Tau Phosphorylation and Amyloid-β Deposition in the Presence of Formaldehyde

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a relentless progression. It is associated with amyloid-β (Aβ) peptide deposition in senile plaques and hyperphosphorylated Tau protein in neurofibrillary tangles in the AD patients’ brain. Aβ accumulation occurs in early preclinical stage as a trigger factor for AD pathogenesis followed by silence of synapses and Tau hyperphosphorylation. However, what triggers Aβ deposition and Tau hyperphosphorylation is still under investigation. As an endogenous small-molecule metabolite, formaldehyde is produced by multiple cellular processes, including lipid oxidation, protein denaturation, sugar decomposition, methanol degradation, oxidative stress, DNA demethylation, and semicarbazide-sensitive amine oxidase (SSAO) catalyzation (see Chap. 2). Recent studies demonstrated that formaldehyde plays a pivotal role in the development of age-related neurodegenerative diseases by inducing the cellular component malfunction, such as Tau hyperphosphorylation, Aβ aggregation, and cell apoptosis. However, the underlying molecular mechanisms remain largely elusive. This chapter briefly introduces recent progresses on production and accumulation of formaldehyde with aging and the signaling pathways of formaldehyde, leading to dysfunction of nuclear Tau protein, aggregation of Aβ, as well as dysfunction of ApoE in vitro and in vivo. Formaldehyde acts as an effective trigger of Tau protein hyperphosphorylation in cell lines, primary cultured neurons, mouse brains, as well as monkey brains. During formaldehyde-induced Tau hyperphosphorylation, activation of Tau phosphorylation kinases glycogen synthase kinase 3 beta (GSK-3β) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) as well as suppression of protein phosphatase 2A (PP2A) were shown to be highlighted pathways. Long-term incubation of N2a cells with formaldehyde at the pathological concentration referred to AD patients resulted in formaldehyde accumulation also inducing Tau hyperphosphorylation and morphological changes of neuronal processes and neurites. Both Tau hyperphosphorylation and Aβ deposition were found in the hippocampus and cerebral cortex of rhesus monkeys through a long-term feeding with low concentration of methanol in drinking water or cerebral ventricle injection, and those monkeys suffered from decline of cognitive abilities as well. Formaldehyde is shown to be a strong trigger of Aβ deposition and Tau phosphorylation, so that the dysmetabolism of endogenous formaldehyde should occur in the early stage of AD as formaldehyde disturbs nervous system in different pathways and in diverse manners.