Tau as a drug
target in
Alzheimer’s
disease
PHM146 Presentation
Group Members:
Caitlin Johnston
Philip Yiu
PHM142 Fall 2014
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Garry Truong
Lauren Chan
An Introduction to Alzheimer’s Disease (AD)
• “Progressive neurodegenerative disorder that leads
to dementia” (Buée et al. 2000)
 Neurofibrillary degeneration  dementia 
death
• Functional impairment and loss of neurons leads to
decreased memory and other cognitive functions
• Two types:
1. Sporadic (SAD): more common, agedependent, genetic and environmental risk
factors
2. Familial (FAD): less than 1% of AD patients,
result of gene mutations
Image source: (American Health
Associations’ Alzheimer’s Disease Research)
An Introduction to Tau Protein
• A part of the Microtubule-associated
protein (MAP) family that specializes
in the axonal body of the neurons
within the brain, but can also be
found in dendrites within the CNS
• Has a family of six isoforms
• Provides stability to the axonal
microtubules and facilitates the
movement of neuronal impulses
Image: Schematic of tau protein (Blennow et. al., 2006)
When phosphorylated by kinases, tau dissociates from the microtubules.
Conversely, it can be bound to microtubules (MT) through dephosphorylation
by a phosphatase.
Biological Pathways in AD
Image: Aβ precursor protein (APP) and tau processing in neurons (La Ferla, 2008)
Tau protein in AD
Image: Flowchart of tau
hyperphosphorylation and tangle
formation (Blennow et. al., 2006)
Possible areas of drug targeting
1) Tau hyperphosphorylation
2) Tau aggregation/misfolding
3) Ubiquitination
4) Microtubule disassembly
Tau as a drug target: General strategies (Overview)
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
1)
2)
3)
4)
5)
Inhibiting tau hyperphosphorylation
Inhibiting tau aggregation/misfolding
Increasing tau clearance
Targeting microtubule stabilization
Immunization strategies
Strategy #1: Kinase Inhibitors
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
Note: The focus of this
presentation will be on
inhibiting tau
hyperphosphorylation.
1)
2)
3)
4)
5)
Inhibiting tau hyperphosphorylation
Inhibiting tau aggregation/misfolding
Increasing tau clearance
Targeting microtubule stabilization
Immunization strategies
Strategy #1: Kinase Inhibitors
Reduced Neurofibrillary
Degeneration
Li
Strategy #2: Aggregation inhibitors
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
•
•
Hyperphosphorylated tau aggregates together and blocks proteolysis, leading to
cellular stress and causing neural autophagy in AD patients.
Example treatment strategy: Small molecules, such as methylene blue, can be
used to block the binding between tau molecules and prevent aggregation.
Strategy #3: Tau clearance
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
•
•
Promote the catabolism of tau to (theoretically) reduce tau protein levels
Two tau degradation pathways to theoretically target:
1. Ubiquitin-proteasome system (UPS): proteasome stimulators
2. Macroautophagy: autophagy stimulators (targeting tau aggregates)
Strategy #4: Microtubule (MT) stabilizers
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
•
•
•
Hyperphosphorylation inhibits the binding that promotes nucleation and growth of MT
MT destabilizes  causes changes in internal neuron structure, disrupts transport
Example treatment strategy: Epothilone D (EpoD) has been shown to reverse effects
Strategy #5: Immunization strategies
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
•
•
Use immune system to clear pathological protein aggregation such as Aβ plaques, but
studies have shown that clearing of Aβ plaques may have little to no effect on AD patients.
Two approaches: (1) active: introduce foreign antigen resembling tau peptide;
(2) passive: introduce antibodies against pathological tau and Aβ.
Strategy #5.1: Active Immunization strategies
B-cell
Tau-like peptide
Plasma
Cells
IMMUNE RESPONSE
• Injection of Tau-like peptide into body
• T-cell detects the peptide as a foreign threat and initiates an immune
response
• Downstream of the immune response pathway, anti-tau antibodies are
synthesized
Strategy #5.1: Active Immunization strategies
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
Reduced Neurofibrillary Degeneration
and NFT levels
Pathological Tau
Strategy #5.2: Passive Immunization strategies
Image: Targets for pharmacological modulation of tau and tau function (Wolfe, 2012)
Reduced Neurofibrillary Degeneration
And NFT levels
Pathological Tau
• Inject Anti-tau antibodies into the body
• Pathological Tau proteins, through an immune response initiated by the
Antibodies are eliminated
References
Blennow, Kaj, Mony J de Leon, and Henrik Zetterberg.
