Naslov
Novel non-transgenic tauopathy model induced by inoculation of human tau fibrils and tau oligomers into the rat entorhinal cortex

Autori
Langer Horvat, Lea ; Šimić, Goran

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Neurologia Croatica 72 (Supplement 1) / Šimić, Goran ; Mimica, Ninoslav - Zagreb : Denona, 2023, 73-74

Skup
2nd Congress of the Croatian Alzheimer Alliance

Mjesto i datum
Varaždin, Hrvatska, 29.03.2023. - 01.04.2023

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
Alzheimer’s disease ; cognition ; tau fibrils ; tau oligomers ; tauopathy rat model

Sažetak
Emerging experimental evidence suggests that the spread of tau pathology in the brain in human neurodegenerative disorders reflects the propagation of misfolded tau along neuroanatomically connected brain regions, with the first changes seen in the brainstem and entorhinal cortex spreading trans-synaptically along specific pathways to other brain regions. Most of the in vivo spreading of tau has been shown in transgenic mouse models that overexpress mutated or wild-type human tau. The use of genetic models of familial Alzheimer's disease (AD) may not represent the complete picture of the disease in humans. Therefore, other types of animal models relevant to the sporadic form, which represents over 95 % of all AD cases, must be developed. In the study, we aimed to characterize possible pathological changes and the propagation of different forms of tau species in non-transgenic 3-4 months-old wild-type Wistar rats after a single unilateral injection of human tau oligomers and tau fibrils into the medial entorhinal cortex (mEC). We determined whether tau fibrils and tau oligomers would induce neurofibrillary changes and propagate like AD and whether this tau-related pathology would correlate with cognitive impairment. We injected human tau fibrils and tau oligomers stereotaxically into the mEC and examined the distribution of tau-related changes at different time points (4, 8, and 11 months post-injection) using antibodies AT8 for early phosphorylation and MC1 for aberrant conformation of tau. Colocalization was performed with the synaptophysin antibody to analyze whether inoculated tau proteins enter synapses and affect their decay. We observed that tau oligomers and tau fibrils exhibit different effects in terms of the ability to propagate tau-related changes. Both variants of inoculated tau proteins rapidly spread via anterograde axonal transport to the hippocampus and various parts of the neocortex, including the primary motor and somatosensory areas. Rats inoculated with human tau fibrils showed, as early as 4 months after inoculation, a spread of phosphorylated tau protein at the AT8 epitopes throughout the brain and faster propagation of neurofibrillary changes than with human tau oligomers. The severity of tau changes after inoculation of human tau oligomers and tau fibrils correlated with impairments in spatial working memory and cognition, as measured by the T-maze, novel object recognition, and object location tests. We concluded that this non-transgenic rat model of tauopathy, especially when using human tau fibrils, demonstrates rapidly developing pathologic alterations in neurons and synapses together with cognitive and behavioral changes through the anterograde and retrograde spreading of neurofibrillary degeneration. Therefore, it represents a promising novel model for experimental studies of primary and secondary tauopathies, especially AD.

Izvorni jezik
Engleski

Znanstvena područja
Biologija, Temeljne medicinske znanosti, Kliničke medicinske znanosti, Kognitivna znanost (prirodne, tehničke, biomedicina i zdravstvo, društvene i humanističke znanosti), Biotehnologija u biomedicini (prirodno područje, biomedicina i zdravstvo, biotehničko područje)

POVEZANOST RADA