Abstract
Many gaps in our understanding of Alzheimer’s disease remain despite intense research efforts. One such prominent gap is the mechanism of Tau condensation and fibrillization. One viewpoint is that positively charged Tau is condensed by cytosolic polyanions. However, this hypothesis is likely based on an overestimation of the abundance and stability of cytosolic polyanions and an underestimation of crucial intracellular constituents – the cationic polyamines. Here, we propose an alternative mechanism grounded in cellular biology. We describe extensive molecular dynamics simulations and analysis on physiologically relevant model systems, which suggest that it is not positively charged, unmodified Tau that is condensed by cytosolic polyanions but negatively charged, hyperphosphorylated Tau that is condensed by cytosolic polycations. Our work has broad implications for anti-Alzheimer’s research and drug development and the broader field of tauopathies in general, potentially paving the way to future etiologic therapies.
Highlights
Many gaps in our understanding of Alzheimer’s disease remain despite intense research efforts
We present extensive molecular dynamics simulations and analysis, grounded in cellular biology, which challenge the in vitro view, expressed by certain researchers, of positively charged Tau being condensed into neurofibrillary tangles by negatively charged heparin and RNA, and supplant it with a physiologically relevant picture of negatively charged hyperphosphorylated Tau being condensed by positively charged cellular polyamines – spermine and spermidine
In order to assess the behavior of the cellular polyamine spermine in the presence of unmodified and hyperphosphorylated 4R-Tau, we performed 1 μs-long all-atom molecular dynamics (MD) simulations of both variants in the presence of spermine, placing 8 Tau chains and 44 spermine molecules in the unit cell, along with a physiological concentration of NaCl
Summary
Many gaps in our understanding of Alzheimer’s disease remain despite intense research efforts. We present extensive molecular dynamics simulations and analysis, grounded in cellular biology, which challenge the in vitro view, expressed by certain researchers, of positively charged Tau being condensed into neurofibrillary tangles by negatively charged heparin and RNA, and supplant it with a physiologically relevant picture of negatively charged hyperphosphorylated Tau being condensed by positively charged cellular polyamines – spermine and spermidine. Our results offer insight into the atomistic mechanisms of neurofibrillary tangle formation in Alzheimer’s disease and the broader class of tauopathy[34] in general, and potentially open the way to developing etiologic treatment and prevention in the future, as opposed to the symptomatic pharmacotherapeutic strategies of the present time
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