Toxic Lipid Secretion: The ISR pathway in microgli

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Toxic Lipid Secretion: The ISR pathway in microglia was shown to drive the synthesis and release of harmful lipids that contribute to synapse loss, a hallmark of Alzheimer’s disease.
Therapeutic Potential: In mouse models, inhibiting ISR activation or lipid synthesis prevented synapse loss and accumulation of neurodegenerative tau proteins, offering a promising pathway for therapeutic intervention.

It looks like the ISR pathway would either be interrupted or regulated by Leronlimab's down regulation of elF2a, and PKR -
Buddyboy20
https://investorshangout.com/post/view?id=6737021

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elF2a and PKR would be more inline for viral challenges.

Unfortunately sci-hub does not have that full science paper yet. From the synopsis (https://www.cell.com/neuron/abstract/S0896-6273(24)00875-4 ) the cellular stress is most likely driven by inflammatory assaults accompanied by mitochondrial dysfunction. Leronlimab can help in both cases. In the case of lipids leronlimab would reduce both triglycerides and LDL cholesterol. Lipids go toxic when there is an overabundance of them. APOE4 which is implicated in Alzheimer's is integral in lipid movement and activity. CCR5 blockade has been shown to restrain APOE4s effects. - ohm20
https://investorshangout.com/post/view?id=6738054

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It looks like targeting the much narrower ISR pathway is not enough. Calico's targeting of elF2b as an agonist failed in ALS. Leronlimab has much broader reach.

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Google’s anti-aging company Calico released disappointing trial results of its first ever drug.

Calico’s fosigotifator was tested for amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disease that affects nerve cells in the brain and spinal cord and leads to paralysis. It was part of the HEALEY ALS Platform Trial, which is testing a series of drugs against the condition.

Calico said on Monday that fosigotifator did not meet its primary or secondary goals after a 24-week trial. The treatment failed to slow disease progression or improve respiratory function and quality of life better than the placebo group. However, an “exploratory” high dose of the drug appeared to preserve muscle strength and respiratory function longer than the placebo.

Fosigotifator targets the integrated stress response (ISR), a cellular mechanism that reduces activity in cells in response to internal or environmental stress.

Calico was founded in 2013 by Google to help understand and “tackle” aging. It is now a subsidiary of Alphabet and has absorbed at least as $3.5 billion in funding, STAT news reports .
https://qz.com/google-calico-als-drug-trial-1851734070?

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Maybe Calico should input "leronlimab" and "aging" or "leronlimab and "ALS" into Google AI since they seem to know nothing about it.