Abstract
Transgenic mice used for Alzheimer’s disease (AD) preclinical experiments do not recapitulate the human disease. In our models, the dietary tryptophan metabolite tryptamine produced by human gut microbiome induces tryptophanyl-tRNA synthetase (TrpRS) deficiency with consequent neurodegeneration in cells and mice. Dietary supplements, antibiotics and certain drugs increase tryptamine content in vivo. TrpRS catalyzes tryptophan attachment to tRNAtrp at initial step of protein biosynthesis. Tryptamine that easily crosses the blood–brain barrier induces vasculopathies, neurodegeneration and cell death via TrpRS competitive inhibition. TrpRS inhibitor tryptophanol produced by gut microbiome also induces neurodegeneration. TrpRS inhibition by tryptamine and its metabolites preventing tryptophan incorporation into proteins lead to protein biosynthesis impairment. Tryptophan, a least amino acid in food and proteins that cannot be synthesized by humans competes with frequent amino acids for the transport from blood to brain. Tryptophan is a vulnerable amino acid, which can be easily lost to protein biosynthesis. Some proteins marking neurodegenerative pathology, such as tau lack tryptophan. TrpRS exists in cytoplasmic (WARS) and mitochondrial (WARS2) forms. Pathogenic gene variants of both forms cause TrpRS deficiency with consequent intellectual and motor disabilities in humans. The diminished tryptophan-dependent protein biosynthesis in AD patients is a proof of our model-based disease concept.
Highlights
Alzheimer’s disease (AD) clinical trials have been a tremendous investment loss
In the initial step of protein biosynthesis, TrpRS catalyzes the attachment of Trp to its cognate tRNAtrp with formation of tryptophanyl tRNAtrp
We suggest that some of these short peptides can serve as markers: Glu-Ser is increased in AD and mild cognitive impairment (MCI) plasma and decreased in AD and MCI cerebrospinal fluid (CSF); Trp-Gly-Phe is decreased in AD/cognitively normal (CN) and AD/MCI plasma; Met-Trp-Gln (MWQ) is decreased in AD/CN and MCI/CN plasma; Pro-Lys-Pro is decreased in AD/CN and AD/MCI in CSF
Summary
Alzheimer’s disease (AD) clinical trials have been a tremendous investment loss. Efforts to combat neurodegeneration associated with AD are hindered by a lack of animal models recapitulating disease.The main reason is that the transgenic mice used for AD preclinical experiments clearly do not recapitulate the etiology of human disease. Alzheimer’s disease (AD) clinical trials have been a tremendous investment loss. Efforts to combat neurodegeneration associated with AD are hindered by a lack of animal models recapitulating disease. The main reason is that the transgenic mice used for AD preclinical experiments clearly do not recapitulate the etiology of human disease. The failed clinical trials indicate that a cause of AD is still unknown. Animal models can certainly be useful to find out more about the biological bases of AD and develop efficient pharmacological treatments. The ethologically-based mouse models of AD would be extremely useful for new preclinical trials. The neuronal loss in brain is a main characteristic of AD. The neurofibrillary tangles (NFT) containing tau protein along with amyloid β (Aβ) plaques are the pathological features of AD brain. The relationship between the primary structure and function of the AD hallmarks tau protein and amyloid precursor protein (APP) has been relatively
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