A New Target for Fighting Tau Tangles in Neurons
Researchers have found that HDAC7 bridges together GSK3β and hyperphosphorylated tau protein (hTau) in neurons, which may spur Alzheimer’s disease. Getting rid of HDAC7 in hTau model mice ameliorated their cognitive decline.
How proteins go wrong
While tau protein is necessary for proper neural function, it is associated with multiple neurological disorders, including Alzheimer’s disease [1]. This is due to its propensity to undergo post-translational modifications, including hyperphosphorylation, which leads to its misfolding and aggregation [2].
Previous work has found that this hyperphosphorylation is due to its interactions with specific phosphatases, such as GSK3β [3]. Excessive GSK3β has been found to appear within the neurons of Alzheimer’s disease patients, where it is co-located with hyperphosphorylated tau (hTau) tangles [4], and later work found that GSK3β is indeed the cause of these tangles [5]. Furthermore, the relationship is bidirectional: tau accumulation encourages the production of even more GSK3β [6].
In a previous study, these researchers found that HDAC7, a histone deacetylase with both enzymatic and non-enzymatic effects within neurons, inhibits the formation of lysosomes and the clearance of tau [7]. Other work found that HDAC7 is associated with inflammatory signals in macrophages [8].
HDAC7 makes tau worse in mice
This team began a further investigation into HDAC7 by injecting 2-month-old mice with an adeno-associated virus (AAV) that caused them to express hTau. This caused a significant increase in HDAC7, while the rest of the HDAC family along with sirtuins went unaffected; this was true for both RNA expression and total protein abundance. These results were confirmed in a different, 13-month-old, mouse model of hTau along with the researchers’ own investigation of human brain tissue derived from Alzheimer’s patients.
The researchers then overexpressed hTau and HDAC7 in the brains of mice and investigated them for cognitive abnormalities. In the initial part of the Morris water maze test, HDAC7 was found to be even more deleterious than hTau in delaying the mice’s ability to reach the platform; in other tests, including the novel object recognition test, the effects of HDAC7 and hTau were roughly similar. As expected, combining the two led to even worse performance, and the amount of hTau was indeed increased due to HDAC7 in these mice.
Both by itself and in the presence of hTau, HDAC7 was found to increase and activate GSK3β while diminishing PP2A, a regulator of tau phosphorylation. This was purely a protein effect; it did not increase its RNA production. Human neuron experiments confirmed these findings.
Stopping HDAC7 fights tauopathy in mice
Deleting HDAC7 appeared to have slight negative effects on cognition in mice that did not express hTau, although these apparent effects were not statistically significant. However, in mice that express hTau, this deletion had substantial and signficant positive effects, diminishing response latency on the Morris water maze test and substantially improving novel object recognition capabilities.
These cognitive benefits were found to be accompanied by increases in crucial synaptic proteins that are reduced by hTau activity. The protein itself was less phosphorylated in the mice that did not produce HDAC7. This was attributed to a reduction in the acetylation of GSK3β, which stabilizes it and permits it to phosphorylate more tau. The specific interaction of HDAC7 was discovered: it was due to its N-terminal activity, with its enzymatic actions being irrelevant to its effects on GSK3β and tau.
The researchers are clear that their “study identifies HDAC7 as a direct binding partner of both tau and GSK3β, forming an HDAC7-GSK3β-tau complex that facilitates the structural proximity necessary for their functional interaction.” They see HDAC7 as a potentially druggable target, and a small molecule that disrupts HDAC7 may be useful in fighting Alzheimer’s disease and other tau-related diseases. However, they also note that human tauopathies are more complex, as other tau isoforms also contribute to such diseases.
Literature
[1] Gan, P. B. C. N. S. (2024). L. Cellular and pathological functions of tau. Nat. Rev. Mol. Cell Biol, 25(11), 845.
[2] Islam, T., Hill, E., Abrahamson, E. E., Servaes, S., Smirnov, D. S., Zeng, X., … & Karikari, T. K. (2025). Phospho-tau serine-262 and serine-356 as biomarkers of pre-tangle soluble tau assemblies in Alzheimer’s disease. Nature medicine, 31(2), 574-588.
[3] Qian, W., Shi, J., Yin, X., Iqbal, K., Grundke-Iqbal, I., Gong, C. X., & Liu, F. (2010). PP2A regulates tau phosphorylation directly and also indirectly via activating GSK-3β. Journal of Alzheimer’s Disease, 19(4), 1221-1229.
[4] Leroy, K., Boutajangout, A., Authelet, M., Woodgett, J. R., Anderton, B. H., & Brion, J. P. (2002). The active form of glycogen synthase kinase-3β is associated with granulovacuolar degeneration in neurons in Alzheimer’s disease. Acta neuropathologica, 103(2), 91-99.
[5] Chakraborty, P., Ibáñez de Opakua, A., Purslow, J. A., Fromm, S. A., Chatterjee, D., Zachrdla, M., … & Zweckstetter, M. (2024). GSK3β phosphorylation catalyzes the aggregation of tau into Alzheimer’s disease-like filaments. Proceedings of the National Academy of Sciences, 121(52), e2414176121.
[6] Zhou, Q., Li, S., Li, M., Ke, D., Wang, Q., Yang, Y., … & Wang, J. Z. (2022). Human tau accumulation promotes glycogen synthase kinase-3β acetylation and thus upregulates the kinase: A vicious cycle in Alzheimer neurodegeneration. EBioMedicine, 78.
[7] Ye, J., Zhong, S., Wan, H., Guo, X., Yao, X., Liu, Q., … & Xiao, S. (2025). Upregulated astrocyte HDAC7 induces Alzheimer-like tau pathologies via deacetylating transcription factor-EB and inhibiting lysosome biogenesis. Molecular Neurodegeneration, 20(1), 5.
[8] Kadier, K., Niu, T., Ding, B., Chen, B., Qi, X., Chen, D., … & Zhu, C. L. (2024). PROTAC‐mediated HDAC7 protein degradation unveils its deacetylase‐independent proinflammatory function in macrophages. Advanced Science, 11(36), 2309459.
About the author
Josh Conway
