Neurofibrillary degeneration can be arrested in an in vivo cellular model of human tauopathy by application of a compound which inhibits tau filament formation in vitro.
Although tau filament formation is a central event in familial tauopathies and Alzheimer's disease (AD), the cellular consequences of neurofibrillary tangle (NFT) formation are poorly understood because of the unavailability of mammalian in vivo cellular models of neurofibrillary degeneration (NFD). We have shown that human tau forms filaments and is associated with cytodegeneration when overexpressed chronically in identified neurons (ABCs) in the lamprey central nervous system (CNS). In this model, degeneration occurs according to a stereotyped sequence that closely resembles the pattern seen in tangle-bearing neurons in AD, with both tau deposition and fragmentation beginning in distal dendrites and progressing proximally over time. This sequence has been divided into four stages ranging from (1) mild beading of terminal dendrites only through (4) extensive dendritic fragmentation and loss. Here, we show that lipid-soluble, low-molecular-weight (approx 300 Da) proprietary compounds that have been demonstrated to block tau filament formation in vitro can significantly retard the progressive degeneration of ABCs that express human tau23. Bath application of one of these compounds for periods of up to 50 d after plasmid injection prevented degeneration beyond stage 2 in 90% of all treated cells, whereas over half of control cells showed severe degeneration by this time. This provides the first in vivo experimental evidence directly supporting a causal role for tau filament formation in the pathogenesis of NFD and suggests that intensive effort toward developing therapeutic agents for AD and other NFDs targeted at blocking tau filament formation is warranted.
Hall
Garth F
GF
Department of Biological Sciences, University of Massachusetts, Lowell, MA 01854, USA. Garth_Hall@uml.edu
Lee
Sangmook
S
Yao
Jun
J
D000818:Animals; D004195:Disease Models, Animal; D018450:Disease Progression; D004353:Drug Evaluation, Preclinical; D005260:Female; D006801:Humans; D007798:Lampreys; D008164:Luminescent Proteins / Q000235:genetics; D008297:Male; D008845:Microinjections; D016874:Neurofibrillary Tangles / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D024801:Tauopathies / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D016875:tau Proteins