title: Formaldehyde at low concentration induces protein tau into globular amyloid-like aggregates in vitro and in vivo.
abstract: Recent studies have shown that neurodegeneration is closely related to misfolding and aggregation of neuronal tau. Our previous results show that neuronal tau aggregates in formaldehyde solution and that aggregated tau induces apoptosis of SH-SY5Y and hippocampal cells. In the present study, based on atomic force microscopy (AFM) observation, we have found that formaldehyde at low concentrations induces tau polymerization whilst acetaldehyde does not. Neuronal tau misfolds and aggregates into globular-like polymers in 0.01-0.1% formaldehyde solutions. Apart from globular-like aggregation, no fibril-like polymerization was observed when the protein was incubated with formaldehyde for 15 days. SDS-PAGE results also exhibit tau polymerizing in the presence of formaldehyde. Under the same experimental conditions, polymerization of bovine serum albumin (BSA) or alpha-synuclein was not markedly detected. Kinetic study shows that tau significantly misfolds and polymerizes in 60 minutes in 0.1% formaldehyde solution. However, presence of 10% methanol prevents protein tau from polymerization. This suggests that formaldehyde polymerization is involved in tau aggregation. Such aggregation process is probably linked to the tau's special "worm-like" structure, which leaves the epsilon-amino groups of Lys and thiol groups of Cys exposed to the exterior. Such a structure can easily bond to formaldehyde molecules in vitro and in vivo. Polymerizing of formaldehyde itself results in aggregation of protein tau. Immunocytochemistry and thioflavin S staining of both endogenous and exogenous tau in the presence of formaldehyde at low concentrations in the cell culture have shown that formaldehyde can induce tau into amyloid-like aggregates in vivo during apoptosis. The significant protein tau aggregation induced by formaldehyde and the severe toxicity of the aggregated tau to neural cells may suggest that toxicity of methanol and formaldehyde ingestion is related to tau misfolding and aggregation.
authors.affiliation: State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Graduate School, Chinese Academy of Sciences, Chaoyang District, Beijing, China.
authors.forename: Chun Lai
authors.initials: CL
authors.lastname: Nie
authors.forename: Yan
authors.initials: Y
authors.lastname: Wei
authors.forename: Xinyong
authors.initials: X
authors.lastname: Chen
authors.forename: Yan Ying
authors.initials: YY
authors.lastname: Liu
authors.forename: Wen
authors.initials: W
authors.lastname: Dui
authors.forename: Ying
authors.initials: Y
authors.lastname: Liu
authors.forename: Martyn C
authors.initials: MC
authors.lastname: Davies
authors.forename: Saul J B
authors.initials: SJ
authors.lastname: Tendler
authors.forename: Rong Giao
authors.initials: RG
authors.lastname: He
mesh_terms: D000079:Acetaldehyde / Q000494:pharmacology*; D000682:Amyloid / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005557:Formaldehyde / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D018625:Microscopy, Atomic Force; D009447:Neuroblastoma / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D013438:Sulfhydryl Compounds / Q000378:metabolism; D016875:tau Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000682:Amyloid; D013438:Sulfhydryl Compounds; D016875:tau Proteins; D005557:Formaldehyde; D000079:Acetaldehyde