Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue

Abstract

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder with no cure and no effective diagnostic criteria. The greatest challenge in effectively treating AD is identifying biomarkers specific for each patient when neurodegenerative processes have not yet begun, an outcome that would allow the design of a personalised therapeutic approach for each patient and the monitoring of the therapeutic response during the treatment. We found that the excessive phosphorylation of the amyloid precursor protein (APP) Tyr682 residue on the APP 682YENPTY687 motif precedes amyloid β accumulation and leads to neuronal degeneration in AD neurons. We proved that Fyn tyrosine kinase elicits APP phosphorylation on Tyr682 residue, and we reported increased levels of APP Tyr682 and Fyn overactivation in AD neurons. Here, we want to contemplate the possibility of using fibroblasts as tools to assess APP Tyr682 phosphorylation in AD patients, thus making the changes in APP Tyr682 phosphorylation levels a potential diagnostic strategy to detect early pathological alterations present in the peripheral cells of AD patients’ AD brains.

Tandem Mass Spectrometry as Strategy for the Selective Identification and Quantification of the Amyloid Precursor Protein Tyr682 Residue Phosphorylation Status in Human Blood Mononuclear Cells

“…However, the real strength of the method is its high specificity in detecting explicitly and exclusively APP-Tyr682 residue phosphorylation. The application of this methods on mononuclear cells from blood of patients with AD can definitely proof whether and in which level the increase in APP Tyr phosphorylation previously demonstrated by immunoprecipitation [ 16 ] is correlated to the specific APP Tyr682 residue. Even though the chromatographic peaks are very close and appear to be not completely separated, MS/MS technology enables to distinguish MQQNGYENPTYK and MQQNGYpENPTYK unambiguously by their different fragmentation pattern as demonstrated by EPI-MRM experiments.…”

“…Previous evidence supports the hypothesis that changes in the APP Tyr682 phosphorylation status influences APP trafficking and promotes the amyloidogenic APP processing to generate Aβ in neurons [ 5 , 7 , 11 , 12 , 13 , 14 , 15 , 17 , 31 ]. Notably, we recently suggested that changes related to APP Tyr682 phosphorylation in fibroblasts may reflect Aβ-related abnormalities in the brain [ 16 ], thus emphasizing the promising potential of using APP Tyr682 phosphorylation levels to develop new diagnostic strategies and to optimize therapeutic approaches with better outcomes in patients who are included in clinical trials [ 5 , 6 , 16 ]. Indeed, all these promising results need the development of a selective and quantitative procedure for the APP Tyr682 phosphorylation detection.…”

“…We previously highlighted the critical role of APP Tyr682 phosphorylation in AD neurons, by promoting Aβ production and neuronal degeneration [ 14 ]. In fact, APP Tyr682 phosphorylation levels increase in familiar AD patients carrying mutations on the presenilin (PSEN) 1 gene as well as in sporadic AD patients [ 15 , 16 , 17 ]. In addition, Fyn tyrosine kinase (TK), which belongs to the Src TK family [ 18 ], elicits APP Tyr phosphorylation at level of the Tyr682 residue, and by doing this, triggers amyloidogenic processes in AD neurons [ 17 ].…”

“…Of note, we recently found that APP Tyr682 phosphorylation increases in fibroblasts of AD patients [ 16 ], opening up to the possibility to use APP Tyr682 phosphorylation level as a potential powerful tool in detecting early signs of AD-related cognitive disorders in peripheral cells. Indeed, cognitive performance reflects the integrity of the peripheral system and alterations in the peripheral system may compromise or exacerbate brain aging or brain dysfunctions [ 27 ].…”

The use of fibroblasts as a valuable strategy for studying mitochondrial impairment in neurological disorders

“…Abnormalities in mitochondrial bioenergetics have also been observed in sAD fibroblasts [ 29 , 39 , 289 ]. Decreased ATP levels, oxidative stress, and defects in calcium handling have been widely documented [ 29 , 39 , 290 , 291 ] (Fig.…”