Schaeffer Evelin L, Catanozi Sergio, West Mark J, Gattaz Wagner F
Laboratory of Neuroscience (LIM-27), Institute of Psychiatry of Clinical Hospital, Faculty of Medicine, University of Sao Paulo, Rua Dr. Ovídio Pires de Campos 785, 05403-010 Sao Paulo, SP, Brazil; Institute of Biomedicine, University of Aarhus, Wilhelm Meyers Allé 3, Building 1234, 8000 Aarhus C, Denmark.
Lipids Laboratory (LIM-10), Endocrinology and Metabolism Division of Clinical Hospital, Faculty of Medicine, University of Sao Paulo, Av. Dr. Arnaldo 455, 01246-000 Sao Paulo, SP, Brazil.
Ann Anat. 2017 Jan;209:51-60. doi: 10.1016/j.aanat.2016.10.002. Epub 2016 Oct 21.
Pyramidal neuron loss in the hippocampal CA1 region is a very early hallmark of Alzheimer disease (AD). Lithium might be a therapeutic strategy for AD due to its neuroprotective and neurotrophic properties. This study used modern stereological techniques to investigate possible CA1 pyramidal neuron loss in 11-month-old triple transgenic AD (3xTg-AD) mice, and also the effects of therapeutic and subtherapeutic lithium doses on the number and density of CA1 pyramidal neurons and volume of CA1 pyramidal layer in 3xTg-AD and wild-type mice treated from 3 to 11 months of age. 3xTg-AD mice displayed CA1 pyramidal layer atrophy that is likely due to reduced neuronal volume because of the absence of neuronal loss. Both lithium treatments of 3xTg-AD mice, which already expressed AD-like pathology, had no effect on CA1 atrophy. However, lithium treatment of wild-type mice, at low (subtherapeutic) doses, induced a significant increase in total CA1 pyramidal neuron number that led to a significant increase in total CA1 pyramidal layer volume. The lithium-induced increase in CA1 neuron number is highly consistent with previous evidence that adult neurogenesis can be exogenously induced in the CA1 pyramidal layer with impact on total CA1 neuron number, thus raising the possibility of the chronic use of low-dose lithium as a strategy to help compensate for neuronal loss in CA1 and perhaps other typically non-neurogenic brain regions in various neurological diseases. With regard to AD, low-dose lithium intervention must be initiated as early as possible in the course of neuropathology for beneficial effects to occur.
海马体CA1区的锥体神经元丢失是阿尔茨海默病（AD）非常早期的一个特征。锂因其神经保护和神经营养特性，可能是一种治疗AD的策略。本研究使用现代体视学技术，调查11月龄的三联转基因AD（3xTg-AD）小鼠中可能存在的CA1锥体神经元丢失情况，以及从3月龄到11月龄接受治疗剂量和亚治疗剂量锂处理的3xTg-AD小鼠和野生型小鼠中，锂对CA1锥体神经元数量、密度以及CA1锥体层体积的影响。3xTg-AD小鼠表现出CA1锥体层萎缩，这可能是由于神经元体积减小所致，因为不存在神经元丢失。对已经表现出AD样病理特征的3xTg-AD小鼠进行的两种锂处理，均对CA1萎缩没有影响。然而，对野生型小鼠进行低（亚治疗）剂量的锂处理，可使CA1锥体神经元总数显著增加，进而导致CA1锥体层总体积显著增加。锂诱导的CA1神经元数量增加与先前的证据高度一致，即成年神经发生可在外源性诱导下在CA1锥体层发生，从而影响CA1神经元总数，因此增加了长期使用低剂量锂作为一种策略的可能性，以帮助补偿各种神经疾病中CA1以及可能其他通常非神经源性脑区的神经元丢失。对于AD而言，必须在神经病理学过程中尽早开始低剂量锂干预，才能产生有益效果。
