Brandon Thomas Suit
Alzheimer's Disease Presentation Outline
- Define and Characterize Alzheimer's Disease (AD)
- Impact of Alzheimer's
- Types of AD, risk factors, etc.
- Past and Present Hypothesis — reduced acetylcholine,
tau hyperphosphorylation, and β-Ameloid plauques.
What is Alzheimer's Disease?
- Alzheimer's is a terminal disease that effects the brain.
- Characterized by a loss of neurons and buildup of plaques and tangles.
- Alzheimer's brains show significant shrinkage in volume.
- The most prevalent form of dementia.
- Generally occurs in patients over the age of 60, but there are genetic
predispositions and an early-onset phenotype.
- Dementia is characterized as a loss of cognitive abilities beyond
what might be attributed to normal aging processes.
- Can include the loss of reasoning ability, memory, language, critical thinking,
learning, and awareness.
- Eventually hinders normal daily functioning of the individual, leading to
loss of independence.
- Dementia patients can be a risk to themselves and to others.
- eg. if allowed to operate motor vehicles... bad.
Early symptoms of Alzheimer's Disease
- Loss of short-term memory.
- Difficulty solving problems or with familiar tasks.
- Decline in spacial reasoning.
- Language difficulties
- Forgetting where things are placed
- Withdrawl from social functions
- Mood swings and personality changes
Presently not well understood
- Associated with plaques or neurofibrillary tangles
- But we'll get to that later...
Neurophysiological Changes in AD
- Massive cell loss and atrophy, especially prevalent in:
- Cortex — memory!
- Hippocampus — role in memory formation
- Ventricle enlargement.
Brain Volumetric Changes
Brain Structural Changes
- 100 billion nerve cells
- 100 trillion synapses
- Think about of that information machinery!
(Computational) Systems Biology
- It takes a cluster of Blue Gene IBM supercomputers to model just
one cortical column.
- That's an area comprising only 2mm x 0.5mm (diameter).
- And it only contains 60,000 neurons...
- Just think about how much information must be lost in an
- Loss of neurons is irreversible.
- Neurons are post-mitotic quiescent cells, permanently in G0.
- Most can never be replaced.
- AD is presently incurable. No treatment halts or slows progression.
- FDA has only approved a few drugs to alleviate the symptoms associated w/ AD.
- Degenerative and terminal.
- 5.3 million Americans have AD.
- 13% of those age 65 and older have AD.
- The state of Georgia has an estimated 120,000 cases.
- 5th leading cause of death amongst those age 65 and older
- The overall 7th leading cause of death according to CDC.
- In 2006, AD ranked just below diabetes by only 17 deaths.
- This year it surpassed diabetes.
- AD is often underreported as it can directly lead to other illnesses
- eg. difficulties swallowing, choking
- falling, accidents
- respiratory illnesses
Care of AD patients
- Many years (5–10, or more) of care are needed.
- Feeding, dressing, bathing, restroom, diapers, etc.
- Impact on health of caregiver is not negligible
- Can also affect the employment, financial status of caregiver
- AD is one of the most costly diseases.
- Estimated cost in 2009 of paid and unpaid care was $144 billion!
- Nursing home costs are unsustainable for most families at over $72k/yr.
- 70% of Alzheimer's patients live at home.
- Medicare and medicaid billed for $123 billion in 2009 (AD and
- What happens when the baby boomers reach 60?
Societal Costs (Projected)
- The World Health Organization predicts that within 30 years, Alzheimer's
will be the number one leading cause of death worldwide.
- Gender is not a risk factor.
- AD affects more women than men, but this is believed to be
due to the longer life expectancy of women.
- High Apolipoprotein E4 cholesterol transporter and high cholesterol are
- There are inheritable forms of AD, as opposed to the more common "sporadic AD".
- Typically an autosomal-dominant inheritance pattern.
- Often an early-onset Alzheimer's, which can exhibit itself at around age 50, or on rare occasions, as early as 30.
- Amyloid precursor protein (Chromosome 21)
- Secretase subunit mutations:
- Presenilin 1 (Chromosome 14)
- Presenilin 2 (Chromosome 1)
- Studies indicate a healthy cardiovascular lifestyle may reduce risk
- Non-steroidal anti-inflammatory drugs (NSAIDs) are also correlated with
a reduced risk of AD.
- I'll get to this mechanism later...
