To investigate the regulatory effect of miR-202-5p on proprotein convertase subtilisin / kexin type 9 (PCSK9) and its effect on neuronal damage in Alzheimer’s disease (AD). Methods SD rats were injected with amyloid β(Aβ) 1-42 into the lateral ventricle to establish an AD model and were randomly divided into normal control,model, ago-miR-202-5p, ago-NC and PCSK9 inhibitor groups. After the administration, spatial memory and learning ability tests were performed. Nissl staining was used to detect neuronal changes in cerebral cortex tissue. Neuron nuclear antigen (NeuN) immunofluorescence was used to detect the number of neurons in cerebral cortex tissue. ELISAs were used to measure the levels of PCSK9, β-amyloid 42 ( Aβ42 ), β-amyloid 40 ( Aβ40 ), and total cholesterol ( TC) in cerebrospinal fluid and tumor necrosis factor-α (TNF-α), interleukin-1β ( IL-1β), and phosphorylated Tau protein (Ptau) in cerebral cortex tissues. qRT-PCR was used to measure miR-202-5p expression in cerebral cortex tissue. Western blot was used to detect PCSK9, LDL receptor-related protein 1 (LRP-1), apolipoprotein E (ApoE), amyloid precursor protein (APP), and β site APP shearing enzyme 1 (BACE1) protein expression in cerebral cortex tissue. Dual luciferase assays were used to verify targeted regulation of PCSK9 by miR-202-5p. An in vitro AD cell model was established and cotransfected with miR-202-5p mimic and an PCSK9 overexpression vector ( pcDNA-PCSK9), and then reversal of the effect of PCSK9 overexpression on miR-202-5p was explored. Results Compared with the normal control group, the spatial memory and learning ability of rats in the model group were decreased, cerebral cortex neuron damage and number were decreased, PCSK9, Aβ42, Aβ40 and cholesterol levels in the cerebrospinal fluid were increased, P-tau and inflammatory factors levels in the cerebral cortex were increased, miR-202-5p expression was decreased, activity of the PCSK9 activation-mediated BACE1-APP-Aβ production pathway was increased, and LRP-1-ApoE-mediated promotion of cholesterol uptake and Aβ clearance activity were decreased (P<0. 05). miR-202-5p overexpression or PCSK9 inhibitor treatment suppressed neuronal damage caused by Aβ42 and Aβ40 deposition, reduced inflammatory factor secretion, inhibited BACE1, APP and Aβ production mediated by PCSK9 activation, and increased LRP-1-ApoE-mediated promotion of cholesterol uptake and Aβ clearance ( P < 0. 05). There was a targeted regulatory effect between miR-202-5p and PCSK9. Upregulation of PCSK9 partially attenuated the anti-AD effect of miR-202-5p overexpression ( P < 0. 05 ). Conclusions miR-202-5p overexpression inhibits Aβ production by suppressing PCSK9 activation and promoting LRP-1-ApoE-mediated cholesterol uptake and Aβ clearance, thereby exerting anti-AD nerve injury effect.