Abstract
Phosphodiesterase 4 (PDE4)-dependent cAMP signaling plays a crucial role in cognitive impairment associated with Alzheimer’s disease (AD). However, whether inhibition of PDE4 subtypes or their splice variants in the prefrontal cortex positively regulates synaptic plasticity and antioxidative stress, and reverses β-amyloid 1–42 (Aβ1–42, Aβ42)-induced cognitive impairment still need to be clarified. The present study determined whether and how PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex reversed Aβ1–42-induced cognitive impairment in behavioral, neurochemical, and molecular biology assays. The results suggested that PDE4D knockdown increased time to explore the novel object and decreased latency to leave the platform in novel object recognition and step-down passive avoidance tests. Further study suggested that PDE4D knockdown decreased the number of working memory errors in the eight-arm maze test. These effects were prevented by PKA inhibitor H89. The subsequent experiment suggested that inhibition of PDE4D in the prefrontal cortex rescued the long-term potentiation (LTP) and synaptic proteins’ expression; it also increased antioxidant response by increasing superoxide dismutase (SOD) and decreasing malondialdehyde (MDA) levels. PDE4D knockdown also increased phosphorylated cAMP response element-binding protein (pCREB), brain-derived neurotrophic factor (BNDF), and anti-apoptotic proteins’ expression, i.e., the ratio of Bcl-2/Bax, and decreased caspase-3 level in the prefrontal cortex. These findings extend the previous findings and support the hypothesis that RNA interference-mediated PDE4D knockdown in the prefrontal cortex ameliorated memory loss associated with synaptic failure in an AD mouse model by its antioxidant, anti-apoptotic, and neuroprotective properties.
Highlights
MATERIALS AND METHODSAlzheimer’s disease (AD), the most common degenerative and irreversible brain disease causing dementia in the elderly, is characterized by progressive cognitive deterioration and memory loss (Selkoe, 2001)
The present study suggested that PDE4D knockdown by microinjection of lenti-PDE4D-miRNA into the prefrontal cortex protects Aβ1–42-induced cognitive and memory impairment in the novel object recognition, step-down passive avoidance, and eight-arm maze tests
The results showed that PDE4D knockdown prevented neurons against oligomeric Aβ1–42 neurotoxicity, as demonstrated by preservation of long-term potentiation (LTP) expression and increased synapse-associated protein expression, e.g., synaptophysin and PSD95, in the prefrontal cortex
Summary
MATERIALS AND METHODSAlzheimer’s disease (AD), the most common degenerative and irreversible brain disease causing dementia in the elderly, is characterized by progressive cognitive deterioration and memory loss (Selkoe, 2001). To evaluate the therapeutic effects of PDE4D deficiency on the cognitive and memory impairment in Aβ1–42-treated mice, behavioral tests such as novel object recognition (NOR) were conducted.
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