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 α-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 ε-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.

High-resolution imaging of pelagic bacteria by Atomic Force Microscopy and implications for carbon cycling

“…Fixatives such as formaldehyde cross-link proteins and nucleic acids (Gustavson, 1956;Nie et al, 2007) and cause cell shrinkage. Different dyes have different quantum yields (Cosa et al, 2001).…”

Formaldehyde increases intracellular calcium concentration in primary cultured hippocampal neurons partly through NMDA receptors and T-type calcium channels

“…Formaldehyde derived from local metastasized tumor tissues excites peripheral nociceptive neurons and thus can induce cancer pain [7] . More surprisingly, we and others found that formaldehyde at low pathological concentrations induces misfolding and aggregation of neuronal tau protein, leading to apoptosis of hippocampal neurons in vitro [8] , and even cognitive impairment in human beings and loss of memory functions in animals [9,10] .…”

“…Tissue-derived endogenous formaldehyde even at such a low concentration can induce pain behavior [7,22] . Previous studies have demonstrated that formaldehyde exposure at 0.01-0.1% (~3.3 to ~33 mmol/L) induces mis-folding and aggregation of tau protein in hippocampal neurons [9] , which is essential to beta-amyloidinduced neurodegeneration [23] . Cognitive impairments in senile dementia have also been associated with elevated endogenous formaldehyde concentration [10] .…”

Chronic Formaldehyde-Mediated Impairments and Age-Related Dementia

“…A formaldehyde molecule first interacts with a Tau monomer. As additional FA molecules interact with other Tau monomers, the FA molecules polymerise, finally resulting in the cross-linking of the Tau molecules (Nie et al, 2007).…”