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 Alzheimer's 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…
Alzheimer's disease is often characterized by an impairment in proteostasis at the endoplasmic reticulum (ER) level. The unfolded protein response (UPR) is a crucial pathway that helps cope with this ER stress, with the transcription factor X-Box binding protein 1 (XBP1) playing a central role in initiating repair programs. Researchers have previously demonstrated that overexpressing active XBP1 in the brains of mice and aged animals using adeno-associated vectors (AAVs) can provide protective effects.
In this study, a new vector has been generated to enable clinical testing. This vector expresses codon-optimized human XBP1s without artificial tags, restricts expression to neurons using the synapsin promoter, and incorporates a novel variant of AAV2 (AAV-TT) with enhanced biodistribution, termed Proteostaser-1. When 5xFAD mice were treated with Proteostaser-1, they showed improvements in spatial learning, synaptic plasticity, and a reduction in amyloid plaque deposition.
Furthermore, when this vector was administered to a sporadic AD model based on intracerebral amyloid injection and oligomers, cognition was also improved. These findings emphasize the potential of the UPR as a strategy to alleviate AD features and maintain synaptic function.
Written by urgent.news from bioRxiv's reporting — not their text. Machine-written — may contain errors; check the original before relying on it.
