PI3K Drugs for Alzheimers, page-28

Thank you for continuously sharing new scientific info!

The publication you just posted speaks of an activation of the PI3K-pathway to positively influence AD / PD.

Given that paxalisib is a PI3K-inhibitor I cannot see the link how it would activate the pathway.

Articles you previously posted mentioned inhibition and in that circumstance I completely get it.

Admittedly bio-chemistry is complex but only one of the two hypotheses can be correct - if the PI3K-pathway indeed plays a role in humans - it either requires an agonist to activate it (no role for paxalisib) or it requires an antagonist to inhibit it (potentially a role for paxalisib).

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Hello Rinnekin -

The publication does speak of activation of the PI3K - but this is in context of  activation of components of the pathway, that have been damaged / stopped working.

Reactivation of the PI3K pathway may be a better word....... (so as to positively influence AD/PD, so to speak)

The possible non cancer applications for the drug...which mostly I have raised - is not overly embraced here. That may be fair enough, given no mention by the company.

The point is though - its all about the SP gap on such news.

I am still VERY keen to stick with a view that the non-cancer value of paxalisib sits at 50/50 in my mind.

We will see, but will give non-cancer a  rest from now on.....leave the subject with this below:
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In Alzheimer’s, Targeting PI3Kδ Enzyme Shows Promise in Mouse Model (alzheimersnewstoday.com)




Next, the researchers tested the impact of CAL-101 — a selective PI3K-delta inhibitor marketed with the brand name Zydelig (idelalisib, by Gilead) for the treatment of B-cell lymphoma — in the nerve cells and microglia collected from mice with Alzheimer’s.

Treatment with CAL-101 significantly reduced the transport of APP inside neurons, likely decreasing its conversion to amyloid-beta and preventing its deposition and toxic effects. It also significantly eased the release of the strong pro-inflammatory molecule TNF-alpha by microglia cells.

“We conclude that inhibiting PI3K [delta] represents a novel therapeutic approach to ameliorate [Alzheimer’s] pathology by dampening plaque accumulation and microglial-dependent neuroinflammation,” the researchers wrote.

Despite the potential of this dual-effect approach for treating Alzheimer’s, more work is still required to translate it to patients. CAL-101 showed effectiveness in vitro, but is not able to cross the blood-brain barrier to reach the brain.

“We are now keen to collaborate with other researchers to work out how to solve the issue of transporting the drug across the blood-brain barrier,” Martínez-Mármol said.
Alice Melão

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