- Novel segmentation techniques/algorithms to automate classification.
FDA-approved drugs to compat symptoms
- There is no drug to cure or slow the progression of Alzheimer's
- Only symptoms can be alleviated.
- I'll get to these later...
- The oldest hypothesis for AD causation.
- Cholinergic hypothesis holds that a reduction in neurotransmitter
Acetylcholine is responsible for AD.
- The Cholinergic system = any Acetylcholine NT modulated synapse
- cf. Serotonergic, GABAergic...
- Acetylcholine was the first neurotransmitter discovered.
- Plays a very important role in perception and attention.
- Damage to the cholinergic system was first implicated with AD-related
- Evidence shows neocortical cholergic function declines rapidly in the
early stages of AD.
- Decreased Acetylcholine is proposed to alter the normal neuron signal
transduction pathway, resulting in observable histopathological changes:
- Hyperphosphorylated Tau, causing neurofibrillary tangles
- Cleaving of APP into β-Amyloid plaques
Prediction of the cholinergic hypothesis
- The cholinergic hypothesis predicts that increasing Acetylcholine levels in AD
patients will stop the disease progression.
- This is a testable hypothesis! All we have to do is increase Acetylcholine
levels or stop them from declining further.
- Acetylcholinesterase is used to degrade acetylcholine.
- It is a membrane-associated protein found at the cholinergic synapses
- A popular treatment has been to inhibit acetylcholinesterase,
slowing the decline of Ach levels in AD patients.
A few FDA Approved AD Medications
- Most present Alzheimer's medications target neurotransmitter systems in some way.
- Exelon® (rivastigmine) — cholinesterase inhibitor (colinergic system)
- Razadyne® (galantamine) — cholinesterase inhibitor
- Aricept® (donepezil) — acetylcholinesterase inhibitor (colinergic
- Namenda® (memantine) — blocks NMDA glutamate receptors (glutamatergic system)
Neostigmine Competitive Inhibitor
Acetylcholinesterase Inhibitory Drugs
- Cholinesterase inhibitors, such as Rivastigmine are FDA approved.
- They have a mild success in treating the symptoms of early AD.
- Unfortunately they do not stop disease progression, especially as ACh
levels continue to drop.
- Preponderance of evidence seems to place cholinergic hypothesis in doubt...
- While ACh levels do decline, something else must be the cause...
- Remember that neurons exhibit extreme regional specialization.
- Axons can be up to 1m in length
- Furthermore, axons lack ribosomal machinery.
- cf. dendrites, which do have free ribosomes.
- The soma is relied upon by the axon as the main site of synthesis.
- Axons can be up to 1000 times the volume of the soma.
- It's apparant that axons require continuous support in order to maintain homeostasis...
- NTs and proteins must be transported a great length.
- Fast anterograde: 200 - 400 mm/day
- Slow bidirectional: 0.17 - 8.6 mm/day
- Mitochondria anterograde: 10 - 40 mm/day
- These requirements call for a more highly developed cytoskeleton than is
seen in most other cell types.
- Loss of MTs would be catastrophic for the neuron as well as its neighbors...
- Neurofibrillary tangles are readily observed in Alzheimer's brains.
- They have been definitively correlated with the loss of neurons, as
the number of tangles grows with disease progression.
- (But are they the cause or just a secondary phenomena?)
- Unfortunately, the mechanism behind the formation of tangles isn't
Tangles from Tau Hyperphosphorylation
- We do know that tangles result from the hyperphosphorylation of Tau
proteins, which cause the Tau proteins to disassociate from the MT.
- We also know that MTs are rapidly degraded when Tau disassociates.
- It can't be good when MTs degrade en masse...
Tangles in brain tissue
Tau protein (1)
- Tau is a microtuble associated protein (MAPT)
- Expressed almost exclusively in the neurons of the CNS.
- Interacts with a wide variety of other proteins, primarily tubulin
- Has an inferred SH3 binding domain and Apolipoprotein E binding.
- Promotes tubulin assembly and MT stability.
Tau binding of MT diagram
Tau protein (2)
- The primary role of Tau is in the stabilization of MTs.
- Tau decreases the critical concentration that promotes tubulin polymerization
- Tau's binding site overlaps with the motor protein binding site, so it can
effectively modulate axonal transport.
