Relevance of Phosphorylation and Truncation of Tau to the Etiopathogenesis of Alzheimer’s Disease

Abstract

Microtubule (MT) associated protein tau is abnormally hyperphosphorylated and aggregated into paired helical filaments (PHFs), which manifest as neurofibrillary tangles (NFTs) in the brains of individuals with Alzheimer’s disease (AD) and related tauopathies. Hyperphosphorylation and truncation of tau have been linked to the progression of the disease. However, the nature of phosphorylation and truncation of tau in AD brain are not very clear. In the present study we investigated the association of phosphorylation and truncation with high-molecular weight oligomers of tau (HMW-tau) in post-mortem AD brain by western blots. We found that tau from AD brain appears as a smear from low molecular weight (LMW) to HMW tau species in western blots developed with pan-tau antibodies. Similar level of LMW-tau was found in AD and control brains, whereas HMW-tau was found in AD brain only. HMW-tau was hyperphosphorylated at multiple sites and not unphosphorylated at Ser46 or Ser198/199/202. HMW-tau was weakly labeled by tau antibodies 43D against a.a. 6–18 and HT7 against a.a. 159–163 of tau, whereas, the C-terminal antibodies, tau46 and tau46.1, strongly labeled HMW-tau. The ratio of HMW-tau/LMW-tau detected by tau antibodies increased as the epitope of the tau antibodies ranges from N-terminal to C-terminal. The level of tau truncated at Asp421 was increased in AD brain, but was poorly associated with the HMW-tau. These findings suggest that tau pathogenesis involves both hyperphosphorylation and dominantly N-terminal truncation of tau in AD.

Cerebrospinal fluid phospho-tau T217 outperforms T181 as a biomarker for the differential diagnosis of Alzheimer’s disease and PET amyloid-positive patient identification

“…This finding is consistent with the increased pT217 levels detected in the brains of AD patients measured using MS methods [13,15,33] or with anti-p-tau antibody AT100, which recognizes pT212, pS214, and pT217 [33]. It is also in keeping with the fact that pT217 has been detected in aggregated tau extracted from AD patients' brains [33,34]. As far as the possible pathological consequences of T217 phosphorylation are concerned, it was previously established that preventing this process by mutating threonine 217 to alanine reduces the ability of p-tau to promote microtubule assembly in vitro [33] and to bind to SH3 domains such as the BIN1 SH3 domain [35].…”

Cholinergic-like neurons carrying PSEN1 E280A mutation from familial Alzheimer’s disease reveal intraneuronal Aβ42 peptide accumulation, hyperphosphorylation of TAU, oxidative stress, apoptosis and Ca2+ flux dysregulation: Therapeutic Implications

“…Several experimental data support A-induced TAU pathology (e.g., [43]). We thus evaluated whether PSEN1 E280A ChLNs display abnormal levels of phosphorylated TAU protein at residues Ser 202 and Thr 205 , two well-known hyperphosphorylated epitopes involved in AD pathology [44]. To this end, wild-type and mutant ChLNs were left in regular culture medium for 0, 2 and 4 days.…”

Compostos bioativos e seus alvos terapêuticos com propriedade Anti-Alzheimer: Uma revisão da literatura

“…O aumento da atividade da GSK3β implica no comprometimento da memória, na hiperfosforilação da tau, no aumento da produção de βA e, consequentemente, nas respostas inflamatórias mediadas por microglia locais associadas à placa (ZHOU et al, 2018b). Além disso, a GSK3β é um mediador chave da apoptose, fato que pode contribuir diretamente na perda neuronal apresentada na DA (PAQUET; DUMURGIER; HUGON, 2015).…”