Amyloid-β with isomerized Asp7 cytotoxicity is coupled to protein phosphorylation

Abstract

Neuronal dysfunction and loss associated with the accumulation of amyloid-β (Aβ) in the form of extracellular amyloid plaques and hyperphosphorylated tau in the form of intraneuronal neurofibrillary tangles represent key features of Alzheimer’s disease (AD). Amyloid plaques found in the brains of AD patients are predominantly composed of Aβ42 and its multiple chemically or structurally modified isoforms. Recently, we demonstrated that Aβ42 with isomerised Asp7 (isoAβ42) which is one of the most abundant Aβ isoform in plaques, exhibited high neurotoxicity in human neuronal cells. Here, we show that, in SH-SY5Y neuroblastoma cells, the administration of synthetic isoAβ42 rather than intact Aβ42 resulted in a significantly higher level of protein phosphorylation, especially the phosphorylation of tau, tubulins, and matrin 3. IsoAβ42 induced a drastic reduction of tau protein levels. Our data demonstrate, for the first time, that isoAβ42, being to date the only known synthetic Aβ species to cause AD-like amyloidogenesis in an animal AD model, induced cell death by disabling structural proteins in a manner characteristic of that observed in the neurons of AD patients. The data emphasize an important role of isoAβ42 in AD progression and provide possible neurotoxicity paths for this particular isoform.

Quantification of N-terminal amyloid-β isoforms reveals isomers are the most abundant form of the amyloid-β peptide in sporadic Alzheimer’s disease

“…Interestingly, it has been found that iso -Asp-7 Aβ 42 compared to wild-type Aβ 42 led to significantly increased phosphorylation of proteins, including tau (MAPT) from SH-SY5Y neuroblastoma cell-culture models. 72 Accumulation of iso-aspartate in proteins is known to be lethal in the PIMT (protein iso-aspartate methyltransferase) deficient mouse, suffering from progressive epileptic seizures. 73 , 74 Soluble Aβ oligomers isolated from Alzheimer’s disease brains have been shown to induce hyperexcitability in individual neurons and neuronal circuits 75–77 Induction of hyperexcitability has been invoked to explain the clinical observation that there is a significantly higher incidence of epilepsy in Alzheimer’s disease patients compared to age-matched controls.…”

Intravenously Injected Amyloid-β Peptide With Isomerized Asp7 and Phosphorylated Ser8 Residues Inhibits Cerebral β-Amyloidosis in AβPP/PS1 Transgenic Mice Model of Alzheimer’s Disease

“…The accumulation of isoD7-Aβ in amyloid plaques can be associated with the processes of spontaneous protein aging ( Moro et al, 2018 ), while the formation of pS8-Aβ was attributed to the ecto-PKA activity ( Kumar et al, 2011 ). Both isoforms of Aβ were suggested to play a role in AD pathogenesis ( Kozin et al, 2016 ; Jamasbi et al, 2017 ; Kugaevskaya et al, 2018 ; Zatsepina et al, 2018 ).…”

Implications of Metal Binding and Asparagine Deamidation for Amyloid Formation

“…The Asn residues show very fast succinimide formation comparing Asp residues [ 18 ]; consequently, isoAsp residues are rapidly accumulated in AβP. The synthetic AβPs in which Asp 7 or Asp 23 is substituted for isoAsp residue show the enhancement of neurotoxicity [ 82 ] or the acceleration of fibril formation [ 83 ], respectively. These results suggest that both FAD mutations in AβP accelerate amyloid fibril formation in the brain of patients owing to the fast generation of the isoAsp residue in the AβP of Tottori and Iowa.…”

“…In addition, AβP 1–42 (D7isoD) acts as a trigger for the formation of dense-core amyloid plaques in the APP transgenic mouse brain [ 81 ]. The phosphorylation of proteins such as tau, tubulins, and matrin 3 is also accelerated by AβP 1–42 (D7isoD) when the peptide is introduced to cultured cells [ 82 ]. The effect of Asp racemization on the fibril formation has also been examined using synthetic peptides.…”