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. 2023;21(1):31-53.
doi: 10.2174/1570159X19666211201095701.

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model

Harald Hampel  1 , Giuseppe Caruso  2 , Robert Nisticò  3   4 , Gaia Piccioni  3   5 , Nicola B Mercuri  6   7 , Filippo Sean Giorgi  8 , Fabio Ferrarelli  9 , Pablo Lemercier  1 , Filippo Caraci  2   10 , Simone Lista  1   11 , Andrea Vergallo  1 , Neurodegeneration Precision Medicine Initiative Npmi
Affiliations

Biological Mechanism-based Neurology and Psychiatry: A BACE1/2 and Downstream Pathway Model

Harald Hampel et al. Curr Neuropharmacol. 2023.

Abstract

In oncology, comprehensive omics and functional enrichment studies have led to an extensive profiling of (epi)genetic and neurobiological alterations that can be mapped onto a single tumor's clinical phenotype and divergent clinical phenotypes expressing common pathophysiological pathways. Consequently, molecular pathway-based therapeutic interventions for different cancer typologies, namely tumor type- and site-agnostic treatments, have been developed, encouraging the real-world implementation of a paradigm shift in medicine. Given the breakthrough nature of the new-generation translational research and drug development in oncology, there is an increasing rationale to transfertilize this blueprint to other medical fields, including psychiatry and neurology. In order to illustrate the emerging paradigm shift in neuroscience, we provide a state-of-the-art review of translational studies on the β-site amyloid precursor protein cleaving enzyme (BACE) and its most studied downstream effector, neuregulin, which are molecular orchestrators of distinct biological pathways involved in several neurological and psychiatric diseases. This body of data aligns with the evidence of a shared genetic/biological architecture among Alzheimer's disease, schizoaffective disorder, and autism spectrum disorders. To facilitate a forward-looking discussion about a potential first step towards the adoption of biological pathway-based, clinical symptom-agnostic, categorization models in clinical neurology and psychiatry for precision medicine solutions, we engage in a speculative intellectual exercise gravitating around BACE-related science, which is used as a paradigmatic case here. We draw a perspective whereby pathway-based therapeutic strategies could be catalyzed by highthroughput techniques embedded in systems-scaled biology, neuroscience, and pharmacology approaches that will help overcome the constraints of traditional descriptive clinical symptom and syndrome-focused constructs in neurology and psychiatry.

Keywords: neurology; precision medicine; psychiatry; systems biology; systems pharmacology; β-site amyloid precursor protein cleaving enzyme (BACE).

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Conflict of interest statement

HH is an employee of Eisai Inc. The present article has been initiated and prepared as part of an academic position at Sorbonne University, Paris, France and it reflects entirely and exclusively his own opinion. HH serves as Senior Associate Editor for the Journal Alzheimer’s & Dementia and does not receive any fees or honoraria since May 2019; before May 2019, he had received lecture fees from Servier, Biogen, and Roche, research grants from Pfizer, Avid, and MSD Avenir (paid to the institution), travel funding from Eisai, Functional Neuromodulation, Axovant, Eli Lilly and Company, Takeda and Zinfandel, GE-Healthcare and Oryzon Genomics, consultancy fees from Qynapse, Jung Diagnostics, Cytox Ltd., Axovant, Anavex, Takeda and Zinfandel, GE Healthcare, Oryzon Genomics, and Functional Neuromodulation, and participated in scientific advisory boards of Functional Neuromodulation, Axovant, Eisai, Eli Lilly and Company, Cytox Ltd., GE Healthcare, Takeda and Zinfandel, Oryzon Genomics, and Roche Diagnostics. He is the inventor of 11 patents and has received no royalties:

•In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Patent Number: 8916388.

•In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Patent Number: 8298784.

•Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20120196300.

•In Vitro Multiparameter Determination Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100062463.

•In Vitro Method for The Diagnosis and Early Diagnosis of Neurodegenerative Disorders Publication Number: 20100035286.

•In Vitro Procedure for Diagnosis and Early Diagnosis of Neurodegenerative Diseases Publication Number: 20090263822.

•In Vitro Method for The Diagnosis of Neurodegenerative Diseases Patent Number: 7547553.

•CSF Diagnostic in Vitro Method for Diagnosis of Dementias and Neuroinflammatory Diseases Publication Number: 20080206797.

