Tau deletion reduces plaque‐associated BACE1 accumulation and decelerates plaque formation in a mouse model of Alzheimer’s disease

Finn Peters, Hazal Salihoglu, Katrin Pratsch, Etienne Herzog, Martina Pigoni, Carmelo Sgobio, Stefan F Lichtenthaler, Ulf Neumann, Jochen Herms
EMBO J. 2019-11-07; :
DOI: 10.15252/embj.2019102345

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Peters F(1)(2), Salihoglu H(1)(2), Pratsch K(1), Herzog E(3)(4), Pigoni M(1)(2), Sgobio C(1), Lichtenthaler SF(1)(2)(5), Neumann U(6), Herms J(1)(2)(7).

Author information:
(1)German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
(2)Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
(3)IINS, UMR 5297, Université Bordeaux, Bordeaux, France.
(4)CNRS, IINS, UMR 5297, Bordeaux, France.
(5)Neuroproteomics, School of Medicine, Klinikum rechts der Isar and Institute for Advanced Study, Technical University of Munich, Munich, Germany.
(6)Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel, Switzerland.
(7)Center for Neuropathology and Prion Research, Ludwig-Maximilians University, Munich, Germany.

In Alzheimer’s disease, BACE1 protease initiates the amyloidogenic processing of
amyloid precursor protein (APP) that eventually results in synthesis of β-amyloid
(Aβ) peptide. Aβ deposition in turn causes accumulation of BACE1 in
plaque-associated dystrophic neurites, thereby potentiating progressive Aβ
deposition once initiated. Since systemic pharmacological BACE inhibition causes
adverse effects in humans, it is important to identify strategies that
specifically normalize overt BACE1 activity around plaques. The
microtubule-associated protein tau regulates axonal transport of proteins, and
tau deletion rescues Aβ-induced transport deficits in vitro. In the current
study, long-term in vivo two-photon microscopy and immunohistochemistry were
performed in tau-deficient APPPS1 mice. Tau deletion reduced plaque-associated
axonal pathology and BACE1 accumulation without affecting physiological BACE1
expression distant from plaques. Thereby, tau deletion effectively decelerated
formation of new plaques and reduced plaque compactness. The data revealed that
tau reinforces Aβ deposition, presumably by contributing to accumulation of BACE1
in plaque-associated dystrophies. Targeting tau-dependent mechanisms could become
a suitable strategy to specifically reduce overt BACE1 activity around plaques,
thereby avoiding adverse effects of systemic BACE inhibition.

© 2019 The Authors. Published under the terms of the CC BY NC ND 4.0 license.

DOI: 10.15252/embj.2019102345
PMID: 31701556

Auteurs Bordeaux Neurocampus