Poblete, N. | Search bioRxiv

bioRxiv2026

Optimized AAV to express the unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease features in mouse models

Proteostasis impairment at the level of the endoplasmic reticulum (ER) is a salient feature of Alzheimers disease (AD). The unfolded protein response (UPR) is the main pathway to cope with ER stress, where the expression of the transcription factor X-Box binding protein 1 (XBP1) is central to establish repair programs. To artificially enforce the adaptive capacity of the UPR in the AD brain, we recently reported the protective effects of overexpressing active XBP1 in the brain using adeno-associated vectors (AAVs) of AD mice, in addition to aged animals. Here we have generated a next generation vector suitable for clinical testing by (i) expressing codon-optimized human XBP1s without artificial tags, (ii) the use of the synapsin promoter to restrict expression to neurons, and (iii) incorporating a novel variant of AAV2 (AAV-TT) with greater biodistribution (here termed Proteostaser-1). Treatment of 5xFAD mice with Proteostaser-1 improved spatial learning and synaptic plasticity, and reduced the deposition of amyloid plaques in the brain. Proteostaser-1 administration also improved cognition in a model of sporadic AD based on the intracerebral injection of amyloid {beta} oligomers. Our results further support the therapeutic potential of the UPR as a strategy to ameliorate AD features and sustain synaptic function.

cell biology↗

bioRxiv2022

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer`s disease by improving synaptic function and proteostasis

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimers disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) is an ER-located kinase and endoribonuclease that operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). A polymorphism in the XBP1 promoter has been suggested as a risk factor for AD. To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in neurons using preclinical models. Overexpression of an active form of XBP1 in the nervous system using transgenic mice significantly reduced the load of amyloid deposits in the cerebral cortex and hippocampus and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved long-term potentiation, memory performance, and dendritic spine density. Quantitative proteomics of the hippocampus revealed that XBP1 expression corrects a large proportion of the alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

animal behavior and cognition↗