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Alzheimer’s Disease (AD)
Alzheimer’s Disease?
• Alzheimer's disease (AD), also known as Senile Dementia of
the Alzheimer Type (SDAT) or simply Alzheimer’s is the
most common form of dementia. This incurable, degenerative,
terminal disease was first described by a German psychiatrist
and neuropathologist Alois Alzheimer in 1906 and was named
after him.
• Alzheimer's disease (AD) is a slowly progressive
neurodegenerative disorder of the brain mostly affects the
elderly and characterized by impairment of memory and
eventually by disturbances in reasoning, planning, language,
and perception.
• Many scientists believe that Alzheimer's disease results from
an increase in the production or accumulation of a specific
protein (beta-amyloid protein) in the brain that leads to nerve
cell death.
• Generally, it is diagnosed in people over 65 years of age.
AD
Signs & Symptoms:
• Memory loss for recent events or new information.
• Progresses into dementia  almost total memory loss
• Inability to converse, loss of language ability
Confirmation of Diagnosis:
• Neuronal (amyloid, b amyloid protein, Ab amyloid) plaques
• Neurofibrillary tangles
• Brain Atrophy, Brain shrinkage (loss of neurons mainly in
the hippocampus and basal forebrain)
Stages of AD
Brain Atrophy in AD
WRONG!
http://abdellab.sunderland.ac.uk/lectures/Neurodegeneration/References/Brain_Neurons_AD_Normal.html
The Anatomical Hallmark of Alzheimer’s Pathology:
Amyloid Plaques and Neurofibrillary Tangles in Brain
Amyloid Plaques
contain large amounts of a 42 amino acid
peptide termed “b-amyloid”, or Ab42
b-amyloid itself is the initial cause of the
pathophysiology that leads to dementia.
Neurofibrillary tangles: rich in cytoskeletal proteins,
especially the microtubule-associated protein, “tau”.
In the tangles: heavily phosphorylated proteins,
which may cause aggregation and precipitation of the
cytoskeleton.
Also generally reduced brain volume, especially in entorhinal cortex and hippocampus
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From http://www.rnw.nl/health/html/brain.html
Structure of amyloid precursor protein (APP)
b-secretase Pathway:
(not drawn to scale)
APP Protein:
b
a
g g
(1) b-secretase cuts APP protein, giving:
(2) g-secretase cuts this residue, giving:
Ab40 Fragment
Soluble
Ab42 Fragment
Unsoluble,
aggregates into
plaques
or
Amyloid precursor protein (APP) is membrane protein that sits in the membrane and extends
outward. It is though to be important for neuronal growth, survival, and repair.
From: www.niapublications.org/pubs/unraveling/01.htm
Enzymes cut the APP into fragments, the most important of which for AD is called b-amyloid (beta-amyloid) or Ab.
From: www.niapublications.org/pubs/unraveling/01.htm
Beta-amyloid is “sticky” so the fragments cling together along with other material outside of the cell, forming the
plaques seen in the AD brain.
From: www.niapublications.org/pubs/unraveling/01.htm
Processing of APP
Two Major Hypotheses for AD:
b amyloid protein (BAP) v. tau
1. BAPtists: The accumulation of a fragment of the amyloid
precursor protein or APP (the amyloid beta 42 residue fragment or
Ab-42) leads to the formation of plaques that kill neurons.
2. TAUists: Abnormal phosphorylation of tau proteins makes them
“sticky,” leading to the break up of microtubules. The resulting
loss of axonal transport causes cell death.
Amyloid Hypothesis
(it’s the plaques)
1. The amyloid precursor protein (APP) is broken down by a series of
secretases (see previous two slides).
2. During this process, a nonsoluble fragment of the APP protein (called Ab42) accumulates and is deposited outside the cell.
3. The nonsoluble or “sticky” nature of Ab-42 helps other protein fragments
(including apoE) to gather into plaques.
4. Somehow the plaques (or possible the migration of Ab-42 outside the
cell) cause neuronal death.
5. PSEN1 & PSEN2 genes  subunits of g secretase.
Theories of How Damage
Occurs in AD
From Inside the Cell: Tangle Formation
Axon
Microtubules
Tangles
Neuron
Tau
Proteins
Paired Helical
Filament
Dendrites
Tau proteins, which
normally stabilize
microtubules in brain cells...
undergo abnormal chemical
changes and assemble into spirals
called paired helical filaments...
thus creating tangles
that disrupt cell functions
and lead to cell death.
