Soler Helena, Dorca-Arévalo Jonatan, González Marta, Rubio Sara Esmeralda, Ávila Jesús, Soriano Eduardo, Pascual Marta
Department of Cell Biology, Parc Científic de Barcelona and Institute of Neurosciences, University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain.
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED, ISCIII), Madrid, Spain; Centro de Biología Molecular Severo Ochoa (CSIC-UAM), Neurobiology Laboratory, Madrid, Spain.
Neurobiol Aging. 2017 Jan;49:40-51. doi: 10.1016/j.neurobiolaging.2016.09.006. Epub 2016 Sep 15.
Alzheimer's disease (AD), the most common cause of dementia nowadays, has been linked to alterations in the septohippocampal pathway (SHP), among other circuits in the brain. In fact, the GABAergic component of the SHP, which controls hippocampal rhythmic activity crucial for learning and memory, is altered in the J20 mouse model of AD-a model that mimics the amyloid pathology of this disease. However, AD is characterized by another pathophysiological hallmark: the hyperphosphorylation and aggregation of the microtubule-associated protein Tau. To evaluate whether tauopathies alter the GABAergic SHP, we analyzed transgenic mice expressing human mutated Tau (mutations G272V, P301L, and R406W, VLW transgenic strain). We show that pyramidal neurons, mossy cells, and some parvalbumin (PARV)-positive hippocampal interneurons in 2- and 8-month-old (mo) VLW mice accumulate phosphorylated forms of Tau (P-Tau). By tract-tracing studies of the GABAergic SHP, we describe early-onset deterioration of GABAergic septohippocampal (SH) innervation on PARV-positive interneurons in 2-mo VLW mice. In 8-mo animals, this alteration was more severe and affected mainly P-Tau-accumulating PARV-positive interneurons. No major loss of GABAergic SHP neurons or PARV-positive hippocampal interneurons was observed, thereby indicating that this decline is not caused by neuronal loss but by the reduced number and complexity of GABAergic SHP axon terminals. The decrease in GABAergic SHP described in this study, targeted onto the PARV-positive/P-Tau-accumulating inhibitory neurons in the hippocampus, establishes a cellular correlation with the dysfunctions in rhythmic neuronal activity and excitation levels in the hippocampus. These dysfunctions are associated with the VLW transgenic strain in particular and with AD human pathology in general. These data, together with our previous results in the J20 mouse model, indicate that the GABAergic SHP is impaired in response to both amyloid-β and P-Tau accumulation. We propose that alterations in the GABAergic SHP, together with a dysfunction of P-Tau-accumulating PARV-positive neurons, contribute to the cognitive deficits and altered patterns of hippocampal activity present in tauopathies, including AD.
阿尔茨海默病（AD）是当今痴呆症最常见的病因，与海马隔区通路（SHP）以及大脑中的其他神经回路改变有关。事实上，在模拟该疾病淀粉样病理的J20小鼠模型中，控制对学习和记忆至关重要的海马节律活动的SHP的GABA能成分发生了改变。然而，AD的另一个病理生理特征是微管相关蛋白Tau的过度磷酸化和聚集。为了评估tau蛋白病是否会改变GABA能SHP，我们分析了表达人突变Tau（G272V、P301L和R406W突变，VLW转基因品系）的转基因小鼠。我们发现，2个月和8个月大的VLW小鼠的锥体神经元、苔藓细胞和一些小白蛋白（PARV）阳性海马中间神经元积累了磷酸化形式的Tau（P-Tau）。通过对GABA能SHP的束路追踪研究，我们描述了2个月大的VLW小鼠中PARV阳性中间神经元上GABA能海马隔区（SH）神经支配的早发性退化。在8个月大的动物中，这种改变更为严重，主要影响积累P-Tau的PARV阳性中间神经元。未观察到GABA能SHP神经元或PARV阳性海马中间神经元的大量丧失，从而表明这种下降不是由神经元丧失引起的，而是由GABA能SHP轴突终末数量和复杂性的降低引起的。本研究中描述的GABA能SHP的减少，靶向海马中PARV阳性/P-Tau积累的抑制性神经元，与海马中节律性神经元活动和兴奋水平的功能障碍建立了细胞相关性。这些功能障碍尤其与VLW转基因品系相关，总体上与AD人类病理相关。这些数据，连同我们之前在J20小鼠模型中的结果，表明GABA能SHP因淀粉样β蛋白和P-Tau积累而受损。我们提出，GABA能SHP的改变，连同积累P-Tau的PARV阳性神经元的功能障碍，导致tau蛋白病（包括AD）中存在的认知缺陷和海马活动模式改变。
