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Clathrin adaptor CALM/PICALM is involved in tau pathology in Alzheimer and other tauopathies.

Kunie Ando1, 2, 3, Karen Tomimura2, 3, Véronique Sazdovitch2, Valerie Suain1, Zehra Yilmaz1, Michèle Authelet1, Marième Ndjim3, Cristina Vergara1, Mounir Belkouch2, 3, Marie-Claude Potier3, Charles Duyckaerts2, 3 and Jean-Pierre Brion1*
  • 1 UNI (ULB Neuroscience Institute), Faculty of medicine, Université Libre de Bruxelles, Belgium
  • 2 AP-HP, Hôpital de la Pitié-Salpêtrière, France
  • 3 Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, and Inserm, U 1127, and CNRS UMR 7225 and ICM, France

Alzheimer’s disease (AD) is the most common form of dementia. AD is characterized by two neuropathological hallmarks: neurofibrillary tangles (NFTs) and amyloid deposits [5]. NFTs are constituted of hyperphosphorylated tau proteins [3] and are observed in other tauopathies [4]. Recent genome-wide association studies (GWAS) have identified two single nucleotide polymorphisms in PICALM gene as genetic susceptibility loci for late-onset Alzheimer’s disease (LOAD) [6-8]. PICALM is a key protein for clathrin-mediated endocytosis and autophagy and thus modulates tau pathology [9]. We hypothesized that PICALM may be dysregulated and may be mislocalized in neurodegenerative brains. This project aimed to analyse the level and localization of PICALM in the brains of various neurodegenerative diseases such as AD, Down syndrome (DS), Pick disease, progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), fronto-temporal lobar degeneration (FTLD) with MAPT P301L mutation (FTLD-P301L), Lewy body dementia, diffuse type (LBD) and FTLD with TDP-43 positive inclusions (FTLD-TDP). We found that the PICALM immunoreactivities were found in tau positive inclusions in specific neurodegenerative diseases: AD, DS, Pick disease and in PSP, but not in CBD and FTLD-P301L cases [1,2]. Astrocytic tau-positive inclusions in tauopathies were devoid of PICALM immunoreactivity. Lewy bodies in LBD and TDP-43 positive inclusions in FTLD-TDP were PICALM negative. The level of soluble PICALM was decreased and inversely correlated with the level of soluble phosphotau in the post-mortem brain homogenates from tauopathies. PICALM decrease was significantly correlated with the levels of autophagy markers such as LC3-II and Beclin-1 in the brain lysates from various neurodegenerative disease brains [2]. These results indicate that there is a close relationship among abnormal PICALM processing, tau pathology and impairment of autophagy. Our results suggest that PICALM and phosphotau interaction occurs in AD, DS, Pick disease and PSP and that PICALM dysregulation may be associated with autophagy dysfunction in various neurodegenerative diseases [1,2]. Résumé court en Français Le traitement efficace de la maladie d’Alzheimer et d’autres maladies neurodégénératives passe par la connaissance de la modification des mécanismes cellulaires impliqués. Dans ce travail, nous nous sommes intéressés à l’autophagie (sert à éliminer certaines régions toxiques contenues dans la cellule, voire la conduire à la mort pour éviter de propager une infection ou si la cellule ne peut plus fonctionner correctement). Dans ce travail nous avons montré qu’à la fois la localisation et la concentration d’une protéine nommée PICALM impliquée dans l’autophagie était modifiée chez les patients souffrant de 3 maladies neurodégénératives : 1) Alzheimer, 2) Pick et 3) Steele-Richardson-Olszewski. Samenvatting in het Nederlands De effectieve behandelingsstrategie van de ziekte van Alzheimer en andere neurodegeneratieve aandoeningen zijn gebaseerd wat we weten over de onderliggende cellulaire werkingsmechanismen. Met dit onderzoek zijn we voornamelijk geïnteresseerd in autofagie (het proces om bepaalde toxische cellulaire stoffen te elimineren, celdood te bevorderen om infectie te vermijden of om of cellulaire malfuncties verder te voorkomen). Deze studie toont aan dat de lokalisatie en concentratie van het eiwit PICALM betrokken bij deze autofage processen en gemodificeerd is bij drie types van neurodegeneratieve aandoeningen: 1) De ziekte van Alzheimer, 2) Pick en 3) Steele-Richardson-Olszewski.

References

1 Ando K, Brion JP, Stygelbout V et al. (2013) Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer's brains. Acta Neuropathol 125: 861-878
2 Ando K, Tomimura K, Sazdovitch V et al. (2016) Level of PICALM, a key component of clathrin-mediated endocytosis, is correlated with levels of phosphotau and autophagy-related proteins and is associated with tau inclusions in AD, PSP and Pick disease. Neurobiol Dis 94: 32-43
3 Brion JP, Couck AM, Passareiro E, Flament-Durand J (1985) Neurofibrillary tangles of Alzheimer's disease: an immunohistochemical study. J Submicrosc Cytol 17: 89-96
4 Buee L, Bussiere T, Buee-Scherrer V, Delacourte A, Hof PR (2000) Tau protein isoforms, phosphorylation and role in neurodegenerative disorders. Brain Res Brain Res Rev 33: 95-130
5 Duyckaerts C, Delatour B, Potier MC (2009) Classification and basic pathology of Alzheimer disease. Acta Neuropathol 118: 5-36
6 Harold D, Abraham R, Hollingworth P et al. (2009) Genome-wide association study identifies variants at CLU and PICALM associated with Alzheimer's disease. Nat Genet 41: 1088-1093
7 Lambert JC, Heath S, Even G et al. (2009) Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 41: 1094-1099
8 Lambert JC, Ibrahim-Verbaas CA, Harold D et al. (2013) Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease. Nat Genet 45: 1452-1458
9 Moreau K, Fleming A, Imarisio S et al. (2014) PICALM modulates autophagy activity and tau accumulation. Nat Commun 5: 4998

Keywords: PICALM, tau, nFTS, Alzheimer’s disease, Pick disease, Progressive Supranuclear Palsy, Autophagy, LC3, Beclin-1

Conference: 6th Belgian Brain Congress, MONS, Belgium, 8 Oct - 8 Oct, 2016.

Presentation Type: Poster Presentation

Topic: Brain and brain diseases: between heredity and environment

Citation: Ando K, Tomimura K, Sazdovitch V, Suain V, Yilmaz Z, Authelet M, Ndjim M, Vergara C, Belkouch M, Potier M, Duyckaerts C and Brion J (2016). Clathrin adaptor CALM/PICALM is involved in tau pathology in Alzheimer and other tauopathies.. Conference Abstract: 6th Belgian Brain Congress. doi: 10.3389/conf.fnagi.2016.03.00017

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Received: 28 Jun 2016; Published Online: 29 Jun 2016.

* Correspondence: MD, PhD. Jean-Pierre Brion, UNI (ULB Neuroscience Institute), Faculty of medicine, Université Libre de Bruxelles, Bruxelles, 1070, Belgium, jpbrion@ulb.ac.be