Metabolic Dementia... and a cure?

Mind-Gut axis involved.

Huntington’s Disease Discovery

Huntington’s disease (HD) phenotype mainfests striatal neuron loss along with debilitating and progressive chorea, dementia, and psychological disturbance. HD genotype is a CAG repeat expansion in the Huntingtin (HTT) gene, translating to an elongated glutamine tract in the huntingtin protein. But we do not know how this mutation leads to cell dysfunction and ultimately, death. However, a PNAS publication now shows direct association of HD with brain urea levels and metabolic processes. Earlier studies from the group also linked Alzheimer’s dementia to urea cycling, so this could be a common mechanism of action for several dementias occurring late in life.

They investigated a transgenic sheep HD model as well as donated HD patient cadavers and were able to establish that the high urea levels occurred before dementia sets in. This opens a big window to potential therapeutic interventions.

More research, however, is needed to discover the source of the elevated urea in HD, particularly concerning the potential involvement of ammonia and a systemic metabolic defect. This could have profound implications for our fundamental understanding of the molecular basis of dementia, and its treatability, including the potential use of therapies already in use for disorders with systemic urea phenotypes. - Garth J. S. Cooper

Urea Cycle congenital disorders of metabolism.

Urea accumulation arises from increased protein catabolism, used as an alternate energy source, in disorders of urea cycle. Increased urea and ammonia levels due to this dysregulation of the urea cycle can cause neurologic impairment.

http://www.acertx.com/

Enzymes in the urea cycle are crucial for converting ammonia into urea, which is then excreted harmlessly in the urine via the kidney. We already have several established oral drugs on the market that can bypass the defects in patients with these inborn errors of urea metabolism - for example, sodium phenylbutyrate. There are also ammonia scavenging medications that allow alternative methods of excretion of the excessive ammonia. And lactulose, a non-absorbable disaccharide, is catabolized by gut bacterial flora to acids (e.g., lactic acid and acetic acid) which lower the colonic pH, thus favoring formation of non-absorbable NH4+ from NH3, trapping NH4+ in the colon and thus reducing plasma ammonia concentrations.

Perhaps these agents could be trialed in patients with early signs of cognitive impairment?

Genetically Engineered E. Coli to the rescue

But let’s not leave out the potential biologic agents as interventions. From Synlogic Inc, an anti-ammonia probiotic:

Hyperammonemia, or excess blood ammonia, is a serious condition that can result in brain damage and death. In pursuit of a potential therapeutic, Kurtz et al. modified the metabolism of a probiotic E. coli strain to overproduce arginine, thereby sequestering some of the ammonia produced by gut bacteria into the amino acid molecules. The engineered strain, called SYNB1020, lowered blood ammonia, increased survival in mouse hyperammonemia models, and showed repeat-dose tolerability in nonhuman primates. A phase 1 dose-escalation study in healthy human volunteers resulted in no serious adverse events and indicated that the bacterium was metabolically active in vivo,

So how about we all get smoothies spiked with probiotics, ammonia scavengers and bypassing amino acids, as our daily dementia prophylaxis? I see a market for a new kind of boomer bar on the not too distant horizon.

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REFERENCES

https://neurosciencenews.com/dementia-cause-8165/

“Brain urea increase is an early Huntington’s disease pathogenic event observed in a prodromal transgenic sheep model and HD cases” PNAS. December 11 2017 doi:10.1073/pnas.1711243115

https://www.acertx.com/patient_physician/urea-cycle-disorders-ucds/

Häberle J, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet Journal of Rare Diseases. 2012;7(32). https://ojrd.biomedcentral.com/track/pdf/10.1186/1750-1172-7-32.pdf

https://medicalxpress.com/news/2019-01-probiotic-strain-escherichia-coli-bacteria.html

An engineered E. coli Nissle improves hyperammonemia and survival in mice and shows dose-dependent exposure in healthy humans https://stm.sciencemag.org/content/11/475/eaau7975

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