Acta Neuropathologica

, Volume 125, Issue 6, pp 861–878 | Cite as

Clathrin adaptor CALM/PICALM is associated with neurofibrillary tangles and is cleaved in Alzheimer’s brains

  • Kunie Ando
  • Jean-Pierre Brion
  • Virginie Stygelbout
  • Valérie Suain
  • Michèle Authelet
  • Robert Dedecker
  • Anaïs Chanut
  • Pascale Lacor
  • Jérémie Lavaur
  • Véronique Sazdovitch
  • Ekaterina Rogaeva
  • Marie-Claude Potier
  • Charles DuyckaertsEmail author
Original Paper


PICALM, a clathrin adaptor protein, plays important roles in clathrin-mediated endocytosis in all cell types. Recently, genome-wide association studies identified single nucleotide polymorphisms in PICALM gene as genetic risk factors for late-onset Alzheimer disease (LOAD). We analysed by western blotting with several anti-PICALM antibodies the pattern of expression of PICALM in human brain extracts. We found that PICALM was abnormally cleaved in AD samples and that the level of the uncleaved 65–75 kDa full-length PICALM species was significantly decreased in AD brains. Cleavage of human PICALM after activation of endogenous calpain or caspase was demonstrated in vitro. Immunohistochemistry revealed that PICALM was associated in situ with neurofibrillary tangles, co-localising with conformationally abnormal and hyperphosphorylated tau in LOAD, familial AD and Down syndrome cases. PHF-tau proteins co-immunoprecipitated with PICALM. PICALM was highly expressed in microglia in LOAD. These observations suggest that PICALM is associated with the development of AD tau pathology. PICALM cleavage could contribute to endocytic dysfunction in AD.


Alzheimer’s disease PICALM Tau NFT Microglia 



This study was supported by ANR Franco-Canada CholAD, INSERM (U975-P-A1L4-RP-RPV10014DDA-R10178DD), by MassImage, INSERM (U975-P-A1L4-RP-RPV10015DDA-R10179DD), by grants from dotation d’équipe, INSERM, and by “Investissements d’avenir” ANR-10-IAIHU-06 to C.D., as well as by grants from the Diane programme (Walloon region) (816856), FRMA/SAO, and the Fonds de la Recherche Scientifique Médicale (3.4504.10) to J.P.B. The brain tissues were kindly provided by the GIE NeuroCEB Brain Bank (France Alzheimer, France Parkinson, ARSEP, CSC). We thank Dr Peter Davies for providing anti-tau antibodies, Drs George and Clayton for anti-α synuclein antibody and Dr. Sabrina Turbant for human tissue preparation. Analysis by confocal microscopy was performed at the cellular imaging platform of Pitié-Salpêtrière PICPS.

Supplementary material

401_2013_1111_MOESM1_ESM.jpg (579 kb)
Fig. S1: PICALM in control and AD brains detected with HPA019061 and sc-6433 anti-PICALM antibodies. a-b: Western blotting for PICALM in the RIPA-soluble and insoluble fractions detected with HPA019061 (a) and with sc-6433 (b). The 75 kDa PICALM isoform was decreased in RIPA-soluble fraction of AD brain lysate. 50 kDa PICALM fragment was detected with HPA019061 whereas 25 kDa fragment was detected with sc-6433. There was an unknown band at 95 kDa detected with sc-6433 in the RIPA-insoluble fraction (asterisk) (b). c: Western blot analysis of ADDLs for their potential cross-reactivity with PICALM antibodies. ADDLs were analysed by western blotting using the anti-Aβ (6E10) antibody and three different anti-PICALM antibodies as indicated. ADDLs were strongly immunoreactive with the 6E10 antibody but were not reactive with the anti-PICALM antibodies. (JPEG 579 kb)
401_2013_1111_MOESM2_ESM.jpg (4.2 mb)
Fig. S2: Immunostaining of PICALM with different anti-PICALM antibodies in control and Down syndrome brains. a-o: PICALM immunostaining with HPA019053 (a, d, g, j, m), HPA019061 (b, e, h, k, n) and sc-6433 (c, f, i, l, o) in endothelial cells (a-c), choroid plexus (d-f), neurons (g-r) in the hippocampus of control brains (a-i) and in the hippocampus of Down syndrome (j-r). PICALM labelling pattern in the endothelial cells and in the choroid plexus was quite similar with all the three anti-PICALM antibodies (a-f). There was non-specific staining of lipofuscin with sc-6433 (i, o). p-r: Anti-PICALM antibodies HPA019053 (p), HPA019061 (q) and sc-6433 (r) were immunoabsorbed with GST-PICALM in prior to immunostaining. Scale bars 20 μm. (JPEG 4283 kb)
401_2013_1111_MOESM3_ESM.jpg (840 kb)
Fig. S3: Absence of PICALM immunoreactivity on isolated PHFs present in sarkosyl insoluble fraction. a: Immunogold staining of isolated PHFs present in the sarkosyl insoluble fraction using anti-PICALM HPA019053 antibody. Isolated PHFs were not immunoreactive with the PICALM antibody. b: Positive control with the anti-tau PHF1 antibody (10 nm gold particles). c: Negative control without primary antibody. Scale bar 0.2 um. d: Western blot analysis of sarkosyl-soluble and insoluble fractions for tau (AT8) and PICALM (HPA019053). PHF-tau was present only in sarkosyl insoluble fraction of AD brains and was absent in control brains. PICALM was not co-enriched with PHF-tau by sarkosyl fraction. (JPEG 840 kb)


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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Kunie Ando
    • 1
    • 2
  • Jean-Pierre Brion
    • 3
  • Virginie Stygelbout
    • 3
  • Valérie Suain
    • 3
  • Michèle Authelet
    • 3
  • Robert Dedecker
    • 3
  • Anaïs Chanut
    • 1
  • Pascale Lacor
    • 4
  • Jérémie Lavaur
    • 2
  • Véronique Sazdovitch
    • 1
  • Ekaterina Rogaeva
    • 5
  • Marie-Claude Potier
    • 2
  • Charles Duyckaerts
    • 1
    • 2
    Email author
  1. 1.Laboratoire de Neuropathologie EscourolleHôpital de la Pitié-Salpêtrière, AP-HPParisFrance
  2. 2.Group of Alzheimer’s and Prion’s diseasesICM Research Centre, UPMC, INSERM UMR S 975, CNRS UMR 7225, Hôpital de la Pitié-SalpêtrièreParisFrance
  3. 3.Laboratory of Histology, Neuroanatomy and Neuropathology, UNI (ULB Neuroscience Institute)Université Libre de BruxellesBrusselsBelgium
  4. 4.Neurobiology DepartmentNorthwestern UniversityEvanstonUSA
  5. 5.Centre for Research in Neurodegenerative Diseases, Faculty of MedicineUniversity of TorontoTorontoCanada

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