Microglia CREB-Phosphorylation Mediates Amyloid-β-Induced Neuronal Toxicity

Article type: Research Article

Authors: Gao, Yuan^a | Liu, En-Jie^a | Wang, Wei-Jin^a | Wang, Ya-Li^a | Li, Xiao-Guang^a | Wang, Xin^a | Li, Shi-Hong^a | Zhang, Shu-Juan^a | Li, Meng-Zhu^a | Zhou, Qiu-Zhi^a | Long, Xiao-Bing^b | Zhang, Hua-Qiu^{b; *} | Wang, Jian-Zhi^{a; c; *}

Affiliations: [a] Pathophysiology Department, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China | [b] Neurosurgery Department, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Hospital, Tongji Medical College, Wuhan, China | [c] Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China

Correspondence: [*] Correspondence to: Jian-Zhi Wang, Pathophysiology Department, School of Basic Medicine, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China. Tel./Fax: +86 27 83693883; E-mail: wangjz@mail.hust.edu.cn and Hua-Qiu Zhang, Neurosurgery Department, Key Laboratory of Ministry of Education of China for Neurological Disorders, Tongji Hospital, Tongji Medical College, Wuhan 430030, China. E-mail: Zhanghq_04@yahoo.com.

Abstract: Extracellular accumulation of amyloid-β (Aβ) forming senile plaques is one of the hallmark pathologies in Alzheimer’s disease (AD), while the mechanisms underlying the neuronal toxic effect of Aβ are not fully understood. Here, we found that intracerebroventricular infusion of the aged Aβ42 in mice only induces memory deficit at 24 h but not at 7 days. Interestingly, a remarkably increased CREB (cAMP response element-binding protein) Ser133-phosphorylation (pS133-CREB) with microglial activation was detected at 24 h but not at 7 days after Aβ infusion. Aβ treatment for 24 h increased pS133-CREB level in microglia of the hippocampal non-granular cell layers with remarkably decreased pS133-CREB immunoreactivity in neurons of the hippocampal granular cell layers, including CA1, CA3, and DG subsets. Inhibition of microglia activation by minocycline or CREB phosphorylation by H89, an inhibitor of protein kinase A (PKA), abolished Aβ-induced microglia CREB hyperphosphorylation with restoration of neuronal function and attenuation of inflammatory response, i.e., reduced levels of interleukin-6 (IL6) and pCREB binding of matrix metalloproteinase-9 (MMP9) DNA. Finally, treatment of the primary hippocampal neurons with Aβ-potentiated microglia media decreased neuronal GluN1 and GluA2 levels, while simultaneous inhibition of PKA restored the levels. These novel findings reveal that intracerebroventricular infusion of Aβ only induces transient memory deficit in mice and the molecular mechanisms involve a stimulated microglial CREB phosphorylation.

Keywords: Alzheimer’s disease, amyloid-β, cAMP response element-binding protein, microglia, protein kinase A

DOI: 10.3233/JAD-180286

Journal: Journal of Alzheimer's Disease, vol. 66, no. 1, pp. 333-345, 2018