The contributions of metabolomics in the discovery of new therapeutic targets in Alzheimer's disease

Abstract

Alzheimer's disease (AD) leads to the progressive loss of memory and other cognitive functions. It is the most common form of dementia in the elderly and has become a major public health problem due to the increase in life expectancy. Although the detection of AD is based on several neuropsychological tests, imaging, and biological analyses, none of these biomarkers allows a clear understanding of the pathophysiological mechanisms involved in the disease, and no efficient treatment is currently available. Metabolomics, which allows the study of biochemical alterations underlying pathological processes, could help to identify these mechanisms, to discover new therapeutic targets, and to monitor the therapeutic response and disease progression. In this review, we have summarized and analyzed the results from a number of studies on metabolomics analyses performed in biological samples originated from the central nervous system, in AD subjects, and in animal models of this disease. This synthesis revealed modified expression of specific metabolites in pathological conditions which allowed the identification of significantly impacted metabolic pathways both in animals and humans, such as the arginine biosynthesis and the alanine, aspartate, and glutamate metabolism. We discuss the potential biochemical mechanisms involved, the extent to which they could impact the specific hallmarks of AD, and the therapeutic approaches which could be proposed as a result.

Insulin and serine metabolism as sex-specific hallmarks of Alzheimer’s disease in the human hippocampus

“…Thus, it is crucial to compare these age-associated metabolic alterations with those occurring in AD for developing new therapeutic strategies for this age-associated, devastating dementia. A recent analysis of the literature on the whole central nervous system (Altine ´- Samey et al, 2021) showed that the pathways most significantly altered in AD are Arg biosynthesis and Ala/Asp/ Glu metabolism, whose metabolites were also confirmed to be significantly changed in our study (Figures 4 and S3B; Table S7).…”

Nicotinamide as potential biomarker for Alzheimer’s disease: A translational study based on metabolomics

“…Interestingly, most of them (i.e., taurine, glutathione, tyrosine, and glutamate) have been previously reported in several studies on metabolomics performed in biological samples from the CNS, both in animal models and in AD patients (Altine-Samey et al, 2021). However, the PLS-DA loadings with the larger absolute weights and the highest VIP scores were NAD and Nam (Supplementary Figure S1).…”

Metabolic Regulations of Smilax china L. against β-Amyloid Toxicity in Caenorhabditis elegans

“…A metabolomic analysis of AD subjects revealed that increased alanine levels were found in the brain gray matter, while lower aspartate levels were found in the brain white matter. AD participants also had higher amounts of glutamate, and neuronal death was linked to the dysregulation of the glutamatergic system [ 49 ]. Changes in glutamate metabolism can impact GABA metabolism because glutamate decarboxylase converts glutamate to GABA, which can be derived from GABA [ 50 ].…”