Intranasal delivery of 9-cis retinoic acid reduces beta-amyloid deposition via inhibiting astrocyte-mediated inflammation

Abstract

Alzheimer's disease (AD) is associated with the accumulation and deposition of a beta-amyloid (Αβ) peptide in the brain, resulting in increased neuroinflammation and synaptic dysfunction. Intranasal delivery of targeted drugs to the brain represents a noninvasive pathway that bypasses the blood-brain barrier and minimizes systemic exposure. The aim of this study was to evaluate the therapeutic effect of intranasally delivered 9-cis retinoic acid (RA) on the neuropathology of an AD mouse model. Herein, we observed dramatically decreased Αβ deposition in the brains of amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic mice (APP/PS1) treated intranasally with 9-cis RA for 4 weeks compared to that in the brains of vehicle-treated mice. Importantly, intranasal delivery of 9-cis RA suppressed Αβ-associated astrocyte activation and neuroinflammation and ultimately restored synaptic deficits in APP/PS1 transgenic mice. These results support the critical roles of Αβassociated neuroinflammation responses to synaptic deficits, particularly during the deposition of Αβ. Our findings provide strong evidence that intranasally delivered 9-cis RA attenuates neuronal dysfunction in an AD mouse model and is a promising therapeutic strategy for the prevention and treatment of AD.

Sodium Butyrate Protects N2a Cells against Aβ Toxicity In Vitro

“…Aβ is produced by the cleavage of APP by βand γ-secretase [29]. Previous studies have found that the overexpression of APP led to the increase of Aβ, which is closely related to the occurrence of AD [30][31][32][33][34][35][36][37][38][39][40][41][42][43]. It has been shown that BHBA can improve cognitive behavior in an Alzheimer's disease mouse model.…”

“…Cells. Aβ [25][26][27][28][29][30][31][32][33][34][35] (synthesized by Shanghai Sangon Biological Engineering Technology & Services Co.) was diluted in distilled water at a concentration of 16 mmol/L and was maintained at 37°C for 7 days to preage the peptide. N2a cells were divided into four groups: the control (NT) group, the NaB (2 mM) group, the Aβ 25-35 (40 μmol/L) treatment group, and the Aβ 25-35 (40 μmol/L) with NaB (2 mM) pretreatment group.…”

“…N2a cells were divided into four groups: the control (NT) group, the NaB (2 mM) group, the Aβ 25-35 (40 μmol/L) treatment group, and the Aβ 25-35 (40 μmol/L) with NaB (2 mM) pretreatment group. Cells were starved for 4 h and then pretreated with 2 mM NaB for 2 h before Aβ [25][26][27][28][29][30][31][32][33][34][35] was added. RNA or protein from N2a cells was extracted after 24 h. Each experiment was repeated three times.…”

“…After 24 hours, the complete medium was removed, and 200 μL prewarmed DMEM basal medium was added for cell starvation. Subsequently, NaB was added after 4 h to pretreat the cells, and after 2 h, Aβ [25][26][27][28][29][30][31][32][33][34][35] was added for stimulation. There were 5 replicates for each test group.…”

“…Cells were incubated with 0, 40, 60, or 80 μM Aβ 25-35 for 24 hours (n = 4, means ± SD, Student's t-test, * * P < 0:01, and * * * P < 0:001). (b) Effect of 2 mM NaB pretreatment on cell viability challenged by 40 μM Aβ 25-35 for 24 hours.Cells were starved for 4 h and then pretreated with 2 mM NaB for 2 h before Aβ[25][26][27][28][29][30][31][32][33][34][35] was added. Cell viability was analyzed by the CCK-8 assay (n = 4, means ± SD, Student's t-test, * * P < 0:01, and * * * P < 0:001).…”