ArticleAlzheimer's & dementia (New York, N. Y.)
A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease.
Article in Alzheimer's & dementia (New York, N. Y.). The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 5 papers.
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Who cites it
5 citing papers in PubMed.
- Lycium Barbarum Polysaccharides Alleviate Parkinson's Disease-Induced Neurodegeneration by Up-Regulating USP10 to Modulate Endoplasmic Reticulum Stress.Neurochemical research · 2026Article
- Systemic delivery of anti-sense oligonucleotide targeting α-synuclein for treatment in a mouse model of multiple system atrophy.Frontiers in aging neuroscience · 2026Article
- Targeting Non-coding RNAs in Neurodegeneration: Advances in Therapeutic RNA Modalities and Next-Gen Delivery Technologies.Current Alzheimer research · 2026Review
- Systemic delivery of anti-sense oligonucleotide targeting a-synuclein for the treatment of multiple system atrophy.Research square · 2025Article
- A splice-switching antisense oligonucleotide targeting APP reduces accumulation of α-synuclein in a mouse model of Parkinson's disease.Alzheimer's & dementia (New York, N. Y.)Article
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5 authors.
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Abstract
Introduction: Alzheimer's disease (AD) and Parkinson's disease (PD) are neurodegenerative disorders characterized by abnormal protein aggregation, with amyloid beta (Aβ) and α-synuclein (α-syn) as key pathological markers. Increasing evidence highlights a pathological interplay between Aβ and α-syn, exacerbating neurodegeneration in both AD and PD. In this study, we evaluated the effects of reducing amyloid precursor protein (APP) processing on α-syn pathology using a splice-switching oligonucleotide (SSO) targeting APP exon 15 in Thy1-α-syn transgenic (α-syn-tg) mice. Methods: α-syn-tg mice received systemic APP SSO treatment. Immunohistochemistry and immunoblotting assessed α-syn, phosphorylated α-syn (P-Syn), and APP C-terminal fragments (CTFs) in the cortex, hippocampus, and thalamus. Neuronal integrity in different brain regions were examined, and behavioral assessments evaluated cognitive and motor functions. Results: APP SSO treatment significantly reduced α-syn and P-Syn in the cortex, hippocampus, and thalamus while also reversing neuronal loss in the hippocampal CA3 region. Interestingly, α-syn-tg mice exhibited elevated levels of alternative APP CTFs, which were reduced by APP SSO treatment, implicating APP processing dysregulation in α-syn pathology. Although behavioral assessments revealed no significant impairments or improvements in female α-syn-tg mice. Discussion: Our findings demonstrate that targeting APP reduces α-syn pathology and rescues neuronal loss, supporting the therapeutic potential of APP modulation in synucleinopathies. While no behavioral changes were observed in transgenic mice, further research exploring different models and conditions may provide additional insights into the full range of therapeutic benefits. Future studies should optimize delivery methods and explore combination therapies to enhance outcomes in neurodegenerative diseases with overlapping proteinopathies. Highlights: APP-targeting SSO reduces α-syn and P-Syn in α-syn-tg mice.APP SSO lowers APP CTFs, linking APP processing to α-syn pathology.Neuronal loss in the hippocampal CA3 region is restored following APP SSO treatment.Behavioral assessments show no significant changes in female α-syn-tg mice.Findings support APP modulation as a potential strategy for synucleinopathies.
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