High–Molecular-Weight Paired Helical Filaments from Alzheimer Brain Induces Seeding of Wild-Type Mouse Tau into an Argyrophilic 4R Tau Pathology in Vivo

Abstract

In Alzheimer disease, the development of tau pathology follows neuroanatomically connected pathways, suggesting that abnormal tau species might recruit normal tau by passage from cell to cell. Herein, we analyzed the effect of stereotaxic brain injection of human Alzheimer high-molecular-weight paired helical filaments (PHFs) in the dentate gyrus of wild-type and mutant tau THY-Tau22 mice. After 3 months of incubation, wild-type and THY-Tau22 mice developed an atrophy of the dentate gyrus and a tau pathology characterized by Gallyas and tau-positive grain-like inclusions into granule cells that extended in the hippocampal hilus and eventually away into the alveus, and the fimbria. Gallyas-positive neuropil threads and oligodendroglial coiled bodies were also observed. These tau inclusions were composed only of mouse tau, and were immunoreactive with antibodies to 4R tau, phosphotau, misfolded tau, ubiquitin, and p62. Although local hyperphosphorylation of tau was increased in the dentate gyrus in THY-Tau22 mice, the development of neurofibrillary tangles made of mutant human tau was not accelerated in the hippocampus, indicating that wild-type human PHFs were inefficient in seeding tau aggregates made of G272V/P301S mutant human tau. Our results indicate thus that injection of human wild-type Alzheimer PHF seeded aggregation of wild-type murine tau into an argyrophilic 4R tau pathology, and constitutes an interesting model independent of expression of a mutant tau protein.

Propagation of Tau aggregates

“…Similar inclusions, but fewer in number, formed after the intracerebral injection into non-transgenic mice of brain homogenates from human Tauopathies. Similar findings have been reported by others following the injection of AD brain extracts into wild-type mice [78, 79]. …”

“…Overexpression of full-length human wild-type 2N3R tau or mutant P301S tau resulted in seeded aggregation upon exposure to AD seeds [68, 78]. Similar findings were obtained when primary neurons from wild-type mice were treated with Tau filaments from AD brain [79].…”

Prion-like mechanisms in Alzheimer disease

“…Tau seeding differs from Aβ seeding in that tauopathy is readily inducible by AD brain extracts in non-transgenic (wild-type) mice (Audouard et al, 2016; Guo et al, 2016b). In addition, recombinant tau fibrils can fairly efficiently instigate tauopathy in tau-transgenic mice (Lasagna-Reeves et al, 2012; Clavaguera et al, 2013; Iba et al, 2013; Peeraer et al, 2015), although the potency of recombinant tau is less than that of tau that originates in brain samples (Falcon et al, 2015).…”

Transmission of Tau Pathology from Human to Rodent Brain: How to Humanise Animal Models for Alzheimer’s Disease Research

“…Studies also showed differences in propagation (brain areas affected, distance of spreading) after injection of recombinant tau [87,103,104] or native forms [105,107]. Interestingly, tau from human tauopathies brain extracts induced tau pathology mimicking the parent neurodegenerative diseases (Table 2).…”

“…Various forms of tau protein like fibrils [87,103,104], filaments [28,72,105,106] and oligomers [27] or monomers [107,108] display different seeding properties despite the difference in the origin of the seeding tau protein. Studies also showed differences in propagation (brain areas affected, distance of spreading) after injection of recombinant tau [87,103,104] or native forms [105,107].…”