Amyloid-β pathology enhances pathological fibrillary tau seeding induced by Alzheimer PHF in vivo

Abstract

Neuropathological analysis in Alzheimer's disease (AD) and experimental evidence in transgenic models overexpressing frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17) mutant tau suggest that amyloid-β pathology enhances the development of tau pathology. In this work, we analyzed this interaction independently of the overexpression of an FTDP-17 mutant tau, by analyzing tau pathology in wild-type (WT), 5xFAD, APP −/− and tau −/− mice after stereotaxic injection in the somatosensory cortex of short-length native human AD-PHF. Gallyas and phosphotau-positive tau inclusions developed in WT, 5xFAD, and APP −/− but not in tau −/− mice. Ultrastructural analysis demonstrated their intracellular localization and that they were composed of straight filaments. These seeded tau inclusions were composed only of endogenous murine tau exhibiting a tau antigenic profile similar to tau aggregates in AD. Insoluble tau level was higher and ipsilateral anteroposterior and contralateral cortical spreading of tau inclusions was more important in AD-PHF-injected 5xFAD mice than in WT mice. The formation of large plaque-associated dystrophic neurites positive for oligomeric and phosphotau was observed in 5xFAD mice injected with AD-PHF but never in control-injected or in non-injected 5xFAD mice. An increased level of the p25 activator of CDK5 kinase was found in AD-PHF-injected 5xFAD mice. These data demonstrate in vivo that the presence of Aβ pathology enhances experimentally induced tau seeding of endogenous, wild-type tau expressed at physiological level, and demonstrate the fibrillar nature of heterotopically seeded endogenous tau. These observations further support the hypothesis that Aβ enhances tau pathology development in AD through increased pathological tau spreading.

Propagation of Tau Pathology: Integrating Insights From Postmortem and In Vivo Studies

“…When AD-derived tau filaments were injected in transgenic mice with Ab plaque pathology, this led to the formation of all 3 major types of AD tau pathology in an animal model (i.e., NFTs, neuropil threads, and tau aggregates in dystrophic neurites) (103,104). This is noteworthy because the range of tau pathologies observed in AD has not been observed in previous transgenic mouse models expressing both Ab and tau pathology (105).…”

Picalm reduction exacerbates tau pathology in a murine tauopathy model

“…For quantitative analysis, Gallyaspositive or AT8-positive neurons in hippocampal Ammon's horn and dentate gyrus were counted on sagittal sections at a lateral level approximately 1 mm from the midline (Allen brain atlas) with a 40X objective as reported previously in Tg30 mice [35]. To analyse the pons and the motor areas (M1 and M2) of the cortex, the density of cells labelled for Gallyas, AT8, phosphorylated neurofilament heavy chain (pNF-H) and p62 was assessed on 10X images by thresholding analyses using NIH ImageJ as previously reported [61]. Area fractions were calculated by measuring the labelled area divided by the total surface of the area analysed.…”

The Positive Side of the Alzheimer’s Disease Amyloid Cross-Interactions: The Case of the Aβ 1-42 Peptide with Tau, TTR, CysC, and ApoA1

“…Since a very recent and detailed review about the in vivo intracerebral seeding of Aβ and Tau in mice [72], has just been released, we will mainly focus on the in vitro studies aiming to deepen the knowledge about the physicochemical aspects of this interaction. The growing interest in understanding the cross-seeded interaction between Aβ and Tau is justified by several in vivo experiments showing that Aβ enhances Tau pathology by increasing the formation of Tau species capable of seeding new aggregates [73][74][75][76][77][78][79][80].…”