BACE1 regulates the proliferation and cellular functions of Schwann cells

Abstract

BACE1 is an indispensable enzyme for generating β-amyloid peptides, which are excessively accumulated in brains of Alzheimer’s patients. However, BACE1 is also required for proper myelination of peripheral nerves, as BACE1-null mice display hypomyelination. In order to determine the precise effects of BACE1 on myelination, here we have uncovered a role of BACE1 in the control of Schwann cell proliferation during development. We demonstrate that BACE1 regulates the cleavage of Jagged-1 and Delta-1, two membrane-bound ligands of Notch. BACE1 deficiency induces elevated Jag-Notch signaling activity, which in turn facilitates proliferation of Schwann cells. This increase in proliferation leads to shortened internodes and decreased Schmidt–Lanterman incisures. Functionally, evoked compound action potentials in BACE1-null nerves were significantly smaller and slower, with a clear decrease in excitability. BACE1-null nerves failed to effectively use lactate as an alternative energy source under conditions of increased physiological activity. Correlatively, BACE1-null mice showed reduced performance on rotarod tests. Collectively, our data suggest that BACE1 deficiency enhances proliferation of Schwann cell due to the elevated Jag1/Delta1-Notch signaling, but fails to myelinate axons efficiently due to impaired the neuregulin1-ErbB signaling, which has been documented.

Molecular differences in Alzheimer's disease between male and female patients determined by integrative network analysis

“…For example, ribosome (hsa03010) was the most significant pathway in both male‐ and female‐specific networks, followed by neurodegenerative disease‐related pathways such as Parkinson's disease (hsa05012) and ErbB signaling (hsa04012). The latter modulates hippocampal γ oscillations, which are important for higher brain processes and are associated with AD . AD (hsa05010) was observed in both male‐ and female‐specific pathways (Figure B), although the annotated genes differed between the two sexes ().…”

Glia-neuron energy metabolism in health and diseases: New insights into the role of nervous system metabolic transporters

“…Refined versions of the ANLSH assert that lactate is produced by astrocytes, and possibly active neurons, and is released into a lactate pool that is eventually used as energy substrate by neurons at rest or during active state (Baltan, 2015). A functional intercellular lactate shuttle, commonly called ANLSH in the CNS, exists in multiple CNS regions (Magistretti et al, 1994; Wender et al, 2000; Baltan, 2015), along with muscle (Gladden, 2004) and potentially peripheral nerve (Vega et al, 1998; Brown et al, 2012; Evans et al, 2013; Stecker and Stevenson, 2015; Hu et al, 2017). Lactate serves as a critical energy substrate for axons, especially long axons, to meet the metabolic needs of transport and signal transduction.…”

“…Growing evidence suggests that lactate is an effective energy source for the peripheral nerves as well, and the lactate shuttle between glial and neurons has been demonstrated in the peripheral nervous system (Vega et al, 1998; Brown et al, 2012; Evans et al, 2013; Stecker and Stevenson, 2015; Hu et al, 2017). These studies have primarily used intact ex-vivo preparations of peripheral nerves.…”

Dominant mutations of the Notch ligand Jagged1 cause peripheral neuropathy

“…The specific involvement of peripheral nerve in CMT2 suggests that p.Ser577Arg and p.Ser650Pro may precipitate disease through a more complex, or tissue-specific, mechanism or mechanisms, potentially involving specific reductions or alterations in Notch receptor trans-activation and/or cis-inhibition. Within the peripheral nervous system, JAG1 is expressed by both axons and Schwann cells, whereas Notch receptor expression appears to occur principally in Schwann cells (23,24). Elevated expression of JAG1 has also been described in reactive spinal cord astrocytes in a mouse model of the inherited neurodegenerative disease spinal muscular atrophy (25).…”