Targeting MicroRNA-485-3p Blocks Alzheimer's Disease Progression

• Published in: International journal of molecular sciences 2021-12, Vol.22 (23), p.13136
• Main Authors: Koh, Han Seok, Lee, SangJoon, Lee, Hyo Jin, Min, Jae-Woong, Iwatsubo, Takeshi, Teunissen, Charlotte E, Cho, Hyun-Jeong, Ryu, Jin-Hyeob
• Format: Article
• Language: English
• Subjects: Advertising executives; Alzheimer Disease - diagnostic imaging; Alzheimer Disease - drug therapy; Alzheimer Disease - etiology; Alzheimer Disease - genetics; Alzheimer's disease; Animals; Antisense oligonucleotides; Apoptosis; Brain; Case-Control Studies; CD36 antigen; Cerebrospinal fluid; Cognitive ability; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - genetics; Cytokines; Cytokines - metabolism; Dementia disorders; Development and progression; Disease Models, Animal; Disks Large Homolog 4 Protein - metabolism; Drug approval; Genetic engineering; Humans; IL-1β; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; MicroRNA; MicroRNAs; MicroRNAs - cerebrospinal fluid; MicroRNAs - metabolism; miRNA; Molecular Targeted Therapy - methods; Motor Neurons - metabolism; Motor Neurons - pathology; Neurodegeneration; neuroinflammation; Neuropathology; Oligonucleotides, Antisense - pharmacology; Pathogenesis; Pathology; Pathophysiology; Phagocytosis; Phagocytosis - drug effects; Phagocytosis - genetics; Positron-Emission Tomography; Proteins; tau; Tau protein; tau Proteins - metabolism; TNF-α; Transgenic animals; Transgenic mice; Tumor necrosis factor-α; β-amyloid
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms222313136

Alzheimer's disease (AD) is a form of dementia characterized by progressive memory decline and cognitive dysfunction. With only one FDA-approved therapy, effective treatment strategies for AD are urgently needed. In this study, we found that microRNA-485-3p (miR-485-3p) was overexpressed in the brain tissues, cerebrospinal fluid, and plasma of patients with AD, and its antisense oligonucleotide (ASO) reduced Aβ plaque accumulation, tau pathology development, neuroinflammation, and cognitive decline in a transgenic mouse model of AD. Mechanistically, miR-485-3p ASO enhanced Aβ clearance via CD36-mediated phagocytosis of Aβ in vitro and in vivo. Furthermore, miR-485-3p ASO administration reduced apoptosis, thereby effectively decreasing truncated tau levels. Moreover, miR-485-3p ASO treatment reduced secretion of proinflammatory cytokines, including IL-1β and TNF-α, and eventually relieved cognitive impairment. Collectively, our findings suggest that miR-485-3p is a useful biomarker of the inflammatory pathophysiology of AD and that miR-485-3p ASO represents a potential therapeutic candidate for managing AD pathology and cognitive decline.