Deep Dive into Dementia
Some surprising therapeutics proposed
I wrote about dementia before, resulting from metabolic derangements of the urea cycle. [see May 15 2021] With this newsletter, we look at other possible mechanisms of action and their proposed fixes.
In the beta amyloid field of dementia research, two old drugs may be candidates for repurposing: gemfibrosil, a cholesterol-lowering drug, and retinoic acid, a vitamin A derivative. Encouraging reports from animal studies point to further examination of their effects on brain, especially astrocytes accumulation of the protein. When used in combination, these two drugs show a reversal — instead reduce amyloid beta in the brain, improving cognitive function in mice [5XFAD mouse model of Alzheimer’s disease].
Astrocytes studied in cell cultures and in Alzheimer's mouse models were stimulated by retinoic acid to phagocytose through the activation of the low-density lipoprotein cholesterol receptor and triggered to subsequently degrade amyloid in lysosomes by gemfibrozil. They mop up the excess protein from the extracellular fluid, engulf it and then break it down.
This is not the first time retinoic acid has been touted as benefic. A study from 2012 described its role in the formation of lymphatic vessels:
Methods and Results—We report that RAs promote proliferation, migration, and tube formation of cultured lymphatic endothelial cells by activating fibroblast growth factor receptor signaling. Moreover, RAs control the expression of cell-cycle checkpoint regulators such as p27Kip1, p57Kip2, and the aurora kinases through both an Akt-mediated nongenomic action and a transcription-dependent genomic action that is mediated by Prox1, a master regulator of lymphatic development. Moreover, 9-cisRA was found to activate in vivo lymphangiogenesis in animals in mouse trachea, Matrigel plug, and cornea pocket assays. Finally, we demonstrate that 9-cisRA can provide a strong therapeutic efficacy in ameliorating experimental mouse tail lymphedema by enhancing lymphatic vessel regeneration.
Conclusion—These in vitro and animal studies demonstrate that 9-cisRA potently activates lymphangiogenesis and promotes lymphatic regeneration in an experimental lymphedema model, presenting it as a promising novel therapeutic agent to treat human lymphedema patients. - Choi et al.
The big news coming just a year after this, was the discovery of brain’s lymphatic system - glymphatics. It was aptly named, “the garbage truck of the brain” because it flushed out the toxins floating in the brain parenchyma, through the neuropil, with each heart beat arterial pulse. Their results show that during sleep a plumbing system may open, letting fluid flow rapidly through the brain. The glymphatic system helps control the flow of cerebrospinal fluid, long thought to be a glial/astrocyte function.
More recent studies looked at the role of glymphatics in Alzheimer’s disease. In this dementia, two kinds of waste materials accumulate in the brain, beta-amyloids and tau proteins. Harmful amyloid plaque and tau tangles are formed not only around the brain tissue but also around the cerebral arteries, stiffening them. Oulu Functional Neuroimaging research group developed a new method for the magnetic resonance imaging of the functioning of the glymphatic system and they studied the changes within affected patients.
"Both the propagation speed of the pulse waves and their direction differ in Alzheimer's patients in comparison to healthy controls. In certain parts of the brain, including the hippocampus and parietal lobes, the direction of propagation of pulse waves was reversed compared to healthy individuals. These parts of the brain play a major role in memory functions," … "We observed that upon arrival, the pulse propagation is abnormal in Alzheimer's patients: too fast in small vessels and too slow in large ones," - Zalán Rajna
We should all be encouraged by these findings, especially the Boomers. Many of us grew up gulping Vit A containing cod liver oil [and still do!] but also now liberally apply the cis retinoic acid on our sun damaged face wrinkles. But the teeners aren’t left out - that acne cream is also brain Draino. Just need to combine it with good nightly sleep and their cognitive capacity, too, can be conserved.
REFERENCES
Sumita Raha et al, Activation of PPARa enhances astroglial uptake and degradation of b-amyloid, Science Signaling (2021). DOI: 10.1126/scisignal.abg4747
Inho Choi et al. 9-Cis Retinoic Acid Promotes Lymphangiogenesis and Enhances Lymphatic Vessel Regeneration. Therapeutic Implications of 9-Cis Retinoic Acid for Secondary Lymphedema Circulation. 2012;125:872–882 https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.111.030296
Maiken Nedergaard, “Garbage Truck of the Brain,” Science 28 June 2013: Vol. 340 no. 6140 pp. 1529-1530; https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3749839/
https://www.nih.gov/news-events/news-releases/brain-may-flush-out-toxins-during-sleep
Zalán Rajna et al. Cardiovascular brain impulses in Alzheimer's disease, Brain (2021). DOI: 10.1093/brain/awab144
Glymphatic system impairment in Alzheimer’s disease and
idiopathic normal pressure hydrocephalus. Trends Mol Med. 2020 March ; 26(3): 285–295. doi:10.1016/j.molmed.2019.11.008 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489754/pdf/nihms-1626125.pdf
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Jin-Hui Yoon et al,
Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage, Nature (2024).
DOI: 10.1038/s41586-023-06899-4
Caffeine boosts enzyme that could protect against dementia, study finds
https://medicalxpress.com/news/2017-03-caffeine-boosts-enzyme-dementia.html