Tau protein (3)
- Characterized as a phosphoprotein
- Souble, hydrophilic in its normal state
- Highly assymetric as Tau is a random coil protein. (monomers are randomly
- When misfolded, it can aggregate into an insouble "sticky" mass.
Neurofibrillary Tangle Mechanism (1)
Phosphorylation of Tau
- Tau can phorphorylated by a variety of kinases to modulate its function
- The largest isoform of Tau has an astounding 79 phosphorylation sites!
- Phosphatases can dephosphorylate Tau under normal conditions
- When Tau becomes hyperphosphorylated, it cannot be dephosphorylated
- Hyperphosphorylated tau aggregates cannot be recruited to stablized MTs,
and later results in MT degradation.
- Tau Protein Kinase I (GSK3)
- Tau Protein Kinase II (cdk5)
- MAP Kinase
- Calmodulin kinase
Neurofibrillary Tangle Mechanism (2)
Loss of dendritic spines
Tau is not essential
- Tau can be replaced with other MAPs.
- A tau knockout in mice was non-lethal. Increased expression of
other MAPs compensated.
- A recent paper states that tau-depleted neurons are resistant to degeneration,
even in the presence of β-Ameloid plaques.
- This would seem to implicate Tau as the cause of AD
- (Of course, there are many camps arguing with different evidence, it's hard
to reach consensus when nobody has actually fixed the problem.)
Completely off-topic, but interesting
- Classically, the synapse has been viewed as the "main" memory storage site in
- MTs themselves have been suggested as being involved in the encoding of
- Mechanism: MAPs can modulate opening or closing of MT tracks.
- MTs in turn affect NT release, NT receptors, and organelle positions...
- Evidence: MT depolymeryzing agents can cause amnesia.
MT Memory encoding
- If every MAP encodes some level of temporal information, how much information loss is plausible now?
Review of the Effects of Tangles
- Without MTs, transport cannot occur in the cell. This leads to
starvation of NTs, NT receptors, organelles, etc., primarily at the axons
- Eary stage: loss of dendrites observed
- (The morphology of dendrite processes was controlled by MTs.)
- Late stage: loss of cell body, death of neuron
- Is this where it all starts though? We have no consensus/conclusion...
What about plaque formation?
- The formation of plaques is also strongly implicated in the formation of AD.
- Breakdown of Aymeloid Precursor Protein results in the formation of β-Amyloid plaques (AKA Amyloid-β)
- There are many theorized mechanisms in which β-Amyloid plaques contribute to neuron death.
- Oxidative stress
- Competitive inhibition of NT receptors
- UPR (induced by β-Amyloid) can trigger the apoptotic pathway
- Regardless of the method of action, it results in a loss of synaptic connection between neurons.
Amyloid Precursor Protein (APP) Vizualization
Amyloid Precursor Protein
- What does it do?
- Good question...
- We do know how to implicate APP when it's cleaved into β-Amyloid, but
we're not really sure what to make of its normal physiological role.
- May play some role in neuroplasticity
- May also be involved in cell adhesion
- But we don't really know for sure yet...
APP Cleaving Mechanism
- β-Amyloid is a short peptide fragment, approximately 40 AA's long.
- It builds up in large plaque complexes extracellularly.
- Cleaved from APP by α-, β-, and/or γ-secretases, which are neuronal proteases.
- Drugs are now being designed to inhibit these secretases.
- Mutations in secretase subunits are linked to forms of familial AD.
- β-Amyloid buildup can generate reactive oxygen species (ROS), which have cytotoxic and deleterous effects.
Amyloid Plaque Causing Oxidative Stress
β-Amyloid in Neuroinflammation
- β-Amyloid plaques can cause neuroinflammation, leading to glial cell activation.
- Leukocyte diapedisis and extravasation into the brain also occurs.
- Chronic exposure to pro-inflammatory cytokines causes increased local damage at the initial site of buildup, worsening the condition.
- This would explain why NSAIDs can reduce the risk of Alzheimer's.
β-Amyloid in Neuroinflammation Diagram
- One out of every eight of us (if we make it to 65) is statistically bound to get Alzheimer's.
- We've learned a lot about the pathology, but much research still needs to be done...
- Drugs need to be designed to take advantage of newly discovered signalling pathways.
- We should try to block secretases or stop hyperphosphorylation of tau.
- This presentation was written in my own dialect of Markdown.
- Parsed into S5 html microformat with Python.
Research Sources (Continued)