RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-β42-induced memory deficits in mice.
Phosphodiesterase-4 (PDE4) inhibitors enhance memory, increase hippocampal neurogenesis, and reverse amyloid-β (Aβ)-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-β1-42 (Aβ42) 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-1β (IL-1β), tumor necrosis factor-α (TNF-α), and nuclear factor-κB (NF-κB) to explore the neurochemical mechanisms. Aggregated Aβ42 (0.5 μg/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 Aβ42-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-1β (p < 0.05), TNF-α (p < 0.01), and NF-κB (p65) (p < 0.05) in the hippocampus of Aβ42-challenged mice. These results suggest that long-form PDE4D knockdown may offer a promising treatment for memory loss associated with Alzheimer's disease.
Department of Pharmacology, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, China Departments of Behavioral Medicine & Psychiatry and Physiology & Pharmacology, West Virginia University Health Sciences Center, Morgantown, WV, USA.
Cong
C
Zhang
Yufang
Y
Cheng
Haitao
H
Wang
Chuang
C
Wang
Steven P
SP
Wilson
Jiangping
J
Xu
Han-Ting
HT
Zhang
D016229:Amyloid beta-Peptides / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000172:deficiency* / Q000235:genetics; D004195:Disease Models, Animal; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000139:chemically induced / Q000201:enzymology / Q000628:therapy; D051379:Mice; D008813:Mice, Inbred ICR; D010446:Peptide Fragments / Q000494:pharmacology*; D034622:RNA Interference / Q000502:physiology*; D011930:Reaction Time / Q000187:drug effects / Q000235:genetics; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology
D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42); D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C531980:PDE4D protein, mouse
Alzheimer's disease; PDE4; anti-inflammation; long-form PDE4D; memory