Journal
JOURNAL OF ALZHEIMERS DISEASE
Volume 38, Issue 2, Pages 269-280Publisher
IOS PRESS
DOI: 10.3233/JAD-122236
Keywords
Alzheimer's disease; anti-inflammation; long-form PDE4D; memory; PDE4
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Funding
- National Natural Science Foundation of China-Guangdong [U1032006]
- National Alliance for Research on Schizophrenia and Depression and National Institute on Aging [AG031687]
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Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-beta (A beta)-induced memory deficits. Here, we examined whether long-form PDE4D knockdown by lentiviral RNA construct containing a specific microRNA/miRNA-mir hairpin structure (4DmiRNA) reversed memory impairment caused by amyloid-beta(1-42) (A beta(42)) in mice using the Morris water maze (MWM) and novelty object recognition tests. Western blotting analysis was used to assess protein levels of cAMP response element-binding protein (CREB, unphosphorylated and phosphorylated [pCREB]), brain-derived neurotrophic factor (BDNF), interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), and nuclear factor-kappa B (NF-kappa B) to explore the neurochemical mechanisms. Aggregated A beta(42) (0.5 mu g/side) bilaterally infused in dentate gyrus decreased cAMP levels (p < 0.01) and produced memory deficits in the MWM (p < 0.01) and object recognition tests (p < 0.01). Microinfusions of lentiviruses resulted in downregulated expression of PDE4D4 and 4D5 proteins and reversed A beta(42)-induced cAMP decline (p < 0.05) and memory deficits. Treatment also concomitantly increased pCREB (p < 0.05) and BDNF (p < 0.01) and reduced IL-1 beta (p < 0.05), TNF-alpha (p < 0.01), and NF-kappa B (p65) (p < 0.05) in the hippocampus of A beta(42)-challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease.
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