Summary
Summary Molecular Principles of Brain Disorders
- Course
- Institution
Comprehensive summery of the course. This summary regards the lectures 10 to 13! I grot graded an 8.5! :)
[Show more]
Seller
Follow
leetje99
Reviews received
Content preview
HC 10: therapy 2 and 3 11/11/20Therapy 2: targeting amyloid beta in Alzheimer’s disease
-Currently no treatment for AD.
-Learning objectives:
• Can describe and understands different pharmacological targets.
• Can describe and understands different immunotherapeutic
approaches.
• Understands specific issues related to Aβ/AD trials.
-Formation of Aβ -> Cutting by β-secretase and then by γ-secretase.
• Aβ1-42 -> The form who is more prone to aggregation.
-Important player in the pathogenic cascade of AD, so targeting this
protein may be very effective.
• According to this hypothesis, Aβ aggregation sets up the whole
cascade.
• One tactic against Aβ -> Try to prevent the formation of Aβ!
o The two enzymes that are involved:
▪ γ-secretase -> Presenilin is part of this complex.
• Inhibiting this enzyme -> Often inhibits
the catalytic side of the gamma-secretase.
• But, this doesn’t work good, because the different compounds failed, mainly due to their
lots of side effects.
o Example: Flurizan
o Also, because gamma-secretase cleaves also other molecules, like in the Notch
signaling (what is very important in different processes).
• But, these inhibitors are in trials against cancer! Because sometimes inhibiting Notch is
good in cancer.
• Are not completely of the list, so people did try to better these gamma-secretase
inhibitors, but the last stage also failed (phase III) -> Semagestat
o Peripheral side effects
o Aβ CSF (fluid) levels not affected
o Worsened cognition!
• Someone came with the idea to change the
treatment of gamma-secretase inhibitors -> More
moderate and continuous inhibition would be
preferred!
o In the clinical trials, there were lots of
peaks and lots of abrupt decreased
levels.
o Idea -> treat with a gel what gives a more continuous dose in the body.
, • Trial of Semegastat was too soon probably! We need to get back to bench! First clear
other things.
▪ β-secretase (BASE) -> Transmembrane aspartic protease (-> Uses a
aspartic amino acid)
• Issues with specificity, so if you inhibit β-secretase, you’ll
inhibit lots of more processes (which you need), because it
doesn’t cleave only APP (-).
• BACE knockout phenotypes -> Knockout mice and effect
was observed -> quite severe effects were seen!
• So, you want not to fully inhibit this enzyme! -> Lots of trials
were stopped due to no good results, due to the side effects
and the knockout effects.
• Still under investigation -> Reduced inhibition (not
completely), maybe this effect is enough and less toxic.
• Really adverse effects -> Small, but stable cognitive defect.
o Other BACE inhibitors do the same thing,
suggesting on-target mechanism.
o Scientists said more research is needed to
determine if this can be managed.
o Lower the amount of Aβ probably result in a less development of AD.
-Amyloidogenic processing of APP: (very complicated)
• There are many different truncations, besides Aβ1-40 and Aβ1-42!
• Variants of Aβ who are truncated at resident 3 or resident 11.
o Not clear whether this is due to the β-secretase or due to an enzyme after the β-secretase (-> more likely
explanation).
o Glutamate amino acid ends up at the end of the peptide, but is modified! -> Glutamate replaced by a
PyroGlutamate (pE) on N-terminal -> Ends up with cyclic residue at the end terminus → changes
properties of the peptide.
▪ Replacement is done by Glutaminyl cyclase (QC)
, ▪ So, now you’ll have a (pE)Aβ peptide.
▪ Characteristics:
• Abundantly present in AD brain!
• Accelerated aggregation -> Aggregate much better than non-pyroglutamate peptides.
o Aggregates much faster!
o So, it can really speed up pathogenic processes.
• More neurotoxic! -> Kills more than the non-pyroglutamates variant.
• Proteolytic resistance -> Resistant to degradation of enzymes.
o Have due to this a longer half-life.
▪ So, is this protein an initiation of a pathological cascade? Probably! -> target this!
