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

Adaptive-to-maladaptive IRE1α signaling as a driver of amyloidogenic APP processing in Alzheimer’s disease

Alzheimer’s disease (AD) is increasingly recognized as a disorder of proteostatic failure characterized by progressive disruption of neuronal protein quality control, culminating in amyloid-β (Aβ) accumulation and synaptic dysfunction. Chronic activation of the endoplasmic reticulum (ER) stress response represents one of the earliest molecular alterations detected in vulnerable brain regions and correlates with Braak progression before overt plaque deposition. Inositol-requiring enzyme 1 alpha (IRE1α), the most evolutionarily conserved sensor of the unfolded protein response (UPR), functions as a signaling rheostat within this network through its divergent downstream outputs. Under moderate proteotoxic stress, adaptive IRE1α- X-box binding protein 1 (XBP1) signaling supports ER proteostasis, preserves amyloid precursor protein (APP) quality control, and favors non-amyloidogenic α-secretase processing. Persistent ER stress, however, drives sustained IRE1α hyperactivation and engages regulated IRE1α-dependent decay (RIDD), which destabilizes microRNA (miRNA) networks that normally constrain beta-site APP-cleaving enzyme 1 (BACE1) expression, thereby favoring amyloidogenic APP processing. Accumulating evidence suggests that aging progressively compromises ER proteostatic capacity, thereby redirecting IRE1α signaling away from adaptive XBP1s-mediated responses toward a predominantly RIDD-driven state. This shift may reinforce a self-sustaining cycle in which accumulating Aβ further amplifies ER stress signaling. Here, we examine how dynamic changes in IRE1α signaling bias contribute to amyloidogenic progression in AD and consider whether selective modulation of adaptive versus maladaptive IRE1α outputs may offer stage-dependent therapeutic benefit.

SNCA-targeted transcriptional repression therapy alleviates pathological and behavioral perturbations in a Parkinson's disease mouse model

In vivo proof-of-concept for SNCA-targeted transcriptional repression therapy in a PD-mouse model is provided and its further preclinical development toward investigational new drug enablement is supported.

Development of a Novel AAV-Mediated microRNA Gene Therapy for Spatial Suppression of BACE1 to Improve Cognitive Function in Alzheimer’s Disease Model Mice

The beta-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a promising and rational target for Alzheimer’s disease (AD), but current clinical trials have been disappointing. Consequently, utilizing the intrinsic regulatory mechanisms of BACE1 during AD pathogenesis might provide valuable insights into the treatment of this devastating disease. In this study, we proposed a combination of AAV delivery and microRNA therapeutics targeting AD at its root by sustained and spatial inhibition of BACE1 with a single therapeutic injection. We demonstrate that upregulation of BACE1 is correlated with downregulation of miR-143-3p in the hippocampus of individuals with AD, and miR-143-3p can directly target BACE1 to inhibit Aβ generation. In the brains of 5×FAD model mice, BACE1 levels are found to be elevated with age in the cornu ammonis 1 (CA1) subfield of the hippocampus. AAV-mediated miR-143-3p restoration in the hippocampal CA1 subfield of AD mice can improve cognitive performance, attenuate BACE1 expression, reduce Aβ levels, induce microglia polarization toward the anti-inflammatory phenotype, modulate neural-related genes including Gal3, and promote synaptic functions. Collectively, the AAV-mediated microRNA gene therapy approach developed for spatial suppression of BACE1 can effectively enhance cognitive performance in AD model mice, offering an attractive therapeutic option for AD treatment with long-lasting efficacy.

In APP/PS-1 Transgenic Mice and Aβ-Induced P12 Cell Models, ADCYAP1 Inhibits Neuronal Apoptosis and Autophagy, Thereby Alleviating The Pathology of Alzheimer's Disease.

Oral administration of dibenzoylmethane (DBM) prevents cognitive decline in a C9ORF72-mediated FTD mouse model

Let-7d-5p improves mouse cognitive function by targeting bach1 in Alzheimer's disease.

BACKGROUND MicroRNAs (miRNAs) have emerged as critical modulators in Alzheimer's disease (AD) pathogenesis. The lethal-7 (let-7) family functions as key regulators of cell apoptosis, differentiation, and immune response. Herein, we explore the functions and underlying mechanisms of let-7d-5p in AD progression. METHODS Eight-month-old male APP/PS1 transgenic mice and wild-type C57BL/6 J mice were assigned to the model and control groups, respectively. Model mice received intrahippocampal injections of either a negative control adenovirus (Ad-NC) or a let-7d-5p overexpression adenovirus (Ad-let-7d-5p). The Morris water maze test was conducted to assess cognitive function. Hippocampal histopathological changes were evaluated using hematoxylin and eosin staining. Aβ deposition was detected via immunohistochemical staining. SH-SY5Y cells were transfected with let-7d-5p mimics prior to treatment with 10 μM Aβ1-42. Cell viability and apoptosis were examined using MTT assays and flow cytometry. The expression levels of let-7d-5p and bach1 were measured using RT-qPCR. Western blotting was conducted to evaluate bach1, Bcl-2, and cleaved caspase-3 protein levels. The binding relationship between let-7d-5p and bach1 was verified using luciferase reporter assays. RESULTS In vitro, Aβ1-42 treatment induced the downregulation of let-7d-5p and decrease of cell viability. However, overexpression of let-7d-5p significantly increased let-7d-5p level, enhanced cell viability and inhibited cell apoptosis of Aβ1-42-treated SH-SY5Y cells. Moreover, overexpression of let-7d-5p upregulated Bcl-2 protein levels and downregulated cleaved caspase-3 protein levels in Aβ1-42-treated SH-SY5Y cells. Furthermore, let-7d-5p overexpression ameliorated oxidative stress injury in Aβ1-42-treated SH-SY5Y cells. Importantly, bach1 upregulation counteracted the inhibitory effects of let-7d-5p overexpression on Aβ1-42-induced cellular injury. In vivo, let-7d-5p overexpression mitigated cognitive deficits of AD mice, as indicated by reduced escape latency and increased platform crossings. Additionally, let-7d-5p overexpression attenuated hippocampal histopathological changes and Aβ deposition in APP/PS1 mice. At the molecular level, let-7d-5p targeted bach1 3'UTR and repressed its mRNA and protein expression in vitro and in vivo. Rescue assays further validated that bach1 overexpression restored the protective effect of let-7d-5p on cognitive deficits and pathological injuries. CONCLUSION Let-7d-5p alleviates cognitive deficits in AD by inhibiting Aβ deposition and neuronal apoptosis through targeting bach1.