In the last 25 years, neuroscientists in search of a cure for Alzheimer’s disease (AD) have devoted their efforts to developing therapeutic strategies targeting the amyloid-β (Aβ) peptide. However, considering the questionable results of the clinical trials so far, it is vital to examine other targets and therapeutic approaches to restore cognitive function in AD patients and to slow down disease progression.
In this issue of Molecular Therapy, Duran-Aniotz et al.1 propose a novel therapeutic strategy to rescue the main pathological features of AD. They developed an adeno-associated virus-mediated gene therapy to locally deliver XBP1s, the active form of the X-box binding protein 1 (XBP1), to hippocampal neurons. XBP1 is a master regulator of the unfolded protein response (UPR) and its overexpression in the central nervous system ameliorates Aβ burden, restores synaptic plasticity, and prevents cognitive dysfunction in AD mice.
In neuronal cells, protein homeostasis (referred to as proteostasis) is a critical element to maintain the ability of synapses to preserve their individual characteristics for a long time or modify their composition in response to physiological stimuli. However, during aging, the activity of the proteostasis network declines, which may increase the risk of accumulating abnormal protein aggregates, a hallmark of most neurodegenerative diseases. Upon accumulation of such proteins in the endoplasmic reticulum (ER) lumen, the UPR is initiated to restore protein homeostasis. The UPR starts a whole range of signaling cascades which modifies cellular transcriptional and translational events in an attempt to cope with ER stress and reinstate the ER homeostasis. Mild ER stress can be resolved by the UPR (adaptive UPR), while excessive and chronic ER stress induces prolonged activation of the UPR (maladaptive UPR), leading to the induction of cell death pathways.
Inositol-requiring enzyme 1α (IRE1α) is one of the three ER-resident sensors governing the UPR, and it is responsible for XBP1 activation. IRE1α catalyzes the splicing of XBP1, which results in the expression of an active and stable transcription factor called XBP1s. The activity of XBP1s supports proteostasis by inducing the expression of genes involved in protein folding and quality control mechanisms.2
Considering the relevance of UPR in the control of cellular homeostasis, the IRE1α/XBP1 axis is a promising pharmaceutical candidate for several disorders, including neurodegenerative diseases.3 However, the studies investigating the role of IRE1α/XBP1 signaling pathway in aging and AD provided unexpected results. Despite the expectation that IRE1α signaling might be protective, genetic disruption of IRE1α accelerated age-related cognitive decline in mice and promoted natural accumulation of senescent cells in the hippocampus. Alternatively, artificial bolstering of XBP1s levels prevented the appearance of age-related deterioration in brain function and reversed age-associated cognitive decline in aged mice.4 Similar results were obtained in AD mice models. The genetic ablation of the RNase domain of IRE1α in the nervous system of AD mice significantly reduced amyloid deposition, and restored memory and synaptic plasticity.5 In line with the results obtained in aged mice,4 XBP1s overexpression in AD mice impacted several features of this form of dementia, reducing the load of Aβ deposits and glial activation, paralleled by the rescue of synaptic plasticity phenomena and the restoration of cognitive function.1 The therapeutic potential of XBP1s has been proven by two studies showing that viral vector-mediated XBP1s brain delivery alleviates deficits in neuronal plasticity and memory associated with AD pathology in two different AD mouse models.1,6 These studies highlight the therapeutic potential of XBP1s overexpression that is independent from the IRE1α/XBP1 axis. Remarkably, the unbiased proteomic profiling performed by Duran-Aniotz et al.1 shed light on the pathways affected by XBP1s in AD mice. The proteomic analysis revealed altered expression of a cluster of proteins related to synaptic function and neurodegenerative diseases, whereas no changes in canonical XBP1s target genes involved in proteostasis or UPR were detected.
Duran-Aniotz et al.1 introduce a new concept beyond the conventional role of XBP1s in UPR and reveal that this transcription factor can be considered a regulator of synaptic function in physiological and pathological conditions. XBP1s is relevant for contextual memory formation and for the potentiation of synaptic transmission because it regulates the expression of memory-related genes such as the brain-derived neurotrophic factor (BDNF).7 Moreover, in response to BDNF treatment, XBP1 mRNA splicing is locally activated in neurites, followed by translocation of XBP1s into the nucleus to promote neurite outgrowth.8 However, Duran-Aniotz et al.1 demonstrate that the protective effects of XBP1s in AD mice are independent of BDNF. They identified a cluster of genes associated with actin cytoskeleton dynamics that were dramatically altered in the AD model, which were fully corrected by the genetic overexpression of XBP1s. Among these genes, one of the strongest hits was cofilin1, a master regulator of actin dynamics in spines.
In the synapse, the actin cytoskeleton is a crucial element to maintain the dendritic spine architecture and to orchestrate the spine’s morphology remodeling driven by synaptic activity. The disturbance of actin-binding proteins, which regulate actin cytoskeleton dynamics, could be a common principle in many neurological disorders characterized by synaptic failure. Several studies analyzing AD postmortem tissue, animal and cellular models suggest that AD pathology has a deleterious effect on the pathways governing the actin cytoskeleton. Cofilin1 is one of the main architects of spine shape and spine remodeling upon long-term potentiation. The mechanisms controlling cofilin1 activity in spines are altered in AD patients and AD mouse models.9 In addition, cofilin1 is a component of “cofilin-actin rods,” persistent rod-like structures that contain primarily cofilin and actin. In neurons, cofilin-actin rods are formed upon stressor exposure and can be detected in the brain of AD patients.10
XBP1s can also be considered as a key element promoting the resilience of the synapses to stressors. Duran-Aniotz et al.1 showed that mice overexpressing XBP1s in the brain were fully protected against the adverse effects of Aβ oligomer exposure. Neurons are highly vulnerable to perturbations, and aging increases neuronal vulnerability to stressors. XBP1s can promote a protective mechanism through its ability to engage signaling pathways to boost synaptic function. Nonetheless, how XBP1s increases neuronal resilience to stressors warrants further analysis. Does XBP1s prevent cofilin1-actin rod generation upon stressor exposure? Is XBP1s counteracting synapse frailty in aging thorough the stabilization of the actin cytoskeleton in spines? Even though synaptic dysfunction is among the most common and transversal pathological feature in neurodegeneration, it is critical to investigate whether XBP1s is implicated in the mechanisms underlying synaptic failure in other neurodegenerative diseases, not just in protein misfolding or aggregate formation.
The results of Duran-Aniotz et al.1 highlight the importance of unraveling novel cellular mechanisms underlying synaptic failure in aging and neurodegeneration. These studies will be pivotal to tackle the next challenges in the field: (1) promoting synapse resilience during aging to prevent neurodegeneration, (2) tracing synaptic dysfunction to identify a temporal window for disease intervention before neurons undergo cell death, and (3) designing synapse-tailored therapeutic strategies to specifically restore synaptic plasticity.
Acknowledgments
I acknowledge funding from the Italian Ministry of University and Research (PRIN 202039WMFP) and from Fondazione Cariplo (grant no. 2018-0511).
Declaration of interests
The author declares no competing interests.
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