▪ The enzyme Glutaminyl cyclase (QC) may be a good therapeutic target!
• An inhibitor was developed -> PBD150 -> Strongly reduces plaque load in Tg2576 mice!
o Also less aggregation is seen.
o It does not inhibit already formed plaques!! (logic, because it targets the
beginning of the formation).
-Another therapeutic tactic -> PE3 Aβ vaccination -> Reduces plaques!
• This approach removes poly-glutamate Aβ (plaques of this) instead off prevention of the formation of it.
• Reduction in the plaque load in the hippocampus and in the cerebellum.
• Was given before plaque formation and none/less plaques were formed.
• Therapeutic trial -> Start the treatment when the plaques already were formed -> You see also a reduction!
-Exciting results! The PQ912 QC inhibitor is in trials (phase 2) and passive vaccination against PyroGlu Aβ (phase 2).
-Vaccinations:
• Two forms:
o Active vaccination -> Introducing an antigen into the patient and the patients itself can produce a
response against this and so produces antibodies.
o Passive vaccination -> Antibodies are arrived form an external source (for example a cell culture) and
introduced to the patient.
▪ More used for people with a low immune system or intact, like cancer patients, elderly or
immune deficient people.
, • Both used for corona vaccinations.
• Problem with neurodegenerative diseases, vaccine has to cross the blood brain barrier (BBB)!
o Hard because an antibody is a quit big molecule.
o Peripheral sink hypothesis -> Achieving an effect, without the translocation of antibodies across the BBB.
▪ Peripheral sink -> blood
▪ Aβ levels are in an equilibrium between the brain and the blood, so if you remove the Aβ from
the blood, you shift the equilibrium, so that also the Aβ from the brain will be cleared (to restore
the equilibrium).
• We do not know if this is the case, it’s a hypothesis.
• Active immunization of APP model in mice -> completely clearance of the plaques in the brain! Amazing!
o Not only clear the pathology, but also clearance of the symptoms can be achieved! -> Tested with
memory task: object recognition test.
▪ Object what they haven’t seen before (red box) -> start to investigate it.
▪ A novel object is introduced -> green round thing.
• Normal memory -> start to investigate the green object, because the red box they
already know.
o Should be more than 50% (the time they are with the green round object)
o Time looking at green round thing strongly reduced with dementia/AD.
• Inefficient memory -> also investigate red box and spent less time investigating the
green round thing.
o Started to treat the mice with an inefficient memory (PDAPP mice) with the active immunization! -> 24
months, 6 weeks treatment (1 injection a week) -> At 24 months the memory is better and rescued!
▪ What is happening in the brain? -> Staining the Synaptophysin (-> A marker for how many
synapses there are in the brain/brain tissue).
• Synaptophysin reactivity went up upon Aβ vaccination! So, networks are repaired! More
neurotransmission can take place!
o Non-tg -> wild type mice
o More lighter green -> more synapses.
The benefits of buying summaries with Stuvia:
Guaranteed quality through customer reviews
Stuvia customers have reviewed more than 700,000 summaries. This how you know that you are buying the best documents.
Quick and easy check-out
You can quickly pay through credit card or Stuvia-credit for the summaries. There is no membership needed.
Focus on what matters
Your fellow students write the study notes themselves, which is why the documents are always reliable and up-to-date. This ensures you quickly get to the core!
Frequently asked questions
What do I get when I buy this document?
You get a PDF, available immediately after your purchase. The purchased document is accessible anytime, anywhere and indefinitely through your profile.
Satisfaction guarantee: how does it work?
Our satisfaction guarantee ensures that you always find a study document that suits you well. You fill out a form, and our customer service team takes care of the rest.
Who am I buying these notes from?
Stuvia is a marketplace, so you are not buying this document from us, but from seller leetje99. Stuvia facilitates payment to the seller.
Will I be stuck with a subscription?
No, you only buy these notes for $5.15. You're not tied to anything after your purchase.
Can Stuvia be trusted?
4.6 stars on Google & Trustpilot (+1000 reviews)
52510 documents were sold in the last 30 days
Founded in 2010, the go-to place to buy study notes for 14 years now