Turbo - just wanted to thank you again for pointing me in the direction of those papers. I have continued to read and my interest in this subject area has only increased. I am obviously no expert and my understanding of the following information could be totally erroneous, so take it with a grain of salt.
I came across another very recent paper that seemed to suggest that properly functioning Microglia can in fact dissolve Beta Amyloid Plaques, which I understand are the visible form of abnormal protein aggregation that you referenced in your reply -
Microglia degrade Alzheimer’s amyloid-beta deposits extracellularly via digestive exophagy - ScienceDirect.
This would possibly address the issue you raised and the challenge highlighted in the ChatGPT response. I subsequently loaded the article into Chat GPT and asked it to review the identified challenge in light of this information. It originally spat out the following answer "
Upon reviewing the information from the provided link, it appears that the article discusses the potential of intranasal drug delivery for treating Alzheimer's disease. This method has shown promise in delivering therapeutic agents directly to the brain, potentially bypassing the blood-brain barrier and enhancing drug efficacy.While NNZ-2591 is not specifically mentioned in the article, the concept of intranasal delivery could be relevant to its application. If NNZ-2591 were formulated for intranasal administration, it might achieve higher concentrations in the brain, potentially enhancing its therapeutic effects on neuroinflammation, microglial modulation, and synaptic connectivity.However, it's important to note that even with improved delivery methods, NNZ-2591's primary mechanisms do not directly target beta-amyloid plaques or tau tangles, which are central to Alzheimer's pathology. Therefore, while intranasal delivery could enhance the drug's effectiveness in modulating neuroinflammation and supporting neuronal health, additional strategies would likely be necessary to address the specific protein aggregations characteristic of Alzheimer's disease.In summary, the information from the article suggests that intranasal delivery could potentially improve the brain-targeted efficacy of drugs like NNZ-2591. However, further research would be needed to determine its effectiveness against the specific pathological features of Alzheimer's disease."I updated the prompt to confirm that 2591 does in fact cross the blood brain barrier and also asked it to confirm whether it had understood the article, because on my reading, the article suggested that Microglia can effectively target Beta Amyloid Plaques. It subsequently noted the following "
You're absolutely right—thank you for clarifying. Microglia indeed play a critical role in targeting beta-amyloid plaques. According to recent studies, including the one you referenced, microglia can help clear these plaques under certain conditions. However, when misregulated, they may exacerbate plaque-related damage and contribute to neuroinflammation. Given NNZ-2591's ability to modulate microglial function and reduce neuroinflammation, it may indirectly aid in clearing or mitigating the effects of beta-amyloid plaques, even though it doesn't directly bind to or target the plaques themselves. Additionally, since NNZ-2591 crosses the blood-brain barrier, its therapeutic potential for brain-related conditions is enhanced. This makes NNZ-2591 potentially more relevant to Alzheimer's treatment than initially suggested, particularly in addressing both neuroinflammation and microglial dysfunction. Further investigation into its specific effects on microglial interactions with beta-amyloid would be necessary to fully understand its scope of benefit."
Another very recent study/article (Jan 2025) also talks the correlation between microglial activity and Alzheimer's, noting the "
Emerging evidence shows that homeostatic dysregulation of the brain immune system, especially that orchestrated by microglia, plays an important role in disease onset and progression. Thus, a major question is how to modulate the phenotype and function of microglia to treat AD."
Inhaled xenon modulates microglia and ameliorates disease in mouse models of amyloidosis and tauopathy | Science Translational Medicine
I just thought this was all really interesting and wanted to share. I could be completely off base with my understanding of the science but if I am not, then I really do think we need to make sure that 2591's ability to regulate Microglial activity needs to be sung from the hilltops - given the seeming connection with Alzheimers and other neurological conditions that rely on normal microglial function.
Speaking of other neurological conditions that rely on normal microglial function, I thought it was interesting and wanted to share a few other articles I came across that seem to reinforce this critical area.
- In relation to ALS "which is caused by the progressive dysfunction and death of motor neurons. What leads to the loss of these neurons isn’t completely understood, but inflammation is thought to contribute to the disease’s onset and progression. This inflammation is driven in part by the excessive activation of microglia." Microglia derived from iPSCs may help advance ALS research, therapies (alsnewstoday.com).
- Dysregulated microglia activation, leading to neuroinflammation, is crucial in neurodegenerative disease development and progression, including Alzheimer’s disease, autism spectrum disorder, epilepsy, multiple sclerosis, Lewy body diseases. The Human Microglia Atlas (HuMicA) unravels changes in disease-associated microglia subsets across neurodegenerative conditions | Nature Communications
- Microglia have also been implicated in multiple CNS diseases, including Alzheimer’s disease (AD), multiple sclerosis (MS), Parkinson’s disease (PD), amyotrophic lateral sclerosis, stroke, and glioblastoma. Genes with established genetic associations with disease (for example, TREM2 and APOE with AD) are expressed in microglia and are dysregulated in patients and animal models.
Again, I know that we are not focussing on non-orphan neurodegenerative conditions however if my read is correct then I fear we could be giving the farm, for the price of one egg - excuse the poor analogy. If normal microglial function underpins a range of neurodegenerative conditions of SIGNIFICANT commercial value, in addition to the neurodevelopmental conditions we are looking to currently treat, I would hope that we are leveraging this potential to the absolute maximum.
