Primary neuronal culture as a source for direct reprogramming of the cells

Abstract

Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive cognitive decline. According to the critical role of inflammation in pathogenesis of AD and memory deficits, a cytokine with anti-inflammatory properties like interferon beta (IFNβ), currently used to slow down disease progression and protect against cognitive disturbance in multiple sclerosis, might be also an effective treatment in AD condition. This study aimed to answer if the intranasal (IN) administration of IFNβ with high CNS accessibility can alleviate memory impairments in a mutant APP-overexpressing rat model of AD through modulating inflammatory responses. To address this question, the lentiviruses carrying human amyloid protein precursor (APP) with the Swedish and Indiana mutations (LV-APPSw/Ind) were bilaterally injected in the hippocampus of adult rats. Memory performance was assessed using passive avoidance task on days 49 and 50 after injection. Moreover, the expression of glial markers (GFAP and Iba1) and pro-inflammatory (TNF-α, IL-1β and IL-6) and anti-inflammatory cytokines (IL-10) were evaluated in the hippocampus. Therapeutic effects of IN-administered IFNβ (0.5 μg/kg and 1 μg/kg doses, every other day from day 23 to 50 after lentivirus injection) were examined in the LV-APP-injected rats. Our results showed that over-expression of mutant human APP gene in the hippocampus led to learning and memory deficits concomitant with gliosis and pro-inflammatory responses. Interestingly, treatment of AD-modeled rats with IFNβ ameliorated memory impairments possibly through suppressing gliosis and shifting from pro-inflammatory toward anti-inflammatory status, suggesting that IFNβ may be a promising therapeutic agent to improve cognitive functions and modulate inflammatory responses in an AD-like neurodegenerative context.