Transcript Alzheimer`s disease

Tau as a drug target for
Alzheimer’s Disease
Wen Cong Chen
Michelle Wang
Sameera Toenjes
Christopher Tse
PHM142 Fall 2016
Coordinator: Dr. Jeffrey Henderson
Instructor: Dr. David Hampson
Auguste Deter
the first case
What’s going on in the brain?
Pathophysiology
Pathophysiology
TAU HYPOTHESIS:
Excessive/abnormal
phosphorylation of tau results in
transformation of normal tau into
neurofibrillary tangles
Self Portraits by William Utermohlen
Patents so far
What treatments are available for AD?
Drugs on the market
Possible future treatments for AD?
Inhibition of phosphorylation
Future Drug Targets:
Possible Treatments:
MAP Kinase → phosphorylates Ser-Pro and
Thr-Pro sites
Lithium → inhibits GSK-3
p110mark (protein kinase) → phosphorylates
Ser-262 location mainly
Estradiol → dephosphorylates proline-directed
site
Minocycline → reduces hyperphosphorylation
Natural Products:
- Asian ginseng → enhances PP2A
- Sage → reduces hyperphosphorylation
Prevention of aggregation
Future Drug Targets:
Possible Treatments:
Small molecule inhibitors → bind to
monomeric protein to prevent misfolding
Cinnamon extract
Grape seed → prevents fibrillization
Roots and rhizome of rhubarb → inhibits PHF
(Paired Helical Filaments)
Fungi → inhibits aggregation AND promotes
disassembly of aggregates
Active immunization - general overview
- Active immunity is the same mechanism of action as active vaccinations
- An irregularly folded tau protein is injected into patient (mimics the phosphorylated tau in AD
patient)
- Body recognizes the irregular tau as foreign
- Polyclonal antibodies are made against the irregular tau
- In clinical trials, a section of phosphorylated tau protein was used as an
immunogen
-
Tau378-408, phosphorylated at positions 396 and 404 (both residues were serine)
Macrophages/microglia phagocytose the immunogen and present the immunogen
B cells create immunoglobulin G (IgG) molecules specialized against the Tau378-408
Small proportion of IgG can cross the BBB because of their size
These IgG molecules will bind to irregular tau and signal for their degradation in the
proteasome
Active immunization - available drugs
NONE
Active immunization - research and development
Two vaccines are in clinical trial:
- Tau 378-408, which has been used in clinical trials but the results haven’t
been reported
- Tau 294-305, is currently in phase I clinical trials
Passive immunization - general overview
- Major benefit over active immunization: passive immunization results in less
off-target effects
- Disadvantage: passive immunization must be re-administered more
frequently because you are injecting the IgG antibodies
- Mechanism of action:
-
A ready-made monoclonal antibody is injected into the patient
Some antibodies will cross the BBB
Antibodies will target the phosphorylated tau and target them for degradation in proteasome
There are no memory B cells creating these IgG molecules, so their concentration will
gradually fall
Passive immunization - available drugs
None!
Passive immunization - research and development
Summary
- Alzheimer’s Disease is the most common form of dementia
-
Progressive disease and ultimately fatal
- Tau Hypothesis
-
Excessive/abnormal phosphorylation of tau results in transformation of normal tau into neurofibrillary tangles
- All currently available drugs to treat AD only treat the symptoms of AD
-
Cholinesterase Inhibitors & NMDA Receptor Antagonists
- Future drug targets:
-
Inhibiting phosphorylation of tau
Preventing aggregation of tau
- Active and passive immunization will reduce tau pathology
-
No current drugs, but many are in clinical trial
More potential for passive vaccines than active vaccines
References
Amyloid Plaques. Retrieved October 9th, 2016, from http://thecandidazone.com/wp-content/uploads/2014/10/amyloid-plaques-credit-slideshare.net_.jpg
How Alzheimer's Changes the Brain. Retrieved October 9th, 2016, from http://library.cqpress.com/cqresearcher/file.php?path=/images/CQ_Researcher/r20150724howitchanges.gif
U.S. Patent Filings. Retrieved October 9th, 2016, from http://pubs.acs.org/cen/_img/88/i14/8814cover_patentBig.gif
ALVAREZ‐DE‐LA‐ROSA, M., Silva, I., Nilsen, J., Perez, M., GARCÍA‐SEGURA, L. M., Ávila, J., & Naftolin, F. (2005). Estradiol prevents neural tau
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Boutajangout, A., Ingadottir, J., Davies, P., & Sigurdsson, E. M. (2011). Passive immunization targeting pathological phospho‐tau protein in a mouse model reduces
functional decline and clears tau aggregates from the brain. Journal of neurochemistry, 118(4), 658-667.
Calcul, L., Zhang, B., Jinwal, U. K., Dickey, C. A., & Baker, B. J. (2012). Natural products as a rich source of tau-targeting drugs for Alzheimer's disease. Future
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Götz, J., & Ittner, L. M. (2008). Animal models of Alzheimer's disease and frontotemporal dementia. Nature Reviews Neuroscience, 9(7), 532-544.
Hong, M., Chen, D. C., Klein, P. S., & Lee, V. M.-Y. (1997). Lithium reduces tau phosphorylation by inhibition of glycogen synthase kinase-3. Journal of Biological
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