november 29 th therapeutic approaches in ad: -beta and gamma secretase inhibitors
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November 29 th Therapeutic approaches in AD: -Beta and gamma secretase inhibitors -Abeta immunotherapy -Tau -Tau immunotherapy -Ongoing treatments in AD. Model for g -secretase complex and its interaction to the substrates. - PowerPoint PPT PresentationTRANSCRIPT
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November 29th
Therapeutic approaches in AD:
-Beta and gamma secretase inhibitors
-Abeta immunotherapy
-Tau
-Tau immunotherapy
-Ongoing treatments in AD
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Model for -secretase complex and its interaction to the substrates
The bars represent the transmembrane domains of the the proteins constituting the -secretase complex
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- and -secretase : possible therapeutic targets in AD?
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Could BACE be considered as a therapeutic target for AD?In favor:
1- BACE is the primary -secretase aspartyl protease that cleaves APP generating -amyloid species (secondary role of BACE2)
2-BACE KO mice DO NOT have amyloidogenic processing of APP
Against:
1-BACE+/- heterozygous mice do not show altered production of -amyloid and APP C-terminal fragments
2-BACE cleaves a number of other substrates, including *Amyloid Precursor Like Proteins APLP1 and APLP2*Low-density lipoprotein receptor (LDLR)-related protein LRPThus, targeting BACE for the treatment of AD would result in loss of BACE activity towards the other substrates, with possible consequent implications on their physiological function.
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Singer et al.,
APP processing and A42 production are reduced in BACE knockdown mice
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Singer et al.,
A load and plaque size are reduced in BACE knockdown mice
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Hu et al.,
BACE KO mice show hypomyelination of hippocampal neurons…
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Hu et al.,
…and of the optic and sciatic nerves
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Hu et al.,
BACE KO- mediated hypomyelination is due to reduced activation of neuregulin
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BACE inhibitor
ADAM inhibitor
BACE inhibition reduces or delays myelination in vitro
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Thus reducing BACE levels (or activity) may lead to neurodegeneration as side effect
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Non-peptidic BACE inhibitor reduces Abeta levels in AD mice and Dogs
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Non-peptidic BACE inhibitor reduces Abeta levels in healthy volunteers in a dose-dependent fashion
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Non-peptidic BACE inhibitor reduces A levels in both plasma and CSF
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BACEKO retinal epithelium
Rat retinal epithelium
Vehicle BACE inhibitor
BACE inhibitor causes cytosolic accumulation of granular material This effect is NOT associated to its role as beta-secretase inhibitor
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APP intrabodies, to affect APP transport and BACE-mediated amyloidogenic processing
sFv1sFv1-KDEL
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APP intrabody carrying a KDEL motif for ER retention impairs APP maturation
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APP intrabodies reduce Abeta production
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-secretase cleaves different substrates
Some of these substrates have crucial activity in regulating cell fate decision. In this respect, targeting -secretase for the treatment of AD is not an easy task, as blocking -secretase activity would have consequences on the physiological functions of the other protein substrates.
What about targeting -secretase for the treatment of AD?
Bart De Strooper
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-secretase, in particular PS1 and PS2 are not an easy therapeutic target for the treatment of AD
Could Nicastrin be a good target?
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The mechanism by which nicastrin selectively recognizes the substrates
Nicastrin recognizes specific sequences in the N-terminal portion of C99 (and possibly of C83) and Notch C-terminal fragment.
Shah et al.,
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BACE-secretase
Mechanism by which Nicastrin participates in the “Regulated Intracellular Proteolysis” RIP
Steps:1-The substrates gets in close proximity with the -secretase complex (i.e. after internalization from the plasma membrane).2-Nicastrin specifically recognizes the substrate, and binds to it.3-Presenilin (PS1) cuts the substrate within the exposed sequence (in the case of APP will be the A sequence).
Shah et al.,
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Chemical blocking of the N-terminal portion of the substrates will regulate nicastrin capability to recognize and to bind to it.
Implications for the treatment for AD
Will bind to Nicastrin
Will NOT bind to Nicastrin
Shah et al.,
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How to target A oligomers?
Using molecules that interfere with the structure of the oligomer and break it up to single A monomers.
Advantages of this therapeutic approach would be:1-decreased accumulation of A oligomers, thus reduced formation of-amyloid plaques
2-the single A monomers have higher chances to be removed by the action of clearing enzymes like neprilysin or Insulin Degrading Enzyme IDE
3-both intracellular and extracellular formed A oligomers would be targeted and disrupted.
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New approaches for future therapeutic intervention in AD
1-molecules that disrupt the structure of the A oligomers
2-use of selected - or -secretase inhibitors.
