Metabolic, Phenotypic, and Neuropathological Characterization of the Tg4-42 Mouse Model for Alzheimer’s Disease

Abstract

Background: Preclinical Alzheimer’s disease (AD) research strongly depends on transgenic mouse models that display major symptoms of the disease. Although several AD mouse models have been developed representing relevant pathologies, only a fraction of available mouse models, like the Tg4-42 mouse model, display hippocampal atrophy caused by the death of neurons as the key feature of AD. The Tg4-42 mouse model is therefore very valuable for use in preclinical research. Furthermore, metabolic biomarkers which have the potential to detect biochemical changes, are crucial to gain deeper insights into the pathways, the underlying pathological mechanisms and disease progression. Objective: We thus performed an in-depth characterization of Tg4-42 mice by using an integrated approach to analyze alterations of complex biological networks in this AD in vivo model. Methods: Therefore, untargeted NMR-based metabolomic phenotyping was combined with behavioral tests and immunohistological and biochemical analyses. Results: Our in vivo experiments demonstrate a loss of body weight increase in homozygous Tg4-42 mice over time as well as severe impaired learning behavior and memory deficits in the Morris water maze behavioral test. Furthermore, we found significantly altered metabolites in two different brain regions and metabolic changes of the glutamate/4-aminobutyrate-glutamine axis. Based on these results, downstream effects were analyzed showing increased Aβ 42 levels, increased neuroinflammation as indicated by increased astro- and microgliosis as well as neuronal degeneration and neuronal loss in homozygous Tg4-42 mice. Conclusion: Our study provides a comprehensive characterization of the Tg4-42 mouse model which could lead to a deeper understanding of pathological features of AD. Additionally this study reveals changes in metabolic biomarker which set the base for future preclinical studies or drug development.

N-Truncated Aβ Starting at Position Four—Biochemical Features, Preclinical Models, and Potential as Drug Target in Alzheimer’s Disease

“…Synaptic hyperactivity of hippocampal pyramidal neurons is therefore an early event in AD pathology. 18 F-Fluorodeoxyglucose ( 18 F-FDG)-PET in combination with magnetic resonance imaging (MRI) in Tg4–42 mice was used for analyzing cerebral brain glucose metabolism in vivo (Hinteregger et al, 2021 ). Tg4–42 mice demonstrated lower glucose uptake correlating with neuron loss and memory deficits in an age-dependent manner (Bouter et al, 2018 ).…”

“…Moreover, small RNA sequencing of the microRNAome in the hippocampus of Tg4–42 mice revealed microRNAs involved in learning, memory function, and synaptic signaling (Bouter et al, 2020 ). Metabolic changes of the glutamate/4-aminobutyrate-glutamine axis correlated with neurological deficits, neurodegeneration, and elevated CSF levels of neurofilament light chain in aged Tg4–42 mice (Hinteregger et al, 2021 ). Tg4–42 mice harbor more than 20 copies of the transgene in exon 2 of the retinoic acid receptor β (RARB) leading to decreased expression of RARB, which could have an (at least partial) effect on the phenotype (Hinteregger et al, 2020 ).…”

Neuroimaging of Mouse Models of Alzheimer’s Disease

“…The rTg4510 transgenic mouse, an increasingly popular AD model, reported severe hippocampal and neocortical atrophy with concomitant increased ventricles [ 137 ], where females had larger volume decrements than males and both sexes were reduced significantly compared to WT [ 138 ]. Other AD mouse models, such as ApoE4 (24 months), Tau4RDeltaK and Tg4–42 mice, also exhibited significant hippocampal and whole brain volume decrements [ 139 , 140 , 141 ].…”

“…The authors suggest that regional GABA levels may contribute to the sex disparities observed in AD; but this awaits further study. In a recently developed tau mouse model of AD, Tg4-42, reduced 4-aminobutyrate, Gln and lactate in the cortex were reported, with reductions in 4-aminobutyrate in the caudate putamen [ 139 ]. These reductions mirrored increased levels of metabolizing enzymes and increasing Aβ42 levels with increased neuroinflammation and neuronal loss [ 139 ].…”

“…In a recently developed tau mouse model of AD, Tg4-42, reduced 4-aminobutyrate, Gln and lactate in the cortex were reported, with reductions in 4-aminobutyrate in the caudate putamen [ 139 ]. These reductions mirrored increased levels of metabolizing enzymes and increasing Aβ42 levels with increased neuroinflammation and neuronal loss [ 139 ]. The Tg4-42 mouse replicates the progressive neuronal loss observed in human AD subjects.…”