S-Space College of Medicine/School of Medicine (의과대학/대학원) Dept. of Biomedical Sciences (대학원 의과학과) Theses (Ph.D. / Sc.D._의과학과)
A study on the attenuating effects of neuregulin-1 on cognitive function impairments and its action mechanisms in an Alzheimer’s disease animal model
뉴레글린-1의 알츠하이머병 동물 모델에서의 인지기능 개선 효과 및 그 기전에 관한 연구
- 의과대학 의과학과
- Issue Date
- 서울대학교 대학원
- 학위논문 (박사)-- 서울대학교 대학원 : 의과학과, 2015. 2. 김혜선.
- Introduction: Alzheimer’s disease (AD), the most common form of dementia, is a chronic neurodegenerative disease causing progressive impairment of memory and other cognitive functions. Pathologically, AD brain is characterized by two types of lesion: senile or neuritic plaques and neurofi brillary tangles. It has been proposed that AD is a synaptic failure. Loss of synapses at a fine structural level as well as reduction in synaptic markers have been well documented in early and late stages of AD and have been shown to correlate well with the extent of cognitive deficits. The neuregulin (NRG) family of epidermal growth factor-related proteins is composed of a wide variety of soluble and membrane-bound proteins that mediate their effects via the tyrosine kinase receptors ErbB2 - ErbB4. In the nervous system, the functions of NRG1 are essential for peripheral myelination, the establishment and maintenance of the neuromuscular and sensorimotor systems and the plasticity of cortical neuronal circuits. Heterozygous NRG1-KO mice show impairments in prepulse inhibition and working memory.
Methods & Results: In this study, I demonstrate that an intracerebroventricular infusion of NRG1 attenuates the cognitive function impairments in 13-month-old Tg2576 mice, an animal model of AD. NRG1 was found to rescue the reduction in the number of dendritic spines density in the brain tissues of Tg2576 mice, compared to vehicle-infused mice based on Golgi-Cox staining. This result was also corroborated in vitro in which NRG1 attenuates the oligomeric amyloid beta peptide1-42 (Aβ1-42)-induced reduction in dendritic spine density of rat primary hippocampal neuron cultures. Furthermore, NRG1 was demonstrated to alleviate the reduction in neural differentiation induced by oligomeric Aβ1-42 in mouse fetal neural stem cells.
Conclusions: Taken together, these results suggest that NRG1 has a therapeutic potential for AD by alleviating the reductions in dendritic spine density and neurogenesis in AD brains.