University ziekenhuizen and LIND

Leuven, Belgium

University ziekenhuizen and LIND

Leuven, Belgium

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Barao S.,Center for the Biology of Disease | Barao S.,University ziekenhuizen and LIND | Gartner A.,Center for the Biology of Disease | Gartner A.,University ziekenhuizen and LIND | And 15 more authors.
Cell Reports | Year: 2015

BACE1 is the major drug target for Alzheimer's disease, but we know surprisingly little about its normal function in the CNS. Here, we show that this protease is critically involved in semaphorin 3A (Sema3A)-mediated axonal guidance processes in thalamic and hippocampal neurons. An active membrane-bound proteolytic CHL1 fragment is generated by BACE1 upon Sema3A binding. This fragment relays the Sema3A signal via ezrin-radixin-moesin (ERM) proteins to the neuronal cytoskeleton. APH1B-γ-secretase-mediated degradation of this fragment stops the Sema3A-induced collapse and sensitizes the growth cone for the next axonal guidance cue. Thus, we reveal a cycle of proteolytic activity underlying growth cone collapse and restoration used by axons to find their correct trajectory in the brain. Our data also suggest that BACE1 and γ-secretase inhibition have physiologically opposite effects in this process, supporting the idea that combination therapy might attenuate some of the side effects associated with these drugs. © 2015 The Authors.


De Strooper B.,Center for the Biology of Disease | De Strooper B.,University Ziekenhuizen and LIND | De Strooper B.,University College London | Karran E.,University Ziekenhuizen and LIND | And 2 more authors.
Cell | Year: 2016

The amyloid hypothesis for Alzheimer's disease (AD) posits a neuron-centric, linear cascade initiated by Aβ and leading to dementia. This direct causality is incompatible with clinical observations. We review evidence supporting a long, complex cellular phase consisting of feedback and feedforward responses of astrocytes, microglia, and vasculature. The field must incorporate this holistic view and take advantage of advances in single-cell approaches to resolve the critical junctures at which perturbations initially amenable to compensatory feedback transform into irreversible, progressive neurodegeneration. © 2016 Elsevier Inc.


Chavez-Gutierrez L.,Center for the Biology of Disease | Chavez-Gutierrez L.,University Ziekenhuizen and LIND | De Strooper B.,Center for the Biology of Disease | De Strooper B.,University Ziekenhuizen and LIND | De Strooper B.,University College London
EMBO Journal | Year: 2016

Intramembrane proteolysis by γ-secretases plays major roles in disease pathology and cellular signalling, yet the dynamics of these enzyme complexes and how they recognize substrates remains poorly understood. New work in The EMBO Journal utilizes photo-affinity cross-linking to map APP interactions to different γ-secretase subunits, suggesting a succession of recruitment and engagement steps that lead up to substrate cleavage. © 2016 The Authors


Salta E.,Center for the Biology of Disease | Salta E.,University ziekenhuizen and LIND | Sierksma A.,Center for the Biology of Disease | Sierksma A.,University ziekenhuizen and LIND | And 5 more authors.
EMBO Molecular Medicine | Year: 2016

microRNA-132 (miR-132) is involved in prosurvival, anti-inflammatory and memory-promoting functions in the nervous system and has been found consistently downregulated in Alzheimer's disease (AD). Whether and how miR-132 deficiency impacts AD pathology remains, however, unaddressed. We show here that miR-132 loss exacerbates both amyloid and TAU pathology via inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) upregulation in an AD mouse model. This leads to increased ERK1/2 and BACE1 activity and elevated TAU phosphorylation. We confirm downregulation of miR-132 and upregulation of ITPKB in three distinct human AD patient cohorts, indicating the pathological relevance of this pathway in AD. © 2016 The Authors. Published under the terms of the CC BY 4.0 license


PubMed | University College London, University ziekenhuizen and LIND, University of North Carolina at Chapel Hill, Shantou University and University Miguel Hernández
Type: Journal Article | Journal: Cell reports | Year: 2015

ACE1 is the major drug target for Alzheimers disease, but we know surprisingly little about its normal function in the CNS. Here, we show that this protease is critically involved in semaphorin 3A (Sema3A)-mediated axonal guidance processes in thalamic and hippocampal neurons. An active membrane-bound proteolytic CHL1 fragment is generated by BACE1 upon Sema3A binding. This fragment relays the Sema3A signal via ezrin-radixin-moesin (ERM) proteins to the neuronal cytoskeleton. APH1B--secretase-mediated degradation of this fragment stops the Sema3A-induced collapse and sensitizes the growth cone for the next axonal guidance cue. Thus, we reveal a cycle of proteolytic activity underlying growth cone collapse and restoration used by axons to find their correct trajectory in the brain. Our data also suggest that BACE1 and -secretase inhibition have physiologically opposite effects in this process, supporting the idea that combination therapy might attenuate some of the side effects associated with these drugs.


PubMed | University Ziekenhuizen and LIND, Johnson & Johnson, University College London and German Center for Neurodegenerative Diseases
Type: Journal Article | Journal: Trends in neurosciences | Year: 2016

The protease -site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is required for the production of the amyloid- (A) peptide, which is central to the pathogenesis of Alzheimers disease (AD). Chronic inhibition of this protease may temper amyloid production and cure or prevent AD. However, while BACE1 inhibitors are being pushed forward as drug candidates, a remarkable gap in knowledge on the physiological functions of BACE1 and its close homolog BACE2 becomes apparent. Here we discuss the major discoveries of the past 3 years concerning BACE1 biology and to what extent these could limit the use of BACE1 inhibitors in the clinic.

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