Sources: Dr John Trojanowski and Dr Virginia M. Y. Lee. University of Pennsylvania Medical Center.
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Microtubules are like railroad tracks that transport nutrition and other molecules. Tau-proteins act as
“ties” that stabilize the structure of the microtubules. In AD, tau proteins become tangled, unstabilizing
the structure of the microtubule. Loss of axonal transport results in cell death.
• Loss of cholinergic neurons in the basal
forebrain nuclei; therefore, restoring cholinergic
function might be helpful.
• Choline acetyltransferase (CAT) activity is
reduced in cortex and hippocampus.
• Nicotinic, but not muscarinic, receptors are
reduced.
Therapeutic approaches
1. Cholinesterase inhibitors:
 The first drugs approved for treating AD.
 Enhancement of cholinergic transmission might
compensate for the cholinergic deficit.
 Improve cognitive performance.
2. Inhibiting excitotoxicity
3. Inhibiting neurodegeneration (future target).
Cholinesterase inhibitors
1. Tacrine
•
•
•
•
The first drug approved for treating AD.
Four times daily
Cholinergic side effects (nausea and
abdominal cramps)
Hepatotoxicity
Cholinesterase inhibitors
2. Donepezil (no hepatotoxicity)
3. Rivastigmine:
Long-lasting drug, CNS selective (fewer peripheral
cholinergic side effects).
4. Galantamine:
Acts partly by cholinesterase inhibitor and partly by
activation of brain nicotinic AChRs.
Inhibiting excitotoxicity
• Memantine
– a use-dependent blockade of NMDA
receptors.
Additional Treatments for AD
 Role of dietary factors
•
Low saturated fat diets,
•
Vitamin E – decrease cytotoxicity - may slow the
progression of the disease
 Cholinergic stimulation:
•
Nicotine patch, varenicline (Chantix)
Pharmacologic Options for AD
• Cognitive enhancers; can improve cognition and
functional ability
─ 2 classes
• Cholinesterase inhibitors (ChEIs)
• NMDA-receptor antagonist
Treatment of AD: Cognitive Enhancers
Drug Name
Dosage form
Indication
Donepezil
(Aricept)
Tablet, orally disintegrating table
Mild to severe
Galantamine
(Razadyne®)
Tablet/oral solution
Mild to moderate
Rivastigmine
(Exelon®)
Capsule
Memantine
(Namenda®)
Tablet*,
oral solution*
Extended-release capsule*
Mild to moderate
Patch
Mod to severe
Common Side Effects
NMDA-receptor
antagonist
Cholinesterase inhibitors (ChEIs)
(Donepezil, galantamine, rivastigmine)
•
•
•
•
•
•
Nausea
Vomiting
Diarrhea
Weight loss
Loss of appetite
Muscle weakness
(Memantine)
•
•
•
•
Dizziness
Headache
Constipation
Confusion
National Institute on Aging. Alzheimer’s disease medications. November 2008. NIH Publication
No. 08-3431. Available at: http://www.nia.nih.gov/Alzheimers/Publications/medicationsfs.htm. Accessed
July 24, 2009.
Current theory: Multifactorial, involving
several pathways.
• Protein accumulation:  plaques & tangles
• Inflammation: Unregulated activation of glia
• Lipid distribution: Lipid membrane site of APP
cleavage.
Targets for Future Therapies
• Ab
─ b-secretase inhibitors
─ -secretase inhibitors
─ Monoclonal antibodies
• Tau protein
• Inflammation
• Insulin resistance
Inhibiting neurodegeneration (clinical trials)
Phase II/ Phase III
1.
Inhibitors of Ab aggregation (Immunological approach; antibody
directed against Ab).
2.
Inhibitors of b- and g-secretase.
3.
Immunological approach (antibody directed against Ab).
4.
Aβ vaccination
5.
Statins: HMG-CaA reductase inhibitors
Inhibiting neurodegeneration (clinical trials)
Phase II/ Phase III
6.
Clioquinol (amoebicidal & metal chelating agent): Ab plaques
bind cooper and zinc, thus removal of these metal ions promotes
dissolution of the plaques.
7.
NGF (Nerve growth factor): shortage of growth factors may
contribute to the loss of forebrain cholinergic neurons in
Alzheimer’s disease.
8.
NSAIDs (esp. ibuprofen & indomethacin) reduce Ab42 formation
by regulating g-secretase (unrelated to COX inhibition)