3-used of vaccines, that remove the already deposited plaque
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Decreased A plaque burden in animals overexpressing Insulin Degrading Enzyme (IDE) and Neprilysin
Leissring et al.,
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Hyman and Growdon, Nature Medicine 2006 Vol 12 (7): 755
Aimmunization: clearing A plaques
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Greenberg et al.,
Model of response to A vaccine
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Active and Passive immunization in AD immuno-therapy
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Events leading to AD and roles of A immune-therapy
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Abeta immuno-therapy reduces the plaque load in AD animal model
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Nicoll et al.,
Before immunization, AD patients show plaques with dystrophic neurites (a) and tau staining (b)
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Nicoll et al.,
Areas devoid of A plaques (c) do show NFTs but not dystrophic neurites (d)
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Nicoll et al.,
Areas devoid of plaques show punctate A staining
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Meningoencephalites in AD patients treated with A42 vaccine
Lymphocytes in the leptomeningis
T-lymphocytes
Nicoll et al.,
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Macrophages infiltrates the cerebral white matter in patients treated with A42 vaccine
Vacuolation and refraction in myelinated fibers in the white matter
Infiltration of cerebral white matter by macrophages
Nicoll et al.,
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Different epitopes used for the generation of A antibody
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Ongoing clinical trials for passive Abeta immuno-therapy
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Ongoing clinical trials for active Abeta immuno-therapy
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The protein tau and tau pathology in AD
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Alzheimer’s disease: characterized by extracellular depositions, the -amyloid plaque, and intracellular depositions, the Neurofibrillary Tangles (NFT) comprised of Paired Helical Filaments (PHF), aggregates of hyperphosphorylated protein tau.
Deposition of fibrillar proteinacious material in Alzheimer’s disease
Bossy-Wetzel E, et al., Nat Med. 2004 Jul;10 Suppl:S2-9. Review.
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Origin of PHF and NFT
1-NFT are composed of paired helical filaments (PHF), aggregates of phosphorylated protein tau that form when levels of phosphorylated tau are elevated in the cell.
2-Tau is a microtubule-associated protein that regulates cytoskeleton structure. When highly phosphorylated, tau is sequestered into PHF, and causes disruption of microtubules, that ultimately leads to cell death.
3-Phosphorylation of tau by protein kinases such as the neuron-specific cyclin dependent kinase 5 (cdk5) precedes the formation of PHF that cause neurodegeneration.
4-Importantly, the formation of PHF and NFT is a hallmark in AD and many different neurodegenerative diseases, which together are called tauopathies.
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The human tau gene and the 6 tau isoforms
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Functional domains in tau
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www.emdbiosciences.com
Tau binds to microtubules regulating their connections with other cytoskeletal components such as neurofilaments
This function is regulated by phospho/dephospho state of tau
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Hyperphosphorylatd tau, antibodies and function
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Normal and abnormal phosphorylation of tau
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Tau hyperphosphorylation and NFT in AD
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Tau hyperphosphorylation is not specific of AD, but occurs in other NADD
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Tau hyperphosphorylation and NFT in FTDP-17 and Down’s syndrome
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tau immuno-therapy reduces levels of hyperphosphorylated tau in tau transgenic mice
ptau
Tot tau
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tau immuno-therapy improves health and motor skills, normally impaired in tau-related neurodegeneration
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Tau immuno-therapy dramatically reduces neurofibrillary pathology
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A pathology Tau pathology?
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Transgenic AD mice (APPsweXtauP301L) display both plaque and tau pathology
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APPtgXtauP301Ltg tauP301Ltg
APP pathology increases tau pathology in APPtgXtauP301Ltg
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APP pathology increases tau hyperphosphorylation in an age-dependent fashion
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A42 intracerebral injection in tau Tg mice causes tauopathy
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A42 intracerebral injection in tau Tg mice increases NFTs number
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Br J Clin Pharmacol. 2011 Oct 28. doi: 10.1111/1365-2125.2011.04134.x
Therapeutic targets for A pathology
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Br J Clin Pharmacol. 2011 Oct 28. doi: 10.1111/1365-2125.2011.04134.x
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Other therapeutic approaches used in the treatment of AD
1-Use of cholinesterase inhibitors
2-NSAID (non steroidal antiinflammatory drugs)
3-Anti oxidant vitamins
All these approaches are used in the clinical treatment of AD.In vivo and in vitro, they reduce the amount of A release and slow down the progression of the disease. However, most of the times these are SYMPTOMATIC approaches, as they works in pathways related to AD, but not directly on those pathways that regulate formation and aggregation of A into oligomers and/or plaques.