Ubhi Kiren, Rockenstein Edward, Doppler Edith, Mante Michael, Adame Anthony, Patrick Christina, Trejo Margarita, Crews Leslie, Paulino Amy, Moessler Herbert, Masliah Eliezer
Department of Neurosciences, School of Medicine, University of California, La Jolla, San Diego, CA 92093-0624, USA.
Acta Neuropathol. 2009 Jun;117(6):699-712. doi: 10.1007/s00401-009-0505-4. Epub 2009 Feb 28.
Alzheimer's disease (AD) continues to be the most common cause of cognitive and motor alterations in the aging population. Accumulation of amyloid beta (Abeta)-protein oligomers and the microtubule associated protein-TAU might be responsible for the neurological damage. We have previously shown that Cerebrolysin (CBL) reduces the synaptic and behavioral deficits in amyloid precursor protein (APP) transgenic (tg) mice by decreasing APP phosphorylation via modulation of glycogen synthase kinase-3beta (GSK3beta) and cyclin-dependent kinase-5 (CDK5) activity. These kinases also regulate TAU phosphorylation and are involved in promoting neurofibrillary pathology. In order to investigate the neuroprotective effects of CBL on TAU pathology, a new model for neurofibrillary alterations was developed using somatic gene transfer with adeno-associated virus (AAV2)-mutant (mut) TAU (P301L). The Thy1-APP tg mice (3 m/o) received bilateral injections of AAV2-mutTAU or AAV2-GFP, into the hippocampus. After 3 months, compared to non-tg controls, in APP tg mice intra-hippocampal injections with AAV2-mutTAU resulted in localized increased accumulation of phosphorylated TAU and neurodegeneration. Compared with vehicle controls, treatment with CBL in APP tg injected with AAV2-mutTAU resulted in a significant decrease in the levels of TAU phosphorylation at critical sites dependent on GSK3beta and CDK5 activity. This was accompanied by amelioration of the neurodegenerative alterations in the hippocampus. This study supports the concept that the neuroprotective effects of CBL may involve the reduction of TAU phosphorylation by regulating kinase activity.
阿尔茨海默病（AD）仍然是老年人群认知和运动功能改变的最常见原因。淀粉样β蛋白（Aβ）寡聚体和微管相关蛋白TAU的积累可能是神经损伤的原因。我们之前已经表明，脑活素（CBL）通过调节糖原合酶激酶-3β（GSK3β）和细胞周期蛋白依赖性激酶-5（CDK5）的活性来降低淀粉样前体蛋白（APP）转基因（tg）小鼠的突触和行为缺陷。这些激酶还调节TAU磷酸化，并参与促进神经原纤维病理改变。为了研究CBL对TAU病理的神经保护作用，我们利用腺相关病毒（AAV2）-突变型（mut）TAU（P301L）的体细胞基因转移建立了一种新的神经原纤维改变模型。将Thy1-APP tg小鼠（3个月龄）双侧海马注射AAV2-mutTAU或AAV2-绿色荧光蛋白（GFP）。3个月后，与非转基因对照相比，在APP tg小鼠海马内注射AAV2-mutTAU导致磷酸化TAU的局部积累增加和神经退行性变。与载体对照相比，在注射AAV2-mutTAU的APP tg小鼠中用CBL治疗导致依赖于GSK3β和CDK5活性的关键位点TAU磷酸化水平显著降低。这伴随着海马神经退行性改变的改善。本研究支持这样的观点，即CBL的神经保护作用可能涉及通过调节激酶活性来减少TAU磷酸化。
