Progressive Pathological Changes in Neurochemical Profile of the Hippocampus and Early Changes in the Olfactory Bulbs of Tau Transgenic Mice (rTg4510)

Abstract

Tauopathies such as Alzheimer’s disease and frontotemporal lobe degeneration (FTLD-tau) dementia, characterized by pathologic aggregation of the microtubule-associated tau protein and formation of neurofibrillary tangles, have been linked to neurodegeneration and cognitive decline. The early detection of cerebral abnormalities and the identification of biological contributors to the continuous pathologic processes of neurodegeneration in tauopathies critically hinge on sensitive and reliable measures of biomarkers in the living brain. In this study, we measured alterations in a number of key neurochemicals associated with tauopathy-induced neurodegeneration in the hippocampus and the olfactory bulbs of a transgenic mouse model of FTLD-tauopathy, line rTg4510, using in vivo 1H magnetic resonance spectroscopy (MRS) at 9.4 T. The rTg4510 line develops tauopathy at a young age (4–5 months), reaching a severe stage by 8–12 months of age. Longitudinal measurement of neurochemical concentrations in the hippocampus of mice from 5 months to 12 months of age showed significant progressive changes with distinctive disease staging patterns including N-acetylaspartate (NAA), myo-inositol, γ-aminobutyric acid (GABA), glutathione and glutamine. The accompanying hippocampal volume loss measured using magnetic resonance imaging showed significant correlation (p < 0.01) with neurochemical measurements. Neurochemical alterations in the olfactory bulbs were more pronounced than those in the hippocampus in rTg4510 mice. These results demonstrate progressive neuropathology in the mouse model and provide potential biomarkers of early neuropathological events and effective noninvasive monitoring of the disease progression and treatment efficacy, which can be easily translated to clinical studies.

Brain and Retinal Abnormalities in the 5xFAD Mouse Model of Alzheimer's Disease at Early Stages

“…other two brain regions. Indeed, a slower decay of the volume of olfactory bulb than hippocampus at the early and middle stages of AD was reported in rTg510 mice, another AD mice model (Kim et al, 2017). In another study on 5xFAD mice, an intact olfactory memory from 3 to 15 months of age was reported (O'Leary et al, 2020).…”

Longitudinal hippocampal volumetric changes in mice following brain infarction

“…Whilst on initial inspection this may appear surprising, it likely reflects the paucity of knowledge about brain volume changes in normal rodent aging. Hippocampal volume increases between 5 and 35 weeks of age 38 and 5 and 12 months of age 39 in wild-type mice have been described in different degenerative disease models, including Huntington’s disease and frontotemporal lobe degeneration tauopathy. This increase is presumably due to brain maturation in healthy animals.…”

Improved Sleep, Memory, and Cellular Pathological Features of Tauopathy, Including the NLRP3 Inflammasome, after Chronic Administration of Trazodone in rTg4510 Mice

“…Our work demonstrated that trazodone improved olfactory memory during the first month of treatment but did not affect spatial working memory in rTg4510 mice. Impairments in the olfactory system were previously reported in the rTg4510 mice, while olfactory deficits were observed in tau P301S mice when hippocampal-dependent spatial memory was preserved ( Yang et al, 2016 ; Kim et al, 2017 ). This finding is relevant as early olfactory dysfunction is common in Alzheimer's disease ( Hawkes, 2003 ), often occurring prior to other cognitive impairment.…”