Axonal and Schwann Cell BACE1 Is Equally Required for Remyelination of Peripheral Nerves

Abstract

Inhibition of ␤-site APP cleaving enzyme 1 (BACE1) is being pursued as a therapeutic target for treating patients with Alzheimer's disease because BACE1 is the sole ␤-secretase for generating ␤-amyloid peptide. Knowledge regarding the other cellular functions of BACE1 is therefore critical for the safe use of BACE1 inhibitors in human patients. BACE1 deficiency in mice causes hypomyelination during development and impairs remyelination in injured sciatic nerves. Since BACE1 is expected to be ubiquitously expressed, we asked whether axonal or Schwann cell BACE1 is required for optimal remyelination. By swapping sciatic nerve segments from BACE1-null mice with the corresponding wild-type nerve segments or vice versa, we tested how a deficiency of BACE1 in Schwann cells or axons affects remyelination. Our results show that BACE1 in axons and Schwann cells is similarly important for remyelination of regenerated axons. Nerve injury induces BACE1 transcription and protein levels are elevated in Schwann cells. Expression of type I neuregulin 1 (Nrg1), rather than type III Nrg1, was induced by Schwann cells, and the abolished Nrg1 cleavage in BACE1-null Schwann cells contributed to decreased remyelination of regenerated axons. Hence, this study is the first to demonstrate the equal importance of axonal and Schwann cell BACE1 for remyelination of injured nerves.

CA1 pyramidal neuron gene expression mosaics in the Ts65Dn murine model of Down syndrome and Alzheimer's disease following maternal choline supplementation

“…Although associated with β‐cleavage of APP, leading to greater Aβ and βCTF expression, attenuation of Bace1 levels by MCS may indicate a counterintuitive normalization of APP processing in vulnerable neurons that reflects the importance of steady‐state Aβ and βCTF levels, underscoring the importance of evaluating βCTF expression in DS/AD models (Jiang et al, ). Alternatively, Bace1 deficiency may be considered detrimental, as a loss of Bace1 expression impairs myelination (Hu, Hu, Dai, Trapp, & Yan, ) and causes hippocampal synaptic deficits (Petrus & Lee, ; Wang et al, ; Zhu et al, ), illustrating the need for normative Bace1 levels. MCS also restores the normal expression of two truncated forms of tau ( Mapt2N6D and Mapt2N6P ).…”

Neurological dysfunctions associated with altered BACE1‐dependent Neuregulin‐1 signaling

“…We show that in the case of either a BACE1‐null nerve segment transplanted into a WT recipient or a WT nerve segment transplanted into a BACE1‐null recipient, remyelination is equally impaired, as the increase in g‐ratio is almost identical (Hu et al . ). Nerve injury not only induces expression of BACE1, but also type I Nrg1 by Schwann cells.…”

Diversity Matters: A Revised Guide to Myelination

“…One mechanism by which peripheral neurons regulate levels of Nrg1 is through cleavage of the protein by β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a process which seems to be positively regulated by the metallopeptidase Nardylisin [45]. Recently, it has been shown that BACE1 is also expressed in Schwann cells and that Schwann cell-derived BACE1 is as important as axonal BACE1 in controlling myelination [46,47]. …”