Human CASPR2 antibodies reversibly alter memory and the CASPR2 protein complex.
Annals of Neurology. 2022-03-22; :
DOI: 10.1002/ana.26345
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Human CASPR2 Antibodies Reversibly Alter Memory and the CASPR2 Protein Complex.
Joubert B(#)(1), Petit-Pedrol M(#)(1), Planagumà J(#)(1)(2), Mannara F(1),
Radosevic M(1), Marsal M(2), Maudes E(1), García-Serra A(1), Aguilar E(1),
Andrés-Bilbé A(1)(3), Gasull X(1)(3), Loza-Alvarez P(2), Sabater L(1), Rosenfeld
MR(1), Dalmau J(1)(4)(5).
Author information:
(1)August Pi i Sunyer Biomedical Research Institute, Hospital Clinic, University
of Barcelona, Barcelona, Spain.
(2)Institute of Photonic Sciences, Barcelona Institute of Science and Technology,
Barcelona, Spain.
(3)Neurophysiology Laboratory, Department of Biomedicine, School of Medicine,
Institute of Neurosciences, University of Barcelona, Barcelona, Spain.
(4)Department of Neurology, Perelman School of Medicine, University of
Pennsylvania, Philadelphia, PA, USA.
(5)Catalan Institute for Research and Advanced Studies (ICREA), Barcelona, Spain.
(#)Contributed equally
OBJECTIVE: The encephalitis associated with antibodies against
contactin-associated proteinlike 2 (CASPR2) is presumably antibody-mediated, but
the antibody effects and whether they cause behavioral alterations are not well
known. Here, we used a mouse model of patients’ immunoglobulin G (IgG) transfer
and super-resolution microscopy to demonstrate the antibody pathogenicity.
METHODS: IgG from patients with anti-CASPR2 encephalitis or healthy controls was
infused into the cerebroventricular system of mice. The levels and colocalization
of CASPR2 with transient axonal glycoprotein 1 (TAG1) were determined with
stimulated emission depletion microscopy (40-70μm lateral resolution).
Hippocampal clusters of Kv1.1 voltage-gated potassium channels (VGKCs) and
GluA1-containing α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors
(AMPARs) were quantified with confocal microscopy. Behavioral alterations were
assessed with standard behavioral paradigms. Cultured neurons were used to
determine the levels of intracellular CASPR2 and TAG1 after exposure to patients’
IgG.
RESULTS: Infusion of patients’ IgG, but not controls’ IgG, caused memory
impairment along with hippocampal reduction of surface CASPR2 clusters and
decreased CASPR2/TAG1 colocalization. In cultured neurons, patients’ IgG led to
an increase of intracellular CASPR2 without affecting TAG1, suggesting selective
CASPR2 internalization. Additionally, mice infused with patients’ IgG showed
decreased levels of Kv1.1 and GluA1 (two CASPR2-regulated proteins). All these
alterations and the memory deficit reverted to normal after removing patients’
IgG.
INTERPRETATION: IgG from patients with anti-CASPR2 encephalitis causes reversible
memory impairment, inhibits the interaction of CASPR2/TAG1, and decreases the
levels of CASPR2 and related proteins (VGKC, AMPAR). These findings fulfill the
postulates of antibody-mediated disease and provide a biological basis for
antibody-removing treatment approaches. ANN NEUROL 2022.
© 2022 American Neurological Association.
DOI: 10.1002/ana.26345
PMID: 35253937