Regulation of Alpha-Secretase ADAM10 In vitro and In vivo: Genetic, Epigenetic, and Protein-Based Mechanisms

Abstract

ADAM10 (A Disintegrin and Metalloproteinase 10) has been identified as the major physiological alpha-secretase in neurons, responsible for cleaving APP in a non-amyloidogenic manner. This cleavage results in the production of a neuroprotective APP-derived fragment, APPs-alpha, and an attenuated production of neurotoxic A-beta peptides. An increase in ADAM10 activity shifts the balance of APP processing toward APPs-alpha and protects the brain from amyloid deposition and disease. Thus, increasing ADAM10 activity has been proposed an attractive target for the treatment of neurodegenerative diseases and it appears to be timely to investigate the physiological mechanisms regulating ADAM10 expression. Therefore, in this article, we will (1) review reports on the physiological regulation of ADAM10 at the transcriptional level, by epigenetic factors, miRNAs and/or protein interactions, (2) describe conditions, which change ADAM10 expression in vitro and in vivo, (3) report how neuronal ADAM10 expression may be regulated in humans, and (4) discuss how this knowledge on the physiological and pathophysiological regulation of ADAM10 may help to preserve or restore brain function.

Keywords: ADAM10; Alzheimer's disease; aging; alpha-secretase; mouse models; promoter; spine; transcription factors.

Figure 1

Domain structure of ADAM10. ADAM10 consists of several functional distinct domains: (1) prodomain, (2) catalytic domain, (3) cystein-rich disintegrin-like domain, (4) transmembrane domain, (5) cytosolic domain. Upon dimerization (left), the unstructured C-terminus converts into an ordered domain (Deng et al., 2014). Cleavage sites for proteinases such as proprotein convertases [located at the end of the prodomain, (Anders et al., 2001), I], other ADAMs [close to the membrane, (Cissé et al., ; Parkin and Harris, ; Tousseyn et al., 2009) II] or gamma-secretase [within the membrane, (Tousseyn et al., 2009), III] have been identified.

Figure 2

Distribution of ADAM10 mRNA in the murine brain. Sagittal section of C57Bl6/J mouse brain (male) at E18.5 (A1,A2; Image credit: Allen Institute; http://developingmouse.brain-map.org/experiment/show/100055949, ©2016. Allen Institute for Brain Science) and P56 (B1,B2; Image credit: Allen Institute; http://developingmouse.brain-map.org/experiment/show/69514738, ©2016. Allen Institute for Brain Science C1,C2: magnification of hippocampal area of the adult brain). ADAM10 mRNA expression is revealed by in situ hybridization [A1–C1, upper row ISH; A2–C2, lower row expression energy (cells with highest probability of gene expression)]. CA1-3, Cornu Ammonis regions; Cb, cerebellum; Ctx, cerebral cortex; DG, Dentate Gyrus; H, hippocampus; ob, olfactory bulb; SC, Superior Colliculus; Th, thalamus; vmh, ventral mid-/hindbrain

Figure 3

Transcription factors influencing human ADAM10 promoter activity in SH-SY5Y cells. Original data published in: Reinhardt et al. (2014). Factors filtered for effect size (promoter activity above 100+5xSD or below 100-2.5xSD of control) and reproducibility (SD≤ 15% of effect size in at least three independent experiments). Percentage of activating or repressing factors are indicated (left), factors with a general mode of action on transcription such as activator of basal transcription 1 (ABT1) were excluded. The table (right) shows the nine transcription factors with either strongest activating or inhibiting effects on the human ADAM10 promoter ranked from strongest to weakest.

Figure 4

ADAM10's potential two-faced role under conditions of brain injury. Whereas a transiently increased activity/amount of ADAM10 seems to be part of a protective and restorative response to mild neural lesions, a persistent upregulation of ADAM10 as seen following severe lesions may be deleterious.