Biology subjects

Tadros, B.

Publications and source records attributed to Tadros, B..

2 recordsLinked to original sources

bioRxiv2026

The CHIP-LMO7-BAG5 complex controls tau clearance and yields repurposed and newly designed therapeutic candidates for Alzheimer's disease

Through cross-species genetic screens, we identified LMO7 as a regulator of tau levels in vivo. LMO7 bridges the E3 ligase CHIP and its inhibitory cochaperone BAG5, suppressing CHIPs ligase activity and limiting tau ubiquitination and degradation. Adult LMO7 knockdown enhances CHIP activity, reduces total and phosphorylated tau, attenuates gliosis, and rescues memory deficits in tauopathy mice. Guided by AlphaFold-derived structural models and AI-based virtual screening, we developed a CHIP-derived competing peptide and identified FDA-approved drugs that disrupt the complex. Viral delivery of the peptide or oral administration of Telmisartan or MPA-2, an optimized Mycophenolic acid derivative, reduced pathogenic tau without toxicity. These findings establish CHIP-LMO7-BAG5 complex as a druggable node in tau homeostasis, with implications for tauopathies including Alzheimers disease, and STUB1-associated ataxias.

neuroscience↗

bioRxiv2024

The big tau splice isoform resists Alzheimer's-related pathological changes

In Alzheimers disease (AD), the microtubule-binding protein tau becomes abnormally hyperphosphorylated and aggregated in selective brain regions such as the cortex and hippocampus1-3. However, other brain regions like the cerebellum and brain stem remain largely intact despite the universal expression of tau throughout the brain. Here, we found that an understudied splice isoform of tau termed "big tau" is significantly more abundant in the brain regions less vulnerable to tau pathology compared to tau pathology-vulnerable regions. We used various cellular and animal models to demonstrate that big tau possesses multiple properties that can resist AD-related pathological changes. Importantly, human AD patients show a higher expression level of pathology-resisting big tau in the cerebellum, the brain region spared from tau pathology. Our study examines the unique properties of big tau, expanding our current understanding of tau pathophysiology. Altogether, our data suggest that alternative splicing to favor big tau is a viable strategy to modulate tau pathology.

neuroscience↗