Scientists have synthesized a molecule that alleviates Alzheimer’s in a mouse model by targeting inflammation [1].
Aβ or inflammation?
Two of the most prominent – and probably interconnected – symptoms of Alzheimer’s disease are the accumulation of amyloid beta (Aβ) and chronic neuroinflammation. While the first one has been garnering most of the attention, innumerable efforts to combat Alzheimer’s by tackling Aβ have been woefully unsuccessful so far, which is why researchers are increasingly eyeing the inflammation path [2].
Chronic age-related inflammation (inflammaging) has been linked to a variety of diseases of aging, including cardiovascular, metabolic, neurodegenerative, and cancerous. In the brain, chronic inflammation results in large part from microglia, the resident macrophages, becoming overactivated and producing large amounts of pro-inflammatory cytokines, such as TNF-α, IL-6, and IL-1β.
Calming the immune cells down
PPARs (peroxisome proliferator-activating receptors) are a family of transcription factors that dampen the inflammatory response by regulating the expression of various involved genes. As such, they have been studied in the context of metabolic diseases like diabetes but also, more recently, as potential targets in neurodegenerative disorders [3]. All PPAR subtypes downregulate NF-κB, another transcription factor that activates production of pro-inflammatory cytokines, and some subtypes also intervene at a later stage by blocking NF-κB from accessing the target genes.
While several PPAR agonists have been studied, most of them selectively affect certain PPAR subtypes but not others. In the new study, the researchers created a synthetic PPAR agonist called DTMB, which binds to all PPAR subtypes.
In the first experiment, performed on several lines of immune cells, DTMB reduced the production of nitric oxide (NO), the final product of the inflammation response, more significantly than several other PPAR agonists and without showing any cytotoxicity.
The researchers then induced activation of microglia either by lipopolysaccharide (LPS), which is produced by bacteria and used by the immune system to identify a bacterial threat, or by treating the microglia with pre-aggregated Aβ. DTMB drastically decreased the activated microglial production of the pro-inflammatory cytokines TNF-α and IL-6 to the levels observed in quiescent cells.
To investigate the effects of DTMB in vivo, the researchers used a mouse model of Alzheimer’s disease. In the Y-maze and Morris’ water maze, the Alzheimer’s mice demonstrated greatly reduced spatial learning and memory compared to wild-type animals. However, DTMB treatment was able to reverse those changes almost completely.
Inflammation might be the upstream cause
Analysis of the mice’s brains revealed that the amount of Aβ aggregates in the hippocampus and cortex of DTMB-treated mice was significantly lower compared to controls. However, the levels of amyloid precursor protein (APP) – a precursor of Aβ, as the name suggests – were not affected. The treatment also did not decrease the amount of Aβ monomers but only of insoluble aggregates. These intriguing results are in line with some recent research suggesting that inflammation might negatively affect the ability of microglia and other cells to remove Aβ aggregates [4].
Moreover, elements of inflammasomes, the protein complexes that facilitate inflammatory responses, are known to be able to become seeds of Aβ aggregation [5]. According to this emerging paradigm, inflammation is the upstream cause of Alzheimer’s, and quenching it might be more effective than targeting Aβ aggregation.
In addition to neuroinflammation, Alzheimer’s is probably affected by peripheral inflammation, with pro-inflammatory molecules crossing the blood-brain barrier and affecting brain cells [6]. It is known that metabolic dysfunction, the foremost cause of peripheral inflammation, exacerbates Alzheimer’s [7]. Research shows that PPAR agonists reduce peripheral inflammation [8]. As the authors note, this might be adding to the effectiveness of DTMB.
Conclusion
More and more Alzheimer’s researchers are looking towards targeting inflammation as the primary way to finding a cure. This new study describes a synthetic molecule that effectively targets some of the known inflammatory pathways and alleviates Alzheimer’s symptoms in mice.
It must be noted that mouse models of Alzheimer’s are not considered very reliable, and many anti-Alzheimer’s candidate drugs that have failed in human trials previously showed promise in mice. For example, gemfibrozil, a PPARα activator, failed in a phase I clinical trial despite improving memory function in the same mouse model of Alzheimer’s [9]. Nevertheless, targeting inflammation in the context of Alzheimer’s seems promising at the moment, and we expect to see more data coming through soon.
Literature
[1] Oh, E., Kang, J. H., Jo, K. W., Shin, W. S., Jeong, Y. H., Kang, B., … & Kim, K. T. (2022). Synthetic PPAR Agonist DTMB Alleviates Alzheimer’s Disease Pathology by Inhibition of Chronic Microglial Inflammation in 5xFAD Mice. Neurotherapeutics, 1-20.
[2] Kinney, J. W., Bemiller, S. M., Murtishaw, A. S., Leisgang, A. M., Salazar, A. M., & Lamb, B. T. (2018). Inflammation as a central mechanism in Alzheimer’s disease. Alzheimer’s & Dementia: Translational Research & Clinical Interventions, 4, 575-590.
[3] Wójtowicz, S., Strosznajder, A. K., Jeżyna, M., & Strosznajder, J. B. (2020). The novel role of PPAR alpha in the brain: promising target in therapy of Alzheimer’s disease and other neurodegenerative disorders. Neurochemical Research, 45(5), 972-988.
[4] Minter, M. R., Taylor, J. M., & Crack, P. J. (2016). The contribution of neuroinflammation to amyloid toxicity in Alzheimer’s disease. Journal of neurochemistry, 136(3), 457-474.
[5] Venegas, C., Kumar, S., Franklin, B. S., Dierkes, T., Brinkschulte, R., Tejera, D., … & Heneka, M. T. (2017). Microglia-derived ASC specks cross-seed amyloid-β in Alzheimer’s disease. Nature, 552(7685), 355-361.
[6] Wood, H. (2018). Peripheral inflammation could be a prodromal indicator of dementia. Nature Reviews Neurology, 14(3), 127-127.
[7] Barbagallo, M., & Dominguez, L. J. (2014). Type 2 diabetes mellitus and Alzheimer’s disease. World journal of diabetes, 5(6), 889.
[8] Villapol, S. (2018). Roles of peroxisome proliferator-activated receptor gamma on brain and peripheral inflammation. Cellular and molecular neurobiology, 38(1), 121-132.
[9] Chandra, S., & Pahan, K. (2019). Gemfibrozil, a lipid-lowering drug, lowers amyloid plaque pathology and enhances memory in a mouse model of Alzheimer’s disease via peroxisome proliferator-activated receptor α. Journal of Alzheimer’s disease reports, 3(1), 149-168.
