Brain connectivity during Alzheimer’s disease progression and its cognitive impact in a transgenic rat model

Abstract

The research of Alzheimer's disease (AD) in their early stages and its progression till symptomatic onset 12 is essential to understand the pathology and investigate new treatments. Animal models provide a helpful 13 approach to this research, since they allow for controlled follow-up during the disease evolution. In this 14 work, transgenic TgF344-AD rats were longitudinally evaluated starting at 6 months of age. Every 3 15 months, cognitive abilities were assessed by a memory-related task and magnetic resonance imaging 16 (MRI) was acquired. Structural and functional brain networks were estimated and characterized by graph 17 metrics to identify differences between the groups in connectivity, its evolution with age, and its influence 18 on cognition. Structural networks of transgenic animals were altered since the earliest stage. Likewise, 19 aging significantly affected network metrics in TgF344-AD, but not in the control group. In addition, 20 while the structural brain network influenced cognitive outcome in transgenic animals, functional 21 network impacted how control subjects performed. TgF344-AD brain network alterations were present 22 from very early stages, difficult to identify in clinical research. Likewise, the characterization of aging in 23 these animals, involving structural network reorganization and its effects on cognition, opens a window to 24 evaluate new treatments for the disease. 25 1 AUTHOR SUMMARYWe have applied magnetic resonance image based connectomics to characterize TgF344-AD rats, a 26 transgenic model of Alzheimer's disease (AD). This represents a highly translational approach, what is 27 essential to investigate potential treatments. TgF344-AD animals were evaluated from early to advanced 28 ages to describe alterations in brain connectivity and how brain networks are affected by age. Results 29showed that aging had a bigger impact in the structural connectivity of the TgF344-AD than in control 30 animals, and that changes in the structural network, already observed at early ages, significantly 31 influenced cognitive outcome of transgenic animals. Alterations in connectivity were similar to the 32 described in AD human studies, and complement them providing insights into earlier stages and a plot of 33

Candesartan treatment preserves learning and working memory in female TgF344-AD rats

“…We did not demonstrate working or reference memory deficits in TgF344-AD rats at 12-months of age. While some studies have shown deficits in reversal learning as early as six months and impaired performance on learning and reference memory tasks at 10- to 12-months of age when compared to WT rats[52-54], other groups have found no difference between WT and TgF344-AD rats on learning and memory tasks at or beyond 12-months of age[55-57].…”

Spatio-temporal metabolic rewiring in the brain of TgF344-AD rat model of Alzheimer’s disease

“…The cohort evaluated in this work belongs to a wider study, where the animals underwent cognitive evaluation every 3 months by a delayed non match to sample (DNMS) task as previosuly described 12 , and further research should be done to evaluate if the repetition of this task could have an impact in brain metabolism. In addition, only male animals were included in our experiments, and consequently we did not account for sex-related differences in the pathology.…”

“…For this, animal models of AD represent a very convenient approach to study disease progression, particularly at its earliest stages 9,10 . Animal models are suitable for longitudinal studies of AD, since the whole lifespan can be analysed significantly faster than in humans and under controlled conditions 11,12 . Importantly, these models should mimic as close as possible the metabolic changes observed in AD patients and should be studied with the same technologies, to ensure the research is clinically translatable 10 .…”

“…The clearest pathological hallmarks were identified from 16 months on, with neuronal loss, tauopathy and Aβ plaques deposition clearly observed in the cortex, hippocampus and striatum 27 . Since the emergence of TgF344-AD rats, many other alterations have been reported in this model affecting neurotransmission, neuronal connectivity, neurovascular function and cognition among others 12,[29][30][31] . Two recent studies have evaluated brain metabolites in TgF344-AD rats: Chaney et al 32 reported decreased NAA levels in the hippocampus and increased Tau in the thalamus of 18 months old TgF344-AD rats, together with assessment of neuroinflammation, the acetylcholine system, Aβ plaque deposition and tau protein aggregates; while 33 also reported a decrease in hippocampal NAA starting at 10 months of age together with decreases of taurine and creatine and increases in choline.…”

TgF344-AD rat model of Alzheimer’s disease: spatial disorientation and asymmetry in hemispheric neurodegeneration

“…Specifically, the TgF344-AD rat line expresses two mutant human genes: the "Swedish" APP (APPsw) and the Δ exon 9 PS1 (PS1ΔE9). Numerous studies have validated the phenotype of TgF344-AD rats [11][12][13][14], which, since their first description, have been used to test efficacy of deep brain stimulation [15,16], Aβ attenuation therapy [17], anti-inflammatory agents [18], and low-dose brain radiation [19]. Converging data suggest that the time resolution of the symptoms' progression in this transgenic line not only allows for studying AD at both early and advanced stages but also at a prodromal stage [20][21][22][23].…”