De Strooper B.,Center for the Biology of Disease |
De Strooper B.,University ziekenhuizen and |
De Strooper B.,University College London |
Karran E.,University ziekenhuizen and |
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.
Barao S.,Center for the Biology of Disease |
Barao S.,University ziekenhuizen and |
Gartner A.,Center for the Biology of Disease |
Gartner A.,University ziekenhuizen and |
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.