BACE1 is at the crossroad of a toxic vicious cycle involving cellular stress and β-amyloid production in Alzheimer's disease

Abstract

Alzheimer's disease (AD) is a complex age-related pathology, the etiology of which has not been firmly delineated. Among various histological stigmata, AD-affected brains display several cellular dysfunctions reflecting enhanced oxidative stress, inflammation process and calcium homeostasis disturbance. Most of these alterations are directly or indirectly linked to amyloid β-peptides (Aβ), the production, molecular nature and biophysical properties of which likely conditions the degenerative process. It is particularly noticeable that, in a reverse control process, the above-described cellular dysfunctions alter Aβ peptides levels. β-secretase βAPP-cleaving enzyme 1 (BACE1) is a key molecular contributor of this cross-talk. This enzyme is responsible for the primary cleavage generating the N-terminus of "full length" Aβ peptides and is also transcriptionally induced by several cellular stresses. This review summarizes data linking brain insults to AD-like pathology and documents the key role of BACE1 at the cross-road of a vicious cycle contributing to Aβ production.

Figure 1

Oxidative stress mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides trigger oxidative stress by inducing ROS generation and impairing the antioxidant system. Oxidative stress and inflammatory cytokines activates JNK, then its transcription factor AP-1 upregulates BACE1. As BACE1 produces Aβ peptides, a vicious cycle is established. Aβ, amyloid peptide; AP-1, activator protein-1; BACE1, β-secretase βAPP cleaving enzyme 1; JNK, c-Jun N-terminal kinases; ROS, reactive oxygen species.

Figure 2

Inflammation mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides are pro-inflammatory. They activate microglia and astrocytes that release inflammatory mediators. Those activate NF-κB, which is also activated by oxidative stress, ischemia or traumatic brain injury. Pathological activation of NF-κB activates BACE1 transcription, thus increasing Aβ peptides levels and feeding a vicious cycle. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.

Figure 3

Disturbed calcium homeostasis mediates Aβ-induced BACE1 transcriptional activation. Aβ peptides increase cytoplasmic calcium by at least three mechanisms: stimulation of membrane ion channels or receptors; permeabilization of the membrane; and deregulation of internal calcium channels. Presenilins mutations contribute to the latter. Increased calcium then activates the calpain/cdk5/STAT3 pathway and NFAT1. The transcription factors STAT3 and NFAT1 upregulate BACE1, which then produces more Aβ peptides and a positive feedback mechanism is set up. Aβ, amyloid peptide; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; IP3, inositol 1,4,5-triphosphate; NFAT1, nuclear factor of activated T-cells 1; SERCA, sarco endoplasmic reticulum calcium ATPase; STAT, signal transducer and activator of transcription.

Figure 4

Aβ and AGEs activate BACE1 transcription. Aβ peptides activate RAGE. This receptor is also activated by AGEs produced during diabetes mellitus, inflammation or hypoxia. RAGE activation upregulates BACE1 by the activation of the two transcription factors NF-κB and NFAT1. Additionally, AGEs can activate BACE1 by generating oxidative stress. BACE1 contribution to Aβ peptides production then amplifies RAGE activation. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NFAT1, nuclear factor of activated T-cells 1; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.

Figure 5

Traumatic brain injury contributes to Aβ deposition by activating BACE1 transcription. Traumatic brain injury activates BACE1 by inducing oxidative stress and by activating the NF-κB transcription factor. This leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; NF-κB, nuclear factor-κB.

Figure 6

Hypoxia contributes to Aβ deposition by activating BACE1 transcription. Hypoxia activates BACE1 by three distinct mechanisms: generation of oxidative stress and the subsequent activation of the JNK pathway; activation of HIF-1 transcription factor which activates BACE1 promoter directly or indirectly through the activation of NF-κB and RAGE; activation of calpain and cdk5 resulting from increased calcium concentrations. By activating BACE1 transcription, hypoxia thus leads to Aβ deposition. Aβ, amyloid peptide; AGE, advanced glycation end products; BACE1, β-secretase βAPP cleaving enzyme 1; cdk5, cyclin-dependent kinase 5; HIF-1, hypoxia-inducible factor 1; JNK, c-Jun N-terminal kinases; NF-κB, nuclear factor-κB; RAGE, receptor for advanced glycation end products.

Figure 7

Cellular stress, BACE1 and Aβ production are involved in a toxic vicious cycle in AD. Various cellular dysfunctions including oxidative stress, inflammation and calcium homeostasis disturbance occur in AD-affected brains. These alterations activate the transcription of the stress-induced β-secretase BACE1 that contributes to Aβ production. Once yielded at supra-physiological levels, Aβ induces cellular stresses that, in turn activate BACE1, therefore setting up a vicious cycle. Such self-maintained toxicity can lead to cellular cell death. Brain insults like hypoxia and traumatic brain injury contribute to this scheme by inducing cellular stress.