阿尔茨海默病(AD)患者脑中蛋白磷酸酯酶PP2A活性降低和糖原合酶激酶3（GSK-3）活性升高是导致tau蛋白过度磷酸化形成细胞内神经原纤维缠结(NFTs)的主要原因，但其活性改变的机制尚未清楚。研究发现酸性核磷蛋白32（pp32）在AD患者脑内异常高表达，并与过度磷酸化的tau共定位。申请者近期细胞实验发现：下调pp32不但可提高PP2A活性，同时抑制GSK-3活性，为此，我们提出假说：AD患者脑内异常增高的pp32可能通过调节PP2A、GSK-3活性，参与了tau蛋白的病理过程。为验证这一假说，我们拟在N2a、小鼠原代海马神经元和Htau转基因鼠上，采用RNA干扰技术等，从分子、细胞、转基因动物水平探讨和明确下调pp32对AD样tau病理及认知障碍的逆转作用及机制。本研究成果不仅为阐明AD患者脑内PP2A和GSK-3活性异常分子机制具有重要意义，更为预防和治疗AD提供了有效干预靶点。

Protein phosphatase-2A (PP2A) deficiency and glycogen synthase kinase-3 (GSK-3) increase are the primary causes of the abnormal hyperphosphorylation of tau, which composes neurofibrillary tangles (NFTs) in Alzheimer’s disease (AD) brain. However, the mechanism leading to the abnormal changes of PP2A and GSK-3 is not fully characterized. Recent studies have demonstrated that the increased phosphoprotein 32 (pp32) colocalized with the hyperphosphorylated tau in the AD brains. We recently observed that silencing pp32 by Lenti-shRNA interference could induce the activation of PP2A and inactivation of GSK-3, which may reverse hyperphosphorylated tau. Here, we suppose that the increased pp32 play a critical role in tau pathologies and cognitive deficits through abnormal regulations of PP2A and GSK-3 in AD. To confirm this hypothesis, we will investigate the effects and mechanisms of silencing pp32 on PP2A, GSK-3β and tau pathologies in vitro. In addition, we also will explore the effects of silencing pp32 on cognitive deficits in Htau mice. Our data would reveal that targeting pp32 can efficiently rescue tau pathologies and cognitive impairments in Htau mice, suggesting that pp32 could be a promising target for potential AD therapies.