“Alzheimer’s Disease.” Lancet 368 (2006): 387–403.
Web.
LaFerla, Frank M. APP and Tau Processing in Neurons.
Digital image. Amyloid-β and tau in Alzheimer’s
disease. Nature Review, 2008. Web. 22 Sept. 2014.
Buée, L et al. “Tau Protein Isoforms, Phosphorylation and
Role in Neurodegenerative Disorders.” Brain research.
Brain research reviews 33 (2000): 95–130. Web.
Okadaic acid-induced tau-hyperphosphorylation in a
primary rat cortex culture. Digital image. Alzheimer's
Disease and Tauopathy Cell-Based Assays. Fluofarma,
2013. Web. 22 Sept. 2014.
Giacobini, Ezio, and Gabriel Gold. “Alzheimer Disease
Therapy--Moving from Amyloid-Β to Tau.” Nature
reviews. Neurology 9.12 (2013): 677–86. Web. 31 July
2014.
Gong, Cheng-Xin, Inge Grundke-Iqbal, and Khalid Iqbal.
“Targeting Tau Protein in Alzheimer’s Disease.” Drugs
Aging 27.5 (2010): 351–365. Print.
Götz, Jürgen, Arne Ittner, and Lars M Ittner. “Tau-Targeted
Treatment Strategies in Alzheimer’s Disease.” British
journal of pharmacology 165.5 (2012): 1246–59. Web.
17 Sept. 2014.
Himmelstein, Diana S et al. “Tau as a Therapeutic Target in
Neurodegenerative Disease.” Pharmacology &
therapeutics 136.1 (2012): 8–22. Web.
Representation of the brain changes associated with
Alzheimer’s Disease. Digital Image. Healthy brain vs.
Alzheimer’s brain. American Health Associations’
Alzheimer’s Disease Research. 2014. Web. 22
Wischik, CM et al. “Selective Inhibition of Alzheimer
Disease-like Tau Aggregation by Phenothiazines.”
Proceedings of the National Academy of Sciences of
the United States of America 93 (1996): 11213–11218.
Web. 22 Sept. 2014.
Wolfe, Michael S. “The Role of Tau in Neurodegenerative
Diseases and Its Potential as a Therapeutic Target.
Scientifica 796024 (2012): Web. 22 Sept. 2014.
Summary Slide
• BACKGROUND ON TAU PROTEIN: Tau is part of a Microtubule-associated protein (MAP) family that specializes
in the axonal body of the neurons within the brain, but can also be found in dendrites within the CNS
• When phosphorylated by kinases, tau dissociates from the microtubules (MT). Conversely, it can be
bound to MT through dephosphorylation by a phosphatase.
• RELATION TO ALZHEIMER’S DISEASE (AD): One of the causes of AD is the hyperphosphorylation of tau by the
overactive kinases, causing rapid breakdown of MT.
• High concentration of soluble tau leads to aggregation with each individual tau protein and causes
neurofibrillary degeneration by taking up space as a lesion, leading to neuron death and dementia.
• THERE ARE FIVE GENERAL STRATEGIES WHEN CONSIDERING TAU AS A DRUG TARGET:
GENERAL DRUG TARGETING STRATEGY
EXAMPLE
1 Inhibiting tau hyperphosphorylation (e.g. kinase inhibitors)
Lithium and Valproic acid (GSK3β Inhibitors)
2 Inhibiting tau aggregation/folding (e.g. aggregation inhibitors)
Methylene blue
3 Increasing tau clearance (e.g. protease stimulators, autophagy stimulators)
Hsp90 Inhibitors
4 Microtubule stabilization
Epothilone D
5 Immunization strategies (e.g. tau antibodies)
(In development)