Of rodents and men: the mysterious interneuronal pilgrimage of misfolded protein tau in Alzheimer’s disease.
Neurofibrillary degeneration, driven by misfolded protein tau, spreads from the predisposed induction sites and advances in a topographically predictable sequence along connected brain areas. Several mouse model studies have demonstrated that some species of pathologically modified tau, namely insoluble fibrils and soluble oligomers, evoke propagation of the pathology. These results clearly show that the spreading potency of misfolded tau does not depend exclusively on its solubility and/or mutations. The candidate factor responsible for the progression of misfolded protein tau is its disease modified conformation. In this study, we address the question, whether insoluble tau complexes containing either 3R or 4R human misfolded truncated tau (AlzTau) command distinct infectivity and spreading potency. We found that insoluble tau isolated from transgenic rats (SHR24), expressing misfolded 3R AlzTau, was able to infect cortical neurons in the area of injection in SHR72 transgenic rats expressing 4R AlzTau. However this tau was not able to spread into other brain areas. In contrast, administration of insoluble tau isolated from SHR72 transgenic rats was not only able to infect cortical neurons but also induced extensive spreading of neurofibrillary tangles in the adjacent brain areas. These findings suggest the existence of various strains of disease modified tau, tauons displaying different infectivity and spreading potency. Furthermore, the presented rat tauopathy models could serve as a tool for identification and characterization of tauons isolated from Alzheimer's disease brains that would allow stratification of Alzheimer's disease patients.
The Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia.
Lenka
L
Levarska
Norbert
N
Zilka
Santosh
S
Jadhav
Peter
P
Neradil
Michal
M
Novak
D000544:Alzheimer Disease / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007395:Interneurons / Q000378:metabolism* / Q000473:pathology; D016874:Neurofibrillary Tangles / Q000378:metabolism* / Q000473:pathology; D017510:Protein Folding; D051381:Rats; D011918:Rats, Inbred SHR; D055647:Rats, Transgenic; D016875:tau Proteins / Q000009:adverse effects*
C054369:MAPT protein, human; D016875:tau Proteins