Flashcards in AD: Molecular Mechanisms and Animal Models: Part I Deck (23)
The role of tau: physiologically and pathophysiologically?
Phys: tau stabilises microtubules
Pathophys: hyperphosphorylated tau -> destab. MTs -> reduced axonal transport -> aggregates -> neuronal death
Outcome of administering synthetic Aβ?
Decreased long term potentiation (amyloid binds to NMDA, amyloid activates microglia?)
APP synthesis pathway?
APP formed in ER and phosphorylated/glycosylated in Golgi -> secretory vesciles to membrane -> re-internalised in endosomes
Location of action of secretases
alpha-secretase in vesicles + cell surface
gamma-secretase in endosomes + cell-surface
beta-secretase in endosomes
Aβ found intracell and extracell
Beta-secretase MOA on Aβ?
BACE-1 -> intracellular APP cleavage (->increased Aβ) -> neuroregulin cleavage (myelination)
BACE-2 (no amyloid)
Alpha-secretase MOA on Aβ?
ADAM-10 and ADAM-17 involved in APP cleavage (as well as other proteins e.g. TNF-alpha)
Gamma-secretase MOA on Aβ?
Presenilin-1 cleaves at cell surface -> extracellular Aβ
Presenilin-2 acts at lysosomes -> intracelluar Aβ
[gamma-secretase is a protein complex, presenilin domain has cleavage enzymatic activity]
How the body deals with extracellular Aβ?
- phagocytosis (by microglia and astrocytes)
- enzymes degrade Aβ (insulin degrading enzyme-IDE and neprilysin-NEP)
- AporE removes Aβ (ApoE4 is ineffective at clearing Aβ)
- alpha-2 macroglobulin binds to amyloid and directly/indirectly removes it via LRP receptor
- Aβ can re-enter the brain via RAGE]- could extra CNS amyloid contribute to AD...unlikely as BACE-1 and APP expression in CNS
Relationship between Presenilin-1 mutations and amyloid
- tend to have more Aβ42
- more intracellular Aβ (more endosome cleavage)
Relationship between Aβ and prions-experimental evidence?
Iatrogenic prion cases due to human GF -> CJD also had increased Aβ pathology (prion-like spread or auto-catalytic change)
NB: GH pts aren't representative of general popltn.
Amyloid seeding hypothesis and experimental evidence?
Amyloid behaves like a prion
[inject AD amyloid into young WT transgenic mice]
-> WT mouse w/ AD amyloid develop plaques but not in trans-mouse w/out APP or if synthetic amyloid used
Parabiosis experiment outcome?
Trans-animal w/ APP linked to WT animal -> WT had increased amyloid plasma & CNS amyloid deposition
AD from blood transfusion?
Unlikely as amyloid likely to stick in blood vessels instead of entering brain
Overview of types of AD treatment?
[current therapies are symptomatic, need disease-modfiying strategies]
- Aβ-based therapeutics
- Tau-based therapeutics
- Neuronal-based therapeutics
Overview of Aβ-based therapeutics for AD?
- BACE inhibitors and g-secretase inhibitors
- Aβ modulators (affect length of Aβ, makes more Aβ-37 than Aβ-42)
- catabolism induces (increased Aβ metab)
Describe evidence of immunotherapeutic targeting of Aβ?
Inject Aβ]- good evidence in animals (decreased Aβ in brain, increased memory)
Clinical trials show increased sepsis risk
Inject antibodies into Aβ (passive immunisation) -> clin trials show unsuccessful
Overview of Tau-based therapeutics for AD?
- Tau aggregation inhibitors (autophagy enhancers, tau assembly inhib, methylene blue)
- Tau kinase inhibitors (GSK3, CDK5) e.g. lithium
- microtubules stabilisers
- Hsp90 inhibitors (afrects proteasome degradation of tau)
Overivew of neuronal-based therapeutics for AD>
- growth factors (BDGF, NGF)
- NDMA antag (decreased glutamate excitotoxicity)
- anti-oxidants (less ox. stress)
- anti-inflammatories (regular NSAID used correlates with lower AD incidence)
- anti-diabetic drugs -> reduced risk e.g. pioglitazone
Experimental results of NGF gene therapy?
NGF can't cross BBB, limited benefit
Importance of NSAIDS in AD?
Regular NSAIDs use = lower AD incidence]- reduces Aβ formation and tau phosph.
Results of clinical trials for NSAIDs and AD
Unsuccessful- too short? treat pts earlier in disease course
Neuropathological progression of AD overivew?
Amyloid plaque starts in basal forebrain, spreads to rest of cortical areas
NFT (Tau) starts in medial temporal lobe