The transcription factor XBP1s restores hippocampal synaptic plasticity and memory by control of the Kalirin-7 pathway in Alzheimer model

Abstract

Neuronal network dysfunction and cognitive decline constitute the most prominent features of Alzheimer’s disease (AD), although mechanisms causing such impairments are yet to be determined. Here we report that virus-mediated delivery of the active spliced transcription factor X-Box binding protein 1s (XBP1s) in the hippocampus rescued spine density, synaptic plasticity and memory function in a mouse model of AD. XBP1s transcriptionally activated Kalirin-7 (Kal7), a protein that controls synaptic plasticity. In addition, we found reduced levels of Kal7 in primary neurons exposed to Aβ oligomers, transgenic mouse models and human AD brains. Short hairpin RNA-mediated knockdown of Kal7 altered synaptic plasticity and memory formation in naive mice. Further, reduction of endogenous Kal7 compromised the beneficial effects of XBP1s in Alzheimer’s model. Hence, our findings reveal that XBP1s is neuroprotective through a mechanism that engages Kal7 pathway with therapeutic implications in AD pathology.

Link between endoplasmic reticulum stress and autophagy in neurodegenerative diseases

“…These observations suggest that BECN1 in the Central Nervous System (CNS) may be involved in the pathogenesis of neurodegenerative diseases. XBP1 was reported to protect against AD pathology; it was shown that transduction of hippocampus with sXBP1 rescued alterations in spine density, synaptic plasticity and memory loss in an AD mouse model (45). Several mechanisms for the amelioration of AD pathology by sXBP1 have been proposed; one such mechanism is the induction of disintegrin and metalloproteinase 10 (ADAM10) by sXBP1 (46).…”

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

“…Thus, preserving the spines' dynamic and integrity is essential for the brain to develop synaptic networks capable of accurate information processing. Accordingly, tremendous efforts have been oriented toward therapeutic strategies aimed at circumventing Aβ neurotoxicity by activation of signaling pathways (13,19,20) that XBP1 exerts its beneficial effects in the brain through a regulatory loop involving IRE1α, XBP1 and BDNF. Generally consistent with the above findings, another study examined the role of XBP1 in the brains of naive mice and transgenic models of AD (19).…”

“…Accordingly, tremendous efforts have been oriented toward therapeutic strategies aimed at circumventing Aβ neurotoxicity by activation of signaling pathways (13,19,20) that XBP1 exerts its beneficial effects in the brain through a regulatory loop involving IRE1α, XBP1 and BDNF. Generally consistent with the above findings, another study examined the role of XBP1 in the brains of naive mice and transgenic models of AD (19). The report describes a preventive paradigm, as AD transgenic mice had no apparent synaptic and memory deficits at the time of intervention.…”

“…The report describes a preventive paradigm, as AD transgenic mice had no apparent synaptic and memory deficits at the time of intervention. At a later time point, measures of spine density, synaptic plasticity and hippocampal-dependent memory revealed significant improvements in AD mice expressing XBP1 relative to controls (19). The remainder of the study focused on delineating the mechanisms by which changes at the level of dendritic spines occur throughout life and underlie structural mechanisms that control synaptic function and efficacy.…”

“…Dendritic spines are very dynamic structures with diverse shapes (56) that can be influenced by experimental manipulations. These manipulations trigger internal neuronal inputs from other brain regions or external environmental stimuli to impact their density, motility, morphology and activity in both physiological (57,58) and pathological (19,21) contexts. Synaptic changes related to neuronal activity have been extensively explored by using the enriched environment paradigm as a means to study the impact of neuritogenesis and spinogenesis on learning and memory performance (59).…”