Antagonistic Effects of BACE1 and APH1B-γ-Secretase Control Axonal Guidance by Regulating Growth Cone Collapse

Abstract

SummaryBACE1 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.

Seizure-6 proteins highlight BACE1 functions in neurobiology

“…Interestingly, mice deficient in either Sez6 or BACE1 show reduced dendritic spine density (Gunnersen et al, 2007;Savonenko et al, 2008), suggesting that the BACE1-shed ectodomains of Sez6 or Sez6L participate in retrograde and/or paracrine signalling and promote synapse formation and function. Alternatively, the membrane-bound fragment remaining after BACE1 cleavage may be relevant, similar to recent findings on CHL1, another BACE1 substrate (Barao et al, 2015). The observation that BACE1 serves to downregulate surface levels of Sez6 family proteins (as surface levels increase when BACE1 is blocked; (Pigoni et al, 2016) could indicate an activity-dependent proteolytic control of dendritic spine morphology, similar to that seen with metalloprotease cleavage of the post-synaptic adhesion molecule Neuroligin1.…”

Proteolytic ectodomain shedding of membrane proteins in mammals—hardware, concepts, and recent developments

“…Interestingly, also the membrane‐bound fragment remaining after shedding can be biologically active. This is observed for the BACE1‐generated C‐terminal fragment of CHL1, which functions in growth cone collapse during axon guidance in the nervous system (Barao et al , ).…”

Inhibiting BACE1 to reverse synaptic dysfunctions in Alzheimer’s disease

“…BACE1-dependent Nrg1 signaling is required for normal myelination during development, remyelination after injury, and maintenance of muscle spindles [see recent review by (Fleck et al, 2012; Hu et al, 2015)]. Impaired neuronal migration is due to abrogated cleavage of Sema3A-mediated CHL1 cleavage by BACE1 (Barao et al, 2015; Hitt et al, 2012; Kuhn et al, 2012; Zhou et al, 2012). Jag-Notch signaling pathway is important for synaptic function through the control of neurogenesis and brain development [see additional reviews by (Ables et al, 2011; Costa et al, 2003; Marathe and Alberi, 2015)].…”