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Memory enhancement induced by PDE2 knockdown in an Alzheimer's disease model of mice
Author(s) -
Xu Ying,
Chen Zhuoyou,
Pan Jianchun,
Zhang HanTing,
O'Donnell James M.
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.707.6
Subject(s) - hippocampus , neuroinflammation , morris water navigation task , medicine , memory impairment , gene knockdown , endocrinology , inflammation , neuroscience , psychology , apoptosis , chemistry , cognition , biochemistry
PDE2 is the most prevalent of all PDEs expressed in the hippocampus and frontal cortex, regions involved in cognition and especially vulnerable to damage at early stages of AD. Studies suggest that beta‐amyloid 1‐42 (Abeta 1‐42) has a detrimental effect on memory performance that induces the initial and major symptom of Alzheimer's disease (AD) via inhibition of both cAMP/cGMP‐dependent pathway. Microinfusion of Abeta in animal models leads to Abeta deposition, inflammation, neuroapoptosis and memory impairment. However, whether phosphodiesterase 2‐dependent cAMP and/or cGMP pathway is involved in the neuroinflammation and apoptosis that lead to the progression of AD are unclear. The present study found that intraventricular infusion of Abeta1‐42 into bilateral CA1 subregions led to impairment of learning and memory, as evidenced by an increased latency to find the platform and decreased number of platform crossing in the probe trial of the water maze task and decreased 24‐h retention in the step‐down passive avoidance test. The time period that induced the behavioral abnormalities lasted from 2 weeks to 6 months, with the maximal abnormality at 4 months after microinfusion with Abeta 1‐42. These behavioral abnormalities were blocked by microinfusion with lenti‐PDE2‐miRNA at 5′10 6 tu/ml. Four months after microinfusion with Abeta were also found to increase in the expression of IL‐6, IL‐10, IL‐17 and Bax. The decreased expression of BCl‐2, PKA, PKG and brain‐derived neurotrophic factor (BDNF) in the hippocampus were also significant in these Abeta1‐42‐treated mice. These effects were reversed by treatment with lenti‐PDE2‐miRNA at 5′10 6 tu/ml. These findings suggest that inhibition of PDE2 would reverse Abeta‐induced learning and memory deficits at least in part by its regulation of neuroinflammatory and apoptotic processes, which are involved in cAMP/cGMP‐BDNF signaling. Support or Funding Information This study was supported by 2014–2015 American Association of Colleges of Pharmacy New Investigator Award and Changzhou Sci&Tech Program Grant (No. CJ20130023).