Chronic brain hypoperfusion (CBH) is caused by decreased blood flow to the brain and is considered a key predictor of neurodegenerative diseases such as Alzheimer’s disease and vascular dementia. CBH can indirectly lead to cognitive decline by altering the expression of proteins at synapses, where neurons communicate through neurotransmitters released from presynaptic vesicles and recognized by postsynaptic receptors. Researchers recently linked this decline to the microRNA miRNA-153. FM 1-43 experiments showed that overexpression of miRNA-153 impairs presynaptic vesicle release, and in a CBH rat model, overexpression of miRNA-153 decreased the expression of multiple proteins involved in vesicle release. Conversely, knockdown of miRNA-153 rescued these synaptic defects and attenuated cognitive decline in the rat model. These findings deepen our understanding of the role of miRNA-153 in CBH-induced brain dysfunction, and could lead to new drug targets for preventing and treating Alzheimer’s and vascular dementia.