•In Vitro Method for The Diagnosis of Neurodegenerative Diseases Publication Number: 20080199966.

•Neurodegenerative Markers for Psychiatric Conditions Publication Number: 20080131921.

•Method for diagnosis of dementias and neuroinflammatory diseases based on an increased level of procalcitonin in cerebrospinal fluid: Publication number: United States Patent 10921330.

SL received lecture honoraria from Roche and Servier.

AV declares no competing financial interests related to the present article, and his contribution to this article reflects only and exclusively his own academic expertise on the matter. This work was conceptualized and initiated during his previous academic position at Sorbonne University, Paris, France. AV was an employee of Eisai Inc. [Nov 2019 - June 2021]. AV does not receive any fees or honoraria since November 2019. Before November 2019 he had he received lecture honoraria from Roche, MagQu LLC, and Servier.

GC, RN, GP, NBM, FSG, FF, PL, and FC declare no conflict of interest.

Figures

Fig. (1)
Fig. (1)
Schematic representation of amyloid precursor protein (APP) processing pathways. BACE1 functions as the β-secretase enzyme by cleaving the transmembrane APP to release the β-stubs. BACE1 cleavage of APP represents the rate-limiting step for Aβ production. Cleavage of APP by BACE1 liberates the soluble N-terminus of APP, while the C-terminal fragment (CTF-β or C99) remains bound to the membrane. To produce Aβ, the fragment CTF-β is cleaved by β-secretase, which finally releases Aβ into the extracellular space and the APP intracellular domain into the cytoplasm. In a parallel competing non-amyloidogenic pathway, APP is cleaved either by α-secretase or η-secretase to release two additional variants of the APP ectodomain, namely sAPP-α and sAPP-η Abbreviations: Aβ = amyloid-β; APP = amyloid precursor protein; BACE1 = β-site amyloid precursor protein cleaving enzyme 1; CTF-β = β-C-terminal fragment; sAPP = soluble amyloid precursor protein. Note: Adapted from The β-Secretase BACE1 in Alzheimer's Disease. Biological Psychiatry, 2020, S0006-3223(20)30063-9. https://doi.org/10.1016/j.biopsych.2020.02.001
Fig. (2)
Fig. (2)
The BACE1-NRG1 axis. NRG1 is a transmembrane protein expressed mainly in the frontal cortex, hippocampus, and cerebellum, as well as in the peripheral nervous system (PNS) dopaminergic neurons. The NRG1-type I and NRG1-type III isoforms (the latter is the primary variant expressed in the brain) are validated substrates of BACE1. NRG1-type III is a hairpin-shaped protein precursor with two membrane-spanning domains. Its cleavage performed by BACE1 leads to two separate fragments anchored to the membrane: the N-terminal fragment (NTF) (NRG1-NTF) and the C-terminal fragment (NRG1-CTF), on the external and internal (cytosolic) sides of the membrane, respectively. NRG1-induced cellular responses are primarily mediated by binding to tyrosine kinase receptors of the ErbB family, especially to ErbB2, ErbB3, and ErbB4. BACE1-cleaved NRG1-NTF fragment contains an epidermal growth factor (EGF)-like domain that binds and activates the ErbB receptors involved in the NRG1/ErbB signaling pathway. This increases the phosphorylation of downstream signaling molecules: the extracellular signal-regulated kinase (ERK) and the serine/threonine kinase (Akt). The activation of the NRG1/ErbB signaling pathway is necessary to modulate cell survival, synaptic development, glutamatergic transmission (through regulation of NMDA receptor expression and turn-over), neuronal migration, and myelination, and control the internalization of mGluR1 on dopaminergic neurons. Abbreviations: BACE1 = β-site amyloid precursor protein cleaving enzyme 1; EGF = epidermal growth factor; ERK = extracellular signal-regulated kinase; mGLUR1 = group 1 metabotropic glutamatergic receptors; NMDA = N-methyl-D-aspartate; NRG1 = neuregulin-1; NRG1-CTF = NRG1 C-terminal fragment; NRG1-NGF = NRG1 N-terminal fragment; PNS = peripheral nervous system. Note: Adapted from BACE1-Dependent Neuregulin-1 Signaling: An Implication for Schizophrenia. Front Mol Neurosci, 2017, Sep 25;10:302. doi: 10.3389/fnmol.2017.00302.
Fig. (3)
Fig. (3)
