Roles of HDAC6 in the pathogenesis of Alzheimer’s disease

Abstract Background It has recently been demonstrated that HDAC6 depletion ameliorates the impairment of memory function and mitochondrial axonal transport induced by the accumulation of Aβ. However, very little is known about molecular mechanisms through which HDAC6 regulates APP processing. Also, it remains controversial whether HDAC6 induces inflammation or reduces it. Method We analyzed the expression of HDAC6 in AD patients and 5xFAD mice. We confirmed that HDAC6 regulates BACE1 in primary neurons and NLRP3 inflammasome in primary microglia. And we crossed HDAC6 knock‐out mice with 5xFAD mice and got 5xFAD/HDAC6 KO. We compared 5xFAD (n = 11) and 5xFAD/HDAC6 KO (n = 13). We did a nest building test, open field test, Morris water maze, Y‐maze, passive avoidance, and elevated plus maze. After finishing all these behaviour tests, we sacrificed the mouse and checked protein and mRNA. We did Immunohistochemistry using Aβ plaque, NLRP3 inflammasome and synapse‐related markers. We also did RNA‐seq analysis in these mice’s brains. Result We confirmed that the expression of HDAC6 was increased in the AD cortex compared to neuropathologically normal brains. The stability of BACE1 is regulated by its C‐terminal lysine, and HDAC6 deacetylates the C‐terminal lysine of BACE1 by direct binding. Also, HDAC6 deficiency reduced NLRP3 inflammasome activation‐, and subsequent inflammatory responses in microglia. By crossing HDAC6 knock‐out mice with 5xFAD mice, the role of HDAC6 was confirmed in an animal model of AD. HDAC6 deletion improved cognitive function and reduced the protein expression of BACE1 and inflammatory factors in 5xFAD mice. Also, HDAC6‐deficient 5xFAD mice developed fewer dense‐core plaques, IL‐1β, and ASC specks than 5xFAD mice. Furthermore, RNA‐sequencing was analyzed from the hippocampus of 5xFAD and 5xFAD/HDAC6 KO mice. Synapse and neuron development‐related genes were significantly up‐regulated, and type I interferon, immune response, and prion disease‐related genes were down‐regulated in HDAC6‐depleted mice. Finally, we confirmed that the ratio of PSD95 colocalized with C1q was significantly decreased in 5xFAD/HDAC6 KO compared to 5xFAD mice, which suggested that synapse loss was inhibited in AD mice. Conclusion This study reveals distinct functions of HDAC6 and suggests HDAC6 as a significant regulator in the pathogenesis of AD that could be exploited therapeutically.