammatory medicines (like Ibuprofen)

reduce γ-Secretase activity.

But others (like Naproxen, Celebrex, Vioxx) don’t.

University of Tokyo, 2006

slide43

8)

β-Secretase

Developing drugs to inhibit

beta-Secretase.

Has fewer side effects in animals.

2006

slide44

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

slide45

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.

slide46

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.

slide47

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.

slide48

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.

slide51

The seven warning signs of Alzheimer's Disease:

  • 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