2026-05-26 カリフォルニア大学サンディエゴ校（UCSD）
＜関連情報＞
- https://today.ucsd.edu/story/experimental-gene-therapy-shields-brain-from-toxic-protein-damage
- https://alz-journals.onlinelibrary.wiley.com/doi/10.1002/alz.71450
シナプシン促進性カベオリン-1過剰発現の全身投与は、TDP-43誘発性の病理学的認知機能低下および神経変性変化を改善する Systemic delivery of synapsin-promoted caveolin-1 overexpression ameliorates pathological TDP-43–induced cognitive decline and neurodegenerative changes
Dongsheng Wang, Vinh Ta, Hongxia Wang, Jerica Ju, Chun Wang, Christine Chehadeh, Albertina Torreblanca-Zanca, Yessenia Magaña, Michael J. Castle, Shanshan Wang, Brian P. Head
Alzheimer’s & Dementia Published: 26 May 2026
DOI:https://doi.org/10.1002/alz.71450
Abstract
INTRODUCTION
Transactive response DNA-binding protein 43 (TDP-43) proteinopathy is associated with frontotemporal dementia and Alzheimer’s disease (AD). We previously demonstrated that synapsin-promoted caveolin-1 (SynCav1) preserves cognitive function in the mouse model of AD. This study investigated the therapeutic potential of SynCav1 in a mouse model of TDP-43 proteinopathy.
METHODS
AAV-PhP.eB-SynCav1 was delivered systemically to the TDP-43A315T mouse, followed by cognitive evaluation and biochemical and ultrastructural analysis of brain tissue.
RESULTS
SynCav1 exerted robust neuroprotective effects on cognition. Mechanistically, pathological TDP-43 mislocalized to membrane lipid rafts (MLRs), resulting in decreased MLR-associated GluN2A expression and degenerative changes in neuronal ultrastructure. In contrast, SynCav1 delivery alleviated TDP-43 mislocalization on MLRs, stabilized MLR-associated GluN2A expression, and preserved synaptic ultrastructure. Furthermore, SynCav1 mitigated TDP-43–induced mitochondrial hyper-fragmentation and excessive mitochondrial fission signaling.
DISCUSSION
These findings establish a novel link between TDP-43 proteinopathy and MLR instability, supporting SynCav1 as a “neuron-centric” candidate for treating TDP-43–related neurodegeneration.
Highlights
- Systemic AAV-PhP.eB–synapsin-promoted caveolin-1 (SynCav1) gene therapy efficiently crosses the blood–brain barrier and achieves central nervous system–wide neuroprotection.
- SynCav1 prevents learning and memory deficits in a mouse model of transactive response DNA-binding protein 43 (TDP-43) proteinopathy.
- Mutant TDP-43 proteins mislocalize to the membrane lipid rafts (MLRs) and induce loss of MLR-associated GluN2A receptor expression.
- SynCav1 preserves MLR-associated GluN2A expression and maintains excitatory synaptic ultrastructure and total vesicle number.
- SynCav1 mitigates phosphorylation of TDP-43 in the frontal cortex and preserves axonal myelin sheath integrity.
- SynCav1 augments caveolin-1 trafficking to the mitochondria and alleviates mitochondrial hyper-fragmentation by suppressing excessive mitochondrial fission signaling (phosphorylated dynamin-related protein 1, phosphorylated mitochondrial fission factor).
- SynCav1 offers a novel neuron-centric therapeutic strategy for TDP-43–linked neurodegeneration.
