title: A synergic role of caspase-6 and caspase-3 in Tau truncation at D421 induced by H2O 2.
abstract: Tau truncation is widely detected in Alzheimer's disease brain. Caspases activation is suggested to play a significant role in tau truncation at Aspartate 421 (D421) according to their ability to cleave recombinant tau in vitro. Ample evidence has shown that caspase-6 is involved in cognitive impairment and expressed in AD brain. Reactive oxygen species (ROS) can lead to caspase-6 activation and correlate with AD. Here, we transfected human embryonic kidney 293 (HEK 293) cells with Tau 441 plasmid and investigated the role of caspase-6 and caspase-3 in ROS-mediated tau truncation. Our data demonstrated that H2O2 induced oxidative stress and increased tau truncation. Caspase-6 and caspase-3 activity also increased in a dose-dependent manner in HEK 293/Tau cells during H2O2 insult. When cells were treated with an ROS inhibitor N-acetyl-L-cysteine, tau truncation was significantly suppressed. Compared with H2O2 (100 μM)/non-inhibitor group or single-inhibitor groups (z-VEID-fmk, caspase-6 inhibitor or z-DEVD-fmk, and caspase-3 inhibitor), tau truncation induced by H2O2 was effectively reduced in the combinative inhibitors group. Similar results were shown when cells were transfected with specific caspase-3 and caspase-6 siRNA. Inhibition of caspase-6 led to decline of caspase-3 activation. Taken together, our results suggest that the combination of caspase-6 and caspase-3 aggravates tau truncation at D421 induced by H2O2. Caspase-6 may play an important part in activating caspase-3. Further investigation of how the synergic role of caspase-6 and caspase-3 affects tau truncation may provide new visions for potential AD therapies.
authors.affiliation: School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Zhao
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Zhao
authors.forename: Kenghoe
authors.initials: K
authors.lastname: Lok
authors.forename: Zejian
authors.initials: Z
authors.lastname: Wang
authors.forename: Ming
authors.initials: M
authors.lastname: Yin
mesh_terms: D001224:Aspartic Acid / Q000378:metabolism*; D053148:Caspase 3 / Q000502:physiology*; D053178:Caspase 6 / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D057809:HEK293 Cells; D006801:Humans; D016875:tau Proteins / Q000378:metabolism*
chemical_list: D004791:Enzyme Inhibitors; D016875:tau Proteins; D001224:Aspartic Acid; D053148:Caspase 3; D053178:Caspase 6