Aβ42 oligomers modulate β-secretase through an XBP-1s-dependent pathway involving HRD1

Abstract

The aspartyl protease β-site APP cleaving enzyme, BACE1, is the rate-limiting enzyme involved in the production of amyloid-β peptide, which accumulates in both sporadic and familial cases of Alzheimer’s disease and is at the center of gravity of the amyloid cascade hypothesis. In this context, unravelling the molecular mechanisms controlling BACE1 expression and activity in both physiological and pathological conditions remains of major importance. We previously demonstrated that Aβ controlled BACE1 transcription in an NFκB-dependent manner. Here, we delineate an additional cellular pathway by which natural and synthetic Aβ42 oligomers enhance active X-box binding protein XBP-1s. XBP-1s lowers BACE1 expression and activity indirectly, via the up-regulation of the ubiquitin-ligase HRD1 that acts as an endogenous down-regulator of BACE1. Thus, we delineate a novel pathway by which cells could compensate for Aβ42 oligomers production and thus, associated toxicity, by triggering a compensatory mechanism aimed at lowering BACE-1-mediated Aβ production by a molecular cascade involving XBP-1s and HRD1. It thus identifies HRD1 as a potential target for a novel Aβ-centered therapeutic strategy.

The Transcription Factor XBP1 in Memory and Cognition: implications in Alzheimer’s Disease

“…These observations led to the intuitive interpretation that XBP1 levels might be reduced in AD models and/or human patients. Surprisingly, endogenous XBP1 was undetectable in AD models that produced high levels of oligomeric Aβ or in human brains postmortem (19), whereas neurons exposed to Aβ oligomers showed a significant increase of XBP1 levels (42,167). These discrepancies likely reflect a compensatory mechanism triggered by acute exposure to Aβ oligomers, whereas chronic exposure to these neurotoxins, which is more reflective of the in vivo situation, causes an overdrive and collapse of the system.…”

“…Thus, this interplay might fuel a negative signaling loop with XBP1 reducing BACE1 and Aβ. Consequently, this further reduces BACE1 expression/activity, since Aβ has been shown to control BACE1 levels (42,(44)(45)(46). However, one cannot exclude alternative signaling pathways involving p25/CDK5 (47) or LRP1 (48,49).…”

“…In conclusion, this model implicates a dual mechanism wherein XBP1s synergistically promotes synaptic plasticity by fostering spine formation through Kalirin-7 signaling and lowers Aβ levels. Although the mechanisms underlying the XBP1s-dependent decrease of Aβ levels were not fully elucidated in that study, they may require recruitment and activation of enzymes that regulate Aβ levels (41,42,(76)(77)(78)(79) and/or APP metabolism/trafficking (40,(80)(81)(82).…”

“…Moreover, long-term potentiation (LTP), a complex long-lasting form of plasticity involving Ca+/calmodulin-dependent protein kinase (70), at Schaffer collaterals to pyramidal cell synapses was greatly regulate expression and activity of the aspartyl protease β-site APP cleaving enzyme 1 (BACE1) (42), the rate-limiting enzyme involved in the production of Aβ peptide (43), by promoting the activity of the ubiquitin-ligase HRD1 (42). Thus, this interplay might fuel a negative signaling loop with XBP1 reducing BACE1 and Aβ.…”

Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

“…Furthermore, sXBP1 was shown to reduce the level of β-site amyloid precursor protein cleaving enzyme 1 (BACE1), which plays a key role in Aβ production (47). The reduction of BACE1 level is mediated through the ubiquitin-ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) (47) which is also involved in APP degradation and the subsequent reduction in Aβ production (48). Moreover, sXBP1 enhances memory formation possibly by increasing the production of brainderived neurotrophic factor (BDNF) in the CNS (49).…”