Chronic References Flashcards
(17 cards)
Amyloid cascade hypothesis suggests that immune system activation follows AB deposition
Leuzy et al 2019
Genetic risk factors for AD such as APOE4 and TREM2 and PSEN1, 2 and APP
Karch et al 2015
Beta amyloid plaques (PIB) co-localise with microglia PK11195
Edison et al 2008
NSAIDs like Ibuprofen reduce AD-like behaviour in mouse models of AD
WT on the first day of learning take a long time but day 7 go straight to the area of the platform
AD do not learn but when treated with an NSAID, their profile looks more like WT
McKee et al 2008
In humans COX NSAIDs do not illeviate IL-1B release but Fenamates do (better at reducing inflammation)
Mefenamic Acid reduces the inflammation in the brain of AD model.
In a control there is no activated microglia, in AD model there is loads and in NSAID there is decreased, near to control
In the novel object test, NSAID treated look similar to WT
Daniels et al 2016
Injection of HSV1 in 5xFAD AD mouse causes an increase in AB (tagged with GFP-can see in hippocampus)
Biomarker for microglia morphology IBa1, without infection, phagocytose the AB. With infection, preferentially phagocytose this over AB
J Neuroinflammation 2024
There is nuclear NF-KB near the amyloid plaque
Astrocytic cell line treated with AB and stained for NF-KB. Goes from cytosol location to nuclear (translocation)
Amyloid serves as a DAMP signal for the NF-KB pathway
Kaltschmidt et al 1997
Immunostaining to test whether the NLRP3 inflammasome mediators are expressed in the microglia
Co-stained with ASC, NLRP3, caspase-1, GSDMS and IL-1
All are present inside the microglia cells suggesting an intact inflammasome NLRP3 pathway
Acta Neuropathologica 2023
- NLRP3 is activated in AD and is related to memory and function
- In MWM, AD mice cannot perform the tast but when KO the inflammasome, their memory returns
- Using surface marker of microglia, tag amyloid. Microglia has low intracellular AB in the microglia but if KO NLRP3, there is an increase in intracellular AB suggesting an increase in capability, also less amyloid covered in the brain
Heneka et al 2013
Used primary microglia cell isolated from WT brain and treated with AB, also used a reverse sequence (null model)
Found that only the aggregated AB treatment would lead to an increase in IL-1 expression and secretion in the WT primary microglia overtime
In KO for NLRP3 and ASC, AB does not cause an increase in IL-1B
Halle et al 2008
Scientists took Aβ and added ASC specks to it in a lab.
They found that Aβ began to clump together much more — forming heavier oligomers.
This means ASC might act like a “scaffold” or glue, helping Aβ stick to itself and form toxic aggregates.
A lysate is just brain material that’s been broken down into a liquid (containing proteins like Aβ and ASC).
They took this lysate from an Alzheimer’s mouse and injected it into another mouse’s brain.
When the lysate had ASC, new Aβ plaques formed in the second mouse.
But if the ASC was removed from the lysate, even though Aβ was still there, no plaques formed.
SO ASC helps to trigger inflammation and causes aggregation of the AB, forming more plaques
Can see ASC staining in the core of the plaque, suggesting it is the core protein of the amyloid plaque, when KO ASC it improves the performance on the MWM
Venegas et al 2017
Used different classes of NSAID drugs to see which can inhibit IL-1 secretion. Ibuprofen has no effect in IL-1B release but the other classes with similar structures to the fenemate could
Fenamates inhibit ASC inflammasome speck fromation in a cell line (but not ibuprofen)
Cell treated with a hypotonic condition and fenamate, the CL current is reduced due to VRAC being blocked, additional drugs blocking chloride transportation show similar effects at reducing IL-1B
Used Fenamate in a mouse model 3xTgAD mouse used implant osmotic mini pump dosing the drug daily, then tested memory after 2 weeks on the novel object test, after treatment, restored memory function
Then measured the morphology of the microglia in 3 different brain regions. Microglia are more amoeboid in AD compared to WT mice. When treat with fenamate, morphology vecomes more ramified and less expression of IL-1B. Less activation of microglia and IL-1B
Nature Communications, 2016
Fenamates inhibit COX and therefore leads to stomach discomfort, need to find a similar compound with no COX activity
Swanton et al 2020
MCC940 compound which is very potent with an EC50 of 7.5nm, is is specific for the ATP motif of the NLRP3 inflammasome
When apply, it causes the reduction of IL-1B but not TNFa suggesting an NLRP3 specific inhibition
It also improves the cognitive performance in APP/PSN1 mouse model- T-maze. It promotes the non-phlogistic clearance of AB.
Nature Medicine 2015
Adiponectin has a very food inflammatory function, treated microglia with an amyloid beta oligomer, caused activation of NF-KB in the cytosol and the nucleus
When co-treat with APN, it reduced the activation level of NF-KB, so it inhibts the translocation of NF-KB in microglia
It also suppresses AB oligomers-induced IL-1B secretion whereas KO for APN in 5xFAD increases IL-1B levels
J Neuroinflammation, 2019
Stained APN KO mouse
Saw higher NLRP3 expression in the microglia suggesting that APN goes through an NLRP3 dependent pathway to suppress IL-1B
Used a Liver-specific promoter to increase plasma levels of APN, avoids side effects as adeno-associated virus causes only the liver to express the virus, increased APN levels but 50% to maintain physiological levels (AAV gene therapy)
This increases the time spent in the target area searching for the platform and redues AB staining in the cortex and hippocampus, also reduces NLRP3 expression inside microglia, reduces ASC and IL-1B too.
Chun-Laam et al 2024
Zinc deficiency is common in AD
When treat AD model APP/PSN1 with zinc deficient diet, leads to faster development of cognitive decline.
When KO NLRP3 and treat with the same diet, it restores memory function, suggesting deficiency works through the same NLRP3 pathway driving memory impairment
J Neuro, 2021
