PortraitofanAlzheime.gvp

Alzheimers Healthy

1) Loss of neurons(cortical degeneration)

2

3

Prevents tubulin

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?

Figure 14.9

Amyloid Precursor Protein Neuron

Normally cutIn healthy cells

The enzymes that cut these are called ‘Secretases’

(specific proteases)

Figure 14.9

Neuron

Normally cutIn healthy cells

No AD

Amyloid Precursor Protein

Figure 14.9

Neuron

Normally cutIn healthy cells

No ADNo AD

Amyloid Precursor Protein

Figure 14.9

Neuron

Normally cutIn healthy cells

No ADNo ADAD

Amyloid Precursor Protein

Amyloid proteins (40 or 42 amino acid)

cause plaquesto 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)

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

tau protein normally helps microtubule assembly and stability

Microtubules help transfervesicles & send signals

down the axonPhosphorylation of tau

< 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:

Chromosome 21 = Amyloid Precursor Protein

Missense mutations

V717IV717GV717FI716VK670NM671L

Phenotype the same as Late Onset AD,except shows up between ages of 45-60.Late Onset AD don’t have mutation on APP

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 mutatedIn 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)

Copyright restrictions may apply.

Gatz, M. et al. Arch Gen Psychiatry 2006;63:168-174.

• Published in February 2006

• Twin Study (done in Sweden)

• 2800 set of twins over the age of 65 were tested for dementia and AD

Copyright restrictions may apply.

Gatz, M. et al. Arch Gen Psychiatry 2006;63:168-174.

Prevalence of Total Dementia and Alzheimer Disease, Probandwise Concordance Rates, and Tetrachoric Correlations (With 95% Confidence Intervals) by Zygosity and Sex

Of twins (where one has AD) how often do both have AD?

See pages 10-11 of our book

They also calculated heritability

Copyright restrictions may apply.

Gatz, M. et al. Arch Gen Psychiatry 2006;63:168-174.

Prevalence of Total Dementia and Alzheimer Disease, Probandwise Concordance Rates, and Tetrachoric Correlations (With 95% Confidence Intervals) by Zygosity and SexCalculated heritability

of AD to be 58%

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 Americanshave Alzheimers.

What sort of medicinesmight be designed to

fight AlzheimersDisease?

What doesn’t help:

Megadoses of antioxidants Vitamin E and Vitamin C…..

Auburn University, 2005

…they actually appear to hurt!

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 Inhibitorsincrease the amount of Acetylcholine.

This seems to help AD patients.

Acetylcholinesterase Inhibitors:

Tacrine (Tetrahydroaminoacridine) was the1st treatment approved for Alzheimers (1995).

Now, have several other drugs that act thesame way…..basically increasing the levelsof Acetylcholine.

2) High levels of the neurotransmitter, Glutamateoccur in AD patients. This overstimulatesthe 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 lookingto be true!

Kyushu University of Health and Welfare, Japan, 2005

Β-Amyloid shape is affected by Iron, Zinc, Copper, Iron & Aluminum

Aluminum also causes accumulation of tau protein

Clioquinol Originally used against skin infections

Chelates Zinc & Copper and reduces tau tangles & plaquesin 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 regulatesestrogen and testosterone level.

They are investigating ways to modify levels of thishormone in AD patients.

North Carolina, 2006

5) Lipitor (the anti-cholesterol drug) appears to help AD patients

6) Anti-Psychotic Drug to treatSchizophrenia and Bipolar Disease

Used for AD in nursing homes.

Actually makes AD worse.

King’s College, London, February, 2005

γ-Secretase

University of Tokyo, 2006

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.

7)

γ-Secretase

University of Tokyo, 2006

Some anti-inflammatory medicines (like Ibuprofen)reduce γ-Secretase activity.

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

β-Secretase

2006

Developing drugs to inhibit beta-Secretase.

Has fewer side effects in animals.

8)

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 ofAmyloid 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.

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.

12)

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