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
:1. Introduction
2. Materials and Methods
2.1. Human Fibroblasts
2.2. Immunoprecipitation and Western Blot Assays
2.3. Statistical Analysis
3. Results
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
- Robakis, N.K. What Do Recent Clinical Trials Teach Us About the Etiology of AD. Adv. Exp. Med. Biol. 2020, 1195, 167. [Google Scholar] [CrossRef]
- Iannuzzi, F.; Sirabella, R.; Canu, N.; Maier, T.J.; Annunziato, L.; Matrone, C. Fyn Tyrosine Kinase Elicits Amyloid Precursor Protein Tyr682 Phosphorylation in Neurons from Alzheimer’s Disease Patients. Cells 2020, 9, 1807. [Google Scholar] [CrossRef]
- Poulsen, E.T.; Iannuzzi, F.; Rasmussen, H.F.; Maier, T.J.; Enghild, J.J.; Jørgensen, A.L.; Matrone, C. An Aberrant Phosphorylation of Amyloid Precursor Protein Tyrosine Regulates Its Trafficking and the Binding to the Clathrin Endocytic Complex in Neural Stem Cells of Alzheimer’s Disease Patients. Front. Mol. Neurosci. 2017, 10, 59. [Google Scholar] [CrossRef] [PubMed]
- Klevanski, M.; Herrmann, U.; Weyer, S.W.; Fol, R.; Cartier, N.; Wolfer, D.P.; Caldwell, J.H.; Korte, M.; Müller, U.C. The APP Intracellular Domain Is Required for Normal Synaptic Morphology, Synaptic Plasticity, and Hippocampus-Dependent Behavior. J. Neurosci. 2015, 35, 16018–16033. [Google Scholar] [CrossRef] [PubMed]
- Matrone, C. A new molecular explanation for age-related neurodegeneration: The Tyr682 residue of amyloid precursor protein. Bioessays 2013, 35, 847–852. [Google Scholar] [CrossRef] [PubMed]
- Matrone, C.; Iannuzzi, F.; Annunziato, L. The Y682ENPTY687 motif of APP: Progress and insights toward a targeted therapy for Alzheimer’s disease patients. Ageing Res. Rev. 2019, 52, 120–128. [Google Scholar] [CrossRef] [PubMed]
- Matrone, C.; Luvisetto, S.; La Rosa, L.R.; Tamayev, R.; Pignataro, A.; Canu, N.; Yang, L.; Barbagallo, A.P.; Biundo, F.; Lombino, F.; et al. Tyr682 in the Abeta-precursor protein intracellular domain regulates synaptic connectivity, cholinergic function, and cognitive performance. Aging Cell 2012, 11, 1084–1093. [Google Scholar] [CrossRef]
- Poulsen, E.T.; Larsen, A.; Zollo, A.; Jørgensen, A.L.; Sanggaard, K.W.; Enghild, J.J.; Matrone, C. New Insights to Clathrin and Adaptor Protein 2 for the Design and Development of Therapeutic Strategies. Int. J. Mol. Sci. 2015, 16, 29446–29453. [Google Scholar] [CrossRef] [PubMed]
- La Rosa, L.R.; Perrone, L.; Nielsen, M.S.; Calissano, P.; Andersen, O.M.; Matrone, C. Y682G Mutation of Amyloid Precursor Protein Promotes Endo-Lysosomal Dysfunction by Disrupting APP-SorLA Interaction. Front. Cell Neurosci. 2015, 9, 109. [Google Scholar] [CrossRef]
- Zollo, A.; Allen, Z.; Rasmussen, H.F.; Iannuzzi, F.; Shi, Y.; Larsen, A.; Maier, T.J.; Matrone, C. Sortilin-Related Receptor Expression in Human Neural Stem Cells Derived from Alzheimer’s Disease Patients Carrying the APOE Epsilon 4 Allele. Neural Plast. 2017, 2017, 1892612. [Google Scholar] [CrossRef]
- Jakobsen, J.E.; Johansen, M.G.; Schmidt, M.; Liu, Y.; Li, R.; Callesen, H.; Melnikova, M.; Habekost, M.; Matrone, C.; Bouter, Y.; et al. Expression of the Alzheimer’s Disease Mutations AβPP695sw and PSEN1M146I in Double-Transgenic Göttingen Minipigs. J. Alzheimers Dis. 2016, 53, 1617–1630. [Google Scholar] [CrossRef]
- St George-Hyslop, P.H.; Tanzi, R.E.; Polinsky, R.J.; Haines, J.L.; Nee, L.; Watkins, P.C.; Myers, R.H.; Feldman, R.G.; Pollen, D.; Drachman, D. The genetic defect causing familial Alzheimer’s disease maps on chromosome 21. Science 1987, 235, 885–890. [Google Scholar] [CrossRef] [PubMed]
- Matrone, C.; Petrillo, F.; Nasso, R.; Ferretti, G. Fyn Tyrosine Kinase as Harmonizing Factor in Neuronal Functions and Dysfunctions. Int. J. Mol. Sci. 2020, 21, 4444. [Google Scholar] [CrossRef] [PubMed]
- Bachurin, S.O.; Bovina, E.V.; Ustyugov, A.A. Drugs in Clinical Trials for Alzheimer’s Disease: The Major Trends. Med. Res. Rev. 2017, 37, 1186–1225. [Google Scholar] [CrossRef] [PubMed]
