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Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a relentless progression. The development of AD is associated with amyloid-β (Aβ) peptide deposition in senile plaques and hyperphosphorylated Tau protein in neurofibrillary tangles (NTFs) in the AD patients’ brain as well as ApoE4 acting as a risk factor. Aβ accumulation occurs in early preclinical stage as a trigger factor for AD pathogenesis followed by silence of synapses and Tau protein hyperphosphorylation. However, what triggers Aβ deposition and Tau hyperphosphorylation is still under investigation. Recent studies showed that formaldehyde may play a pivotal role in the development of age-related neurodegenerative diseases. In this chapter, we introduce recent progresses on production and accumulation of formaldehyde with ageing and the signaling pathways of formaldehyde leading to dysfunction and aggregation of nuclear Tau protein, Aβ deposition as well as dysfunction of ApoE in vitro and in vivo. Formaldehyde acts as an effective trigger of Tau hyperphosphorylation in neuronal cell lines, primary cultured neurons, mouse brains, and monkey brains. Formaldehyde activates Tau phosphorylation kinases including glycogen synthase kinase 3 beta (GSK-3β), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and suppresses protein phosphatase 2A (PP2A). In primates (Macaca mulatta) experiments, feeding methanol in drinking water and the chronic intracerebroventricular (i.c.v.) injection of formaldehyde can induce AD-like disorders such as memory decline, Aβ deposition or plaques, Tau hyperphosphorylation and (neurofibrillary tangle (NFTs))-like changes, as well as gliosis in hippocampus and cerebral cortex, similar to AD-like changes in mouse experiments under the same conditions. The measurements of naturally aged monkeys demonstrated that concentrations of formaldehyde are associated with changes in amyloid-beta in cerebrospinal fluid (CSF) of rhesus monkeys as aging. The dysmetabolism of endogenous formaldehyde might start to occur in the early stage of age-related cognitive impairment as formaldehyde disturbs human brain functions in multiple pathways.

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Amyloid β Deposition, Tau Phosphorylation, ApoE4 Dysfunction, and Formaldehyde

  • 章节

  • 发表日期：

    2025年

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  • Jing Lu,
  • Rongqiao He

摘要

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with a relentless progression. The development of AD is associated with amyloid-β (Aβ) peptide deposition in senile plaques and hyperphosphorylated Tau protein in neurofibrillary tangles (NTFs) in the AD patients’ brain as well as ApoE4 acting as a risk factor. Aβ accumulation occurs in early preclinical stage as a trigger factor for AD pathogenesis followed by silence of synapses and Tau protein hyperphosphorylation. However, what triggers Aβ deposition and Tau hyperphosphorylation is still under investigation. Recent studies showed that formaldehyde may play a pivotal role in the development of age-related neurodegenerative diseases. In this chapter, we introduce recent progresses on production and accumulation of formaldehyde with ageing and the signaling pathways of formaldehyde leading to dysfunction and aggregation of nuclear Tau protein, Aβ deposition as well as dysfunction of ApoE in vitro and in vivo. Formaldehyde acts as an effective trigger of Tau hyperphosphorylation in neuronal cell lines, primary cultured neurons, mouse brains, and monkey brains. Formaldehyde activates Tau phosphorylation kinases including glycogen synthase kinase 3 beta (GSK-3β), Ca2+/calmodulin-dependent protein kinase II (CaMKII), and suppresses protein phosphatase 2A (PP2A). In primates (Macaca mulatta) experiments, feeding methanol in drinking water and the chronic intracerebroventricular (i.c.v.) injection of formaldehyde can induce AD-like disorders such as memory decline, Aβ deposition or plaques, Tau hyperphosphorylation and (neurofibrillary tangle (NFTs))-like changes, as well as gliosis in hippocampus and cerebral cortex, similar to AD-like changes in mouse experiments under the same conditions. The measurements of naturally aged monkeys demonstrated that concentrations of formaldehyde are associated with changes in amyloid-beta in cerebrospinal fluid (CSF) of rhesus monkeys as aging. The dysmetabolism of endogenous formaldehyde might start to occur in the early stage of age-related cognitive impairment as formaldehyde disturbs human brain functions in multiple pathways.