Presentation on theme: "May 8 th, BIOSE108 Therapeutic approaches in AD: -Beta and gamma secretase inhibitors -Abeta immunotherapy -Tau -Ongoing treatments in AD."— Presentation transcript:
May 8 th, BIOSE108 Therapeutic approaches in AD: -Beta and gamma secretase inhibitors -Abeta immunotherapy -Tau -Ongoing treatments in AD
- and -secretase : possible therapeutic targets in AD?
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 LRP Thus, 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.
Hu et al., BACE KO mice show hypomyelination of hippocampal neurons…
Hu et al., …and of the optic and sciatic nerves Optic Sciatic
Hu et al., BACE KO- mediated hypomyelination is due to reduced activation of neuregulin
BACE inhibitor ADAM inhibitor BACE inhibition reduces or delays myelination in vitro
BACE1KO primary hippocampal neurons have impaired axonal outgrowth
BACE KO mice have axon guidance defects in the hippocampus
L1 (CHL1) t2 a substrate for BACE? BACE KO mice have the same phenotype as the neuronal cell adhesion molecule close homolog of L1 (CHL1) t2 KO mice
CHL1 undergoes BACE1-dependent cleavage in hippocampus
CHL1 and BACE1 co-localize in growth cones of primary hippocampal neurons.
Thus reducing BACE levels (or activity) may lead to neurodegeneration as side effect
-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
Model for -secretase complex and its interaction to the substrates The bars represent the transmembrane domains of the the proteins constituting the - secretase complex
Aldehyde-type calpain and proteasome inhibitors. Weak potency and lack of selectivity: First studied Differential production of Abeta 40 to Abeta 42 Aldehydes are readily hydrated to a form that resembles the transition state of aspartyl protease catalysis. Transition state analogs: whether aldehyde or keto forms, they can be active toward serine and cisteine proteases. Conversion of one of these diﬂuoroalcohol peptidomimetics into an afﬁnity labeling reagent led to identiﬁcation of PS1 NTF and CTF as the direct targets of this type of inhibitor. Hydroxyethylamines, more potent. Can isolate gamma-secretase in a detergent-solubilized state and demonstrate that immunoprecipitation of presenilin brought down gamma-secretase activity. Gamma secretase inhibitors, peptide based inhibitors
DAPT “showed good inhibitory potency orally active in vivo, capable of lowering brain Abeta levels in an APP transgenic mice. The target is the CTF.” Well known DAPT derivatives are the more potent Compound E and LY-411,575, the last one studied in vivo in humans. Compound E: “effective in reducing brain Abeta levels in APP transgenic mice upon oral dosing. However, this compound also illustrated the toxicity issues that might be expected by GSI over Notch (gastrointestinal bleeding and immunosuppression caused by peripheral inhibition of Notch). Despite this ominous result, non-selective GSIs of this type continued to be pursued on evidence from animal studies that careful dosing couldidentify a therapeutic window (e.g. Hyde et al. 2006)”.
Structure of the inhibitors LY-411,575 and LY-D
LY reduces Abeta levels in the plasma and in the brain of TgCRND8 mice
Chronic administration of LY-411,575 causes atrophy of the thymus in TgCNDR8 mice (15 days) One lobule Two lobules
Decreased Lymphocytes B generation in chronically treated TgCNRD8 mice with LY-411,575: Immunosuppression
Chronic administration of LY-411,575 causes deterioration of the intestinal epithelium
Higher doses of Semagacestat
Inactivation of Notch1 causes the formation of skin tumors Notch1KO
Notch sparing GSM Abeta42 lowering GSM PS1-selective g-secretase inhibitor Other more selective gamma-secretase inhibitors
PS2 is part of the gamma-secretase too, and can actively cleave both APP and Notch What could happen if GSIs were designed to target only PS1 and not PS2?
PS2-sparing GSI (MRK-560) reduces A 40 and A 42 levels in plasma and brain plasma brain
Lack of PS2 expression in PS2 KO mice, but not lack of endogenous PS2 expression, exacerbates guts histopathology
PS2 is present, although at moderate levels, in brain, spleen and thymus
Under conditions of PS1-specific inhibition, PS2 can compensate for PS1, although not up-regulated.
PS1 is not an easy therapeutic target for the treatment of AD Could Nicastrin be a good target?
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.,
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.,
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.
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, to remove A deposits and plaques
Events leading to AD and roles of A immune-therapy
Active and Passive immunization in AD immuno-therapy APC: antigen Presenting Cells
Abeta immuno-therapy reduces the plaque load in AD animal model
Nicoll et al., Before immunization, AD patients show plaques with dystrophic neurites (a) and tau staining (b)
Nicoll et al., Areas devoid of A plaques (c) do show NFTs but not dystrophic neurites (d)
Macrophages infiltrates the cerebral white matter in patients treated with A 42 vaccine Meningoencephalites in AD patients treated with AN1792 Vacuolation and refraction in myelinated fibers in the white matter Infiltration of cerebral white matter by macrophages Nicoll et al.,
Ongoing clinical trials for passive Abeta immuno-therapy
Ongoing clinical trials for active Abeta immuno-therapy
The protein tau and tau pathology in AD
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 Jul;10 Suppl:S2-9. Review.
The human tau gene and the 6 tau isoforms
Functional domains in tau
Tau binds to microtubules regulating their connections with other cytoskeletal components such as neurofilaments This function is regulated by phospho/dephospho state of tau
Hyperphosphorylatd tau, antibodies and function
Normal and abnormal phosphorylation of tau
Tau hyperphosphorylation and NFT in AD
Tau hyperphosphorylation is not specific of AD, but occurs in other NADD
Tau hyperphosphorylation and NFT in FTDP-17 and Down’s syndrome
A pathology Tau pathology ?
APPtgXtauP301Ltg tauP301Ltg APP pathology increases tau pathology in APPtgXtauP301Ltg APP pathology increases tau hyperphosphorylation in an age-dependent fashion
A 42 intracerebral injection in tau Tg mice increases NFTs number A 42 intracerebral injection in tau Tg mice causes tauopathy phospho tau Non injected Injected amygdala
Br J Clin Pharmacol Oct 28. doi: / x Therapeutic targets for A pathology
Br J Clin Pharmacol Oct 28. doi: / x
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.