- Matrone, C.; Barbagallo, A.P.; La Rosa, L.R.; Florenzano, F.; Ciotti, M.T.; Mercanti, D.; Chao, M.V.; Calissano, P.; D’Adamio, L. APP is phosphorylated by TrkA and regulates NGF/TrkA signaling. J. Neurosci. 2011, 31, 11756–11761. [Google Scholar] [CrossRef]
- Mehdi, S.J.; Rosas-Hernandez, H.; Cuevas, E.; Lantz, S.M.; Barger, S.W.; Sarkar, S.; Paule, M.G.; Ali, S.F.; Imam, S.Z. Protein Kinases and Parkinson’s Disease. Int. J. Mol. Sci. 2016, 17, 1585. [Google Scholar] [CrossRef]
- Jan, A.; Jansonius, B.; Delaidelli, A.; Bhanshali, F.; An, Y.A.; Ferreira, N.; Smits, L.M.; Negri, G.L.; Schwamborn, J.C.; Jensen, P.H.; et al. Activity of translation regulator eukaryotic elongation factor-2 kinase is increased in Parkinson disease brain and its inhibition reduces alpha synuclein toxicity. Acta Neuropathol. Commun. 2018, 6, 54. [Google Scholar] [CrossRef]
- Kofoed, R.H.; Betzer, C.; Ferreira, N.; Jensen, P.H. Glycogen synthase kinase 3 β activity is essential for Polo-like kinase 2- and Leucine-rich repeat kinase 2-mediated regulation of α-synuclein. Neurobiol. Dis. 2020, 136, 104720. [Google Scholar] [CrossRef]
- Kim, J.; Amante, D.J.; Moody, J.P.; Edgerly, C.K.; Bordiuk, O.L.; Smith, K.; Matson, S.A.; Matson, W.R.; Scherzer, C.R.; Rosas, H.D.; et al. Reduced creatine kinase as a central and peripheral biomarker in Huntington’s disease. Biochim. Biophys. Acta 2010, 1802, 673–681. [Google Scholar] [CrossRef]
- Narayanan, K.L.; Chopra, V.; Rosas, H.D.; Malarick, K.; Hersch, S. Rho Kinase Pathway Alterations in the Brain and Leukocytes in Huntington’s Disease. Mol. Neurobiol. 2016, 53, 2132–2140. [Google Scholar] [CrossRef]
- Nygaard, H.B. Targeting Fyn Kinase in Alzheimer’s Disease. Biol. Psychiatry 2018, 83, 369–376. [Google Scholar] [CrossRef] [PubMed]
- Lee, G.; Newman, S.T.; Gard, D.L.; Band, H.; Panchamoorthy, G. Tau interacts with src-family non-receptor tyrosine kinases. J. Cell Sci. 1998, 111, 3167–3177. [Google Scholar] [PubMed]
- Lee, G.; Thangavel, R.; Sharma, V.M.; Litersky, J.M.; Bhaskar, K.; Fang, S.M.; Do, L.H.; Andreadis, A.; Van Hoesen, G.; Ksiezak-Reding, H. Phosphorylation of Tau by Fyn: Implications for Alzheimer’s Disease. J. Neurosci. 2004, 24, 2304–2312. [Google Scholar] [CrossRef] [PubMed]
Healthy | |||
---|---|---|---|
Genotype | Age (years) | Sex | Source (#) |
Unaffected spouse | 48 | F | AG07865 |
49 | F | AG07871 | |
60 | F | AG08379 | |
66 | F | AG08517 | |
73 | M | AG08509 | |
64 | M | AG08125 | |
fAD 1 Family members | 69 | F | AG07936 |
47 | F | AG07928 | |
42 | M | AG08658 | |
Family member with #AG06848 | 75 | F | AG06846 |
Alzheimer’s Patients | |||
fAD 1 | 41 | F | AG08110 |
38 | F | AG08563 | |
75 | M | AG08245 | |
41 | M | AG08064 | |
43 | M | AG08523 | |
PSEN 1 A246E | 49 | F | AG06840 |
53 | M | AG07872 | |
52 | M | AG06848 family member of AG06846 | |
AD | 61 | F | AG04400 sibling of AG04401and AG04402 |
53 | F | AG04401 sibling of AG04400 and AG04402 | |
60 | F | AG06869 | |
49 | M | AG06844 | |
Apo E3/E4 | 87 | F | AG10788 |
Apo E4/E4 | 47 | M | AG04402 sibling of AG04400and AG04401 |
Other Dementias | |||
Parkinson’s | 57 | M | AG20446 |
53 | M | AG20442 | |
Parkinson’s + AD | 60 | M | AG08527 |
Epilepsy + AD | 52 | F | AG04159 |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
Share and Cite
Iannuzzi, F.; Frisardi, V.; Annunziato, L.; Matrone, C. Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue. Brain Sci. 2021, 11, 103. https://doi.org/10.3390/brainsci11010103
Iannuzzi F, Frisardi V, Annunziato L, Matrone C. Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue. Brain Sciences. 2021; 11(1):103. https://doi.org/10.3390/brainsci11010103
Chicago/Turabian StyleIannuzzi, Filomena, Vincenza Frisardi, Lucio Annunziato, and Carmela Matrone. 2021. "Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue" Brain Sciences 11, no. 1: 103. https://doi.org/10.3390/brainsci11010103
APA StyleIannuzzi, F., Frisardi, V., Annunziato, L., & Matrone, C. (2021). Might Fibroblasts from Patients with Alzheimer’s Disease Reflect the Brain Pathology? A Focus on the Increased Phosphorylation of Amyloid Precursor Protein Tyr682 Residue. Brain Sciences, 11(1), 103. https://doi.org/10.3390/brainsci11010103