BACE1 inhibition more effectively suppresses initiation than progression of β-amyloid pathology
Acta Neuropathol. 2018-01-11; 135(5): 695-710
DOI: 10.1007/s00401-017-1804-9
Read on PubMed
1. Acta Neuropathol. 2018 May;135(5):695-710. doi: 10.1007/s00401-017-1804-9. Epub
2018 Jan 11.
BACE1 inhibition more effectively suppresses initiation than progression of
β-amyloid pathology.
Peters F(1)(2), Salihoglu H(1), Rodrigues E(1), Herzog E(3)(4), Blume T(1)(2),
Filser S(1)(2), Dorostkar M(1)(5), Shimshek DR(6), Brose N(7), Neumann U(6),
Herms J(8)(9)(10).
Author information:
(1)German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17,
81377, Munich, Germany.
(2)Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
(3)Université Bordeaux, IINS, UMR 5297, 33000, Bordeaux, France.
(4)CNRS, IINS, UMR 5297, 33000, Bordeaux, France.
(5)Center for Neuropathology and Prion Research, Ludwig-Maximilians University,
Munich, Germany.
(6)Neuroscience, Novartis Institutes for BioMedical Research (NIBR), Basel,
Switzerland.
(7)Department of Molecular Neurobiology, Max Planck Institute of Experimental
Medicine, Göttingen, Germany.
(8)German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17,
81377, Munich, Germany. .
(9)Munich Cluster of Systems Neurology (SyNergy), Munich, Germany.
.
(10)Center for Neuropathology and Prion Research, Ludwig-Maximilians University,
Munich, Germany. .
BACE1 is the rate-limiting protease in the production of synaptotoxic β-amyloid
(Aβ) species and hence one of the prime drug targets for potential therapy of
Alzheimer’s disease (AD). However, so far pharmacological BACE1 inhibition failed
to rescue the cognitive decline in mild-to-moderate AD patients, which indicates
that treatment at the symptomatic stage might be too late. In the current study,
chronic in vivo two-photon microscopy was performed in a transgenic AD model to
monitor the impact of pharmacological BACE1 inhibition on early β-amyloid
pathology. The longitudinal approach allowed to assess the kinetics of individual
plaques and associated presynaptic pathology, before and throughout treatment.
BACE1 inhibition could not halt but slow down progressive β-amyloid deposition
and associated synaptic pathology. Notably, the data revealed that the initial
process of plaque formation, rather than the subsequent phase of gradual plaque
growth, is most sensitive to BACE1 inhibition. This finding of particular
susceptibility of plaque formation has profound implications to achieve optimal
therapeutic efficacy for the prospective treatment of AD.
DOI: 10.1007/s00401-017-1804-9
PMCID: PMC5904228
PMID: 29327084