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

Abstract

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.

Six genetically linked mutations in the CD36 gene significantly delay the onset of Alzheimer's disease

“…Results of very recent animal studies expand this diversity by demonstrating CD36 involvement in an AD-associated blood brain barrier disruption 70 , and in an interaction with the nerve growth regulator1 (NEGR1) 71 , i.e., in AD-related mechanisms distinct from those active in the amyloid/tau pathways and/or the amyloid-β phagocytosis by microglia. Conversely, another recent report implicated a DNA transcription regulator microRNA (miRNA-485-3p) in the CD36 mediated amyloid-β phagocytosis and even suggested it as a potential AD therapeutic agent 72 . Yet our in silico analyses found no potential interplay of miRNA-485-3p and any of the five AD-related polymorphisms identified by the present whole-gene sequencing study (Table 5 ), thus implying that not all AD-related regulatory sites in CD36 gene must necessarily be located next to (and be influenced by) AD-related SNP’s.…”

NcRNAs: A synergistically antiapoptosis therapeutic tool in Alzheimer's disease

“…MiR‐425‐5p‐HSPB8 axis induced cell apoptosis and promoted Tau phosphorylation in AD, and might act as a new therapeutic target for AD treatment 137 . In addition, miR‐485‐3p was overexpressed in the brain tissues, CSF, and plasma of patients with AD 138 . CD36 was a direct target of miR‐485‐3p 138 .…”

“…CD36 was a direct target of miR‐485‐3p 138 . MiR‐485‐3p‐CD36 axis weakened the phagocytosis of Aβ in vitro and in vivo and might promote cell apoptosis in AD 138 . Table S3 summarizes all the abnormally expressed and cell apoptosis‐related miRNAs in AD patients 132–160 .…”

MicroRNAs in Learning and Memory and Their Impact on Alzheimer’s Disease

“…AD is the most common type of dementia in the elderly, and extensive studies on AD have revealed altered miRNA expression profiles. Many miRNAs are severely dysregulated in the brains of AD patients, including miR-34c (upregulated [ 24 ]), miR-124-3p (downregulated [ 72 , 73 ]; upregulated [ 51 ]), miR-126a-3p (downregulated [ 72 , 74 ]), miR-128b (upregulated [ 53 ]), miR-132/-212 (downregulated [ 74 , 75 , 76 ]), miR-146a (upregulated [ 72 , 77 ]), miR-188-5p (downregulated [ 61 ]), miR-195 (downregulated [ 64 ]), miR-206 (upregulated [ 67 ]), miR-338-5p (downregulated [ 68 ]), and miR-485-5p (downregulated [ 75 ]) vs. miR-485-3p (upregulated [ 71 ]). Figure 1 shows growing evidence that miRNA dysregulation correlates with some major and important aspects of AD pathology that have been proven to cause cognitive impairment in animal models.…”

“…Mechanistically, miR-485-5p directly targeted PACS1, a hallmark of AD, in pericytes [ 70 ]. As miR-485-5p was downregulated in the prefrontal cortex of patients with late-onset AD [ 75 ], miR-485-3p was overexpressed in the brain tissues, CSF, and plasma of patients with AD [ 71 ]. Furthermore, the knockdown of miR-485-3p enhanced Aβ clearance via CD36-mediated phagocytosis, decreased truncated tau levels, and reduced the secretion of proinflammatory cytokines, including interleukin-1β and tumor necrosis factor-α, eventually alleviating cognitive decline in 5xFAD transgenic mice.…”