BACE2 as a common pharmacological target for type 2 diabetes mellitus and Alzheimer’s disease. The evidence observed in animal models of T2DM suggests that BACE2 might represent a novel pharmacological target for the treatment of T2DM [1]. Mice with an in-frame deletion of exon 6 of BACE2 on both alleles (Bace2ΔE6/ΔE6) and ob/ob mice, representing a model of obesity-related insulin resistance, treated with a BACE2 inhibitor (CpdJ), displayed reduced blood glucose levels, improved glucose tolerance, and increased β-cell mass and function. BACE2 suppression is known to promote beta-cell survival and function in an animal model of T2DM induced by human amylin over-expression. These new data have therefore stimulated the development of highly selective and potent human BACE2 inhibitors (Ki < 2nM and selectivity over BACE1 over 500-fold) [2] whose preclinical efficacy in animal models of T2DM remains to be evaluated. These selective BACE 2 inhibitors will represent new pharmacological tools to better validate the role of BACE 2 as a new pharmacological target for the treatment of AD in the future. The one-letter code was used to describe the amylin peptide amino acid sequence. Abbreviations: AD = Alzheimer’s disease; BACE2 = β-site amyloid precursor protein cleaving enzyme 2; DNER = delta and notch-like epidermal growth factor-related receptor; FGFR1 = fibroblast growth factor receptor 1; PLXDC2 = plexin domain-containing protein 2; PMEL = pigment cell-specific melanocyte protein; SEZ6 = seizure-related protein 6; SEZ6L = seizure-related 6 homolog-like; Tmem27 = transmembrane protein 27; T2DM = type 2 diabetes mellitus; VCAM1 = vascular cell adhesion molecule 1. Note: Finally, BACE2 cleaves SEZ6 and its homolog seizure-related 6 homolog-like (SEZ6L) in pancreatic β-cells but not in neurons. BACE2, by acting on its transmembrane protein 27, is implicated in the regulation of pancreatic β-cell function and mass, two parameters that, when impaired, can contribute to type 2 diabetes mellitus (T2DM) pathogenesis. An additional substrate of BACE2 is amylin (also known as human islet amyloid polypeptide), a peptide co-secreted with insulin by β-cells, directly associated with T2DM, whose aggregates and deposits have also been observed in blood vessels and brain parenchyma of late-onset AD patients. As shown in vitro, BACE2 lowers the human amylin aggregation rate through the cleavage at the F15 and F23 sites, reducing its intracellular concentration in β-cells. In contrast, in transgenic mice overexpressing amylin, BACE2 suppression promotes β-cells survival, counteracting the adverse outcomes induced by amylin. BACE2 is also responsible for the proteolytic processing of the pigment cell-specific melanocyte protein required to form functional amyloid fibrils during melanogenesis, explaining the loss of pigmentation observed in preclinical studies of BACE1/2 inhibition. Table 2 illustrates more information about BACE2 substrates, substrate physiological functions, and the effects related to enzyme-substrate interaction. Note: references: [1] Alcarraz-Vizan, G., et al. (2017) Cellular and molecular life sciences: CMLS 74, 2827-2838; [2] Ghosh, A.K., et al. (2019) ChemMedChem 14, 545-560
Fig. (4)
Fig. (4)
Cohorts stratified according to different multimodal-throughput technological platforms (“omic” sciences) are integrated into the disease modeling for classification and prediction of subsets of Alzheimer’s disease and patients with other brain proteinopathies and neurodegenerative diseases. Systems biology is an evolving hypothesis-free, exploratory, holistic (non-reductionistic), global, integrative, and interdisciplinary paradigm using advances in multimodal high-throughput technological platforms that enable the examination of networks of biological pathways, where elevated amounts of structurally and functionally different molecules are simultaneously explored overtime at a system-level (i.e., at the level of molecules and subcellular compartments, cells, group of cells, tissues, organs, apparatuses, or even whole organisms). According to systems biology, organisms are made of systems which are entities consisting in hierarchically self-organized levels with increasing structural complexity resulting in different emerging properties. Adopted with permission from: The Alzheimer Precision Medicine Initiative. J Alzheimers Dis. 2019;68(1):1-24. doi: 10.3233/JAD-181121.
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