Altered Brain Metabolome Is Associated with Memory Impairment in the rTg4510 Mouse Model of Tauopathy

Abstract

Alzheimer’s disease (AD) is characterized, amongst other features, by the pathologic accumulation of abnormally phosphorylated tau filaments in neurons that lead to neurofibrillary tangles. However, the molecular mechanisms by which the abnormal processing of tau leads to neurodegeneration and cognitive impairment remain unknown. Metabolomic techniques can comprehensively assess disturbances in metabolic pathways that reflect changes downstream from genomic, transcriptomic and proteomic systems. In the present study, we undertook a targeted metabolomic approach to determine a total of 187 prenominated metabolites in brain cortex tissue from wild type and rTg4510 animals (a mice model of tauopathy), in order to establish the association of metabolic pathways with cognitive impairment. This targeted metabolomic approach revealed significant differences in metabolite concentrations of transgenic mice. Brain glutamine, serotonin and sphingomyelin C18:0 were found to be predictors of memory impairment. These findings provide informative data for future research on AD, since some of them agree with pathological alterations observed in diseased humans.

Fused Cycloheptatriene–BODIPY Is a High-Performance Near-Infrared Probe to Image Tau Tangles

“…A metabolically induced imbalance between protein kinases and phosphatases is believed to be the main reason for the occurrence of an abnormal level of hyperphosphorylated Tau, which gradually leads to the formation of neurofibrillary tangles (NFTs) . Accumulation of NFTs is considered to be a hallmark of normal brain aging, but when excessive, it becomes pathological and leads to common, and currently incurable, human diseases, including Alzheimer’s disease (AD), frontotemporal dementia, and other tauopathies. − Further, recent evidence increasingly suggests that NFTs are one of the main initiating factors that drive metabolic decline, leading to detrimental effects on the neuron that transforms the normal aging process to the development of AD and other tauopathies. − Thus, noninvasively monitoring the degree of NFTs in live subjects may allow for the assessment of any change in the normal aging process to one of the diseases, while also providing the ability to stage tauopathies, and thus evaluate the efficacy of new therapeutics. − Therefore, the development of improved molecular imaging agents that target NFTs in a highly selective and sensitive manner may prove to be invaluable research and diagnostic tools.…”

The Potential of Metabolomics in Biomedical Applications

“…Together, these data indicate impaired energy metabolism that might be connected to events of neurodegeneration [138]. Similarly, a tauopathy mouse model (rTg4510) found that changes in the levels of metabolites (glutamine, serotonin, and sphingomyelin C18:0) in the brain cortex correlate with memory impairment [70]. Future studies with animal models should validate metabolite profiles using different time points and transgenic models.…”

Taurine or N-acetylcysteine treatments prevent memory impairment and metabolite profile alterations in the hippocampus of high-fat diet-fed female mice

“…In contrast to these observations in rodent models of obesity and diabetes, mouse models for Alzheimer's disease show reduced taurine concentration in the hippocampus and cortex, relative to controls (e.g. Aytan et al, 2016;Takado et al, 2018;Chiquita et al 2019;Tondo et al, 2020).…”

“…Aytan et al ., 2016; Takado et al ., 2018; Chiquita et al . 2019; Tondo et al ., 2020). Interestingly, Takado and colleagues demonstrated an inverse relationship between absolute taurine concentration and tau protein accumulation in rTg4510 mice (Takado et al ., 2018), and Aytan and colleagues showed an inverse correlation between the ratio of taurine-to-creatine and a brain GFAP levels in the 5xFAD model (Aytan et al , 2016), suggesting that taurine depletion is associated with features of neurodegeneration and astrogliosis.…”