The presence of amyloid deposits and tau aggregates are the main characteristics of Alzheimer's disease, and could be related to the neurodegenerative process. Usually, amyloid and tau pathologies are analyzed in an independent way, and is not known if drugs preventing amyloid pathology may also affect tau pathology. One example is 3-amino-1-propane sulfonic acid (3-APS), that maintains beta amyloid peptide in non fibrillary form , whose possible action on tau protein was unknown.
The aggregation of amyloid peptide, or tau protein, can be induced by sGAG, like heparin. However, in the case of amyloid peptide, low molecular weight heparin may reduce the accumulation of beta amyloid aggregates in a mouse model  and compounds, like 3-APS, that mimic the binding of sGAG, can bind to soluble non-fibrillar amyloid peptide, preventing amyloid aggregation . It has been also suggested that the sulfate moieties of sGAG are sufficient to favour the formation of amyloid fibrils , 3-APS has a sulfate moiety, but it appears that this is not enough to induce amyloid aggregation.
In this work, we have found that 3-APS favours tau polymerization into fibrillar aggregates. The appearance of these tau aggregates was not toxic in our cell model, and the addition of 3-APS did not either result in toxicity to cultured neurons. A possible explanation is that 3-APS binds to tau protein through its C-terminal half region and, in this way, it is not affecting to the microtubule binding region present in tau protein, and therefore is not affecting to the microtubule binding function of tau. 3-APS has both a positively and a negatively charged regions. The positively charged region of 3-APS could bind to the negatively charged regions of tau protein, like those present at the C-terminal region of tau, and in consequence, the negative influence of the C-terminal region of tau on its selfassembly, would decrease upon 3-APS binding, allowing tau poymerization . On the other hand the negative charge region of 3-APS could bind to the positive charges residues present in tau, in the C-terminal half of the molecule, residues that are involved in the binding of tau to actin. If it the case 3-APS and actin should compete for the same tau-binding site. Also, it has been indicated that tau binding to actin is through a region closed to the C-terminal of tau molecule . This region contains the NIHHK motif, similar to the VHHQK motif that it has been suggested to be required for the binding of 3-APS to Aβ peptide .
Thus, in the presence of 3-APS, the binding of tau to actin could be decreased if 3-APS overlaps its tau binding site with that of actin. We can not exclude that 3-APS may also bind to the negative charged N-terminal region of tau, with a similar effect on tau assembly , since we did not test a tau variant containing the N-terminal and the tubulin binding regions. Indeed, that possible binding of 3-APS to the N-terminal region of tau may influence the binding of tau to membrane-actin aggregates .
The proposed mechanism to explain the assembly of tau in the presence of 3-APS could not be very different to that suggested for heparin-induced tau assembly. In both cases a tau peptide comprising residues 317 to 335 is enough to form aggregates . In addition, 3-APS could act as a sequestering molecule for tau, but it could not be essential for cell viability. In this way it has been described that the mice lacking tau could develop and live like their wild type counterparts .
There is evidence for a role of sGAG in the formation of amyloid and tau aggregates  and, as indicated in the introduction, a possible toxic effect by promoting amyloid peptide aggregation was suggested for sGAG, but, conversely, it has been described that sGAG like heparan or chondroitin sulfate attenuate the neurotoxic effect of amyloid peptide in primary neuronal cultures , and a role for heparan sulfate as a modulator of Aβ formation, through beta secretase, has been suggested . It will be of interest in further studies, to test for a possible effect of 3-APS on beta secretase activity.
Regarding tau protein, it has been reported that the chondroitin sulfate content inversely correlates with the amount of hyperphosphorylated tau in cortical areas of Alzheimer's disease patients . Thus, a posible neuroprotective role of sGAG in Alzheimer's disease could not be excluded, and the neuroprotective role could be extended to some related compounds like 3-APS, because 3-APS could be used for decreasing Aβ pathology and, although it aggregates tau protein, it is not toxic for cultured cells. Moreover, 3-APS promotes the decrease of tau-actin complexes [28, 29] that could be toxic for the cells .