Topographical Visualization of the Reciprocal Projection between the Medial Septum and the Hippocampus in the 5XFAD Mouse Model of Alzheimer's Disease.

Sujin Kim,Yong Ho Park,Byeong-Hyeon Kim,Seong Gak Jeon,Jaemin Yu,Haram Jung,Hyun Ha Park,Sang Bum Hong,Yunkwon Nam,Doo-Han Yoo,Seong-Kyung Lee,Yu-On Jeong,Minho Moon,Soo Jung Shin,Jihee Kim,Sun-Hyun Park

doi:10.3390/ijms20163992

Abstract

It is widely known that the degeneration of neural circuits is prominent in the brains of Alzheimer’s disease (AD) patients. The reciprocal connectivity of the medial septum (MS) and hippocampus, which constitutes the septo-hippocampo-septal (SHS) loop, is known to be associated with learning and memory. Despite the importance of the reciprocal projections between the MS and hippocampus in AD, the alteration of bidirectional connectivity between two structures has not yet been investigated at the mesoscale level. In this study, we adopted AD animal model, five familial AD mutations (5XFAD) mice, and anterograde and retrograde tracers, BDA and DiI, respectively, to visualize the pathology-related changes in topographical connectivity of the SHS loop in the 5XFAD brain. By comparing 4.5-month-old and 14-month-old 5XFAD mice, we successfully identified key circuit components of the SHS loop altered in 5XFAD brains. Remarkably, the SHS loop began to degenerate in 4.5-month-old 5XFAD mice before the onset of neuronal loss. The impairment of connectivity between the MS and hippocampus was accelerated in 14-month-old 5XFAD mice. These results demonstrate, for the first time, topographical evidence for the degradation of the interconnection between the MS and hippocampus at the mesoscale level in a mouse model of AD. Our results provide structural and functional insights into the interconnectivity of the MS and hippocampus, which will inform the use and development of various therapeutic approaches that target neural circuits for the treatment of AD.

Highlights

Alzheimer’s disease (AD), the most prevalent neurodegenerative disease, is characterized by memory loss, cognition impairments, and the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles [1]
By visualizing brain sections with immunofluorescence against SYN, we found that 4.5-month-old 5XFAD mice exhibited a significant reduction in pre-synaptic terminals in the medial septum nucleus (MS), CA3, dentate gyrus (DG), and Sub, while the 14-month-old 5XFAD mice showed decreased pre-synaptic terminals throughout the entire hippocampal formation (Figure 3)
14-month-old 5XFAD mice showed a reduction in DiI- and Biotinylated dextran amine (BDA)-positive areas throughout the hippocampal formation

Summary

Introduction

Alzheimer’s disease (AD), the most prevalent neurodegenerative disease, is characterized by memory loss, cognition impairments, and the progressive deposition of amyloid-β (Aβ) peptides and neurofibrillary tangles [1]. The interconnection between the MS and hippocampus constitute the septo-hippocampo-septal (SHS) loop, and the neurons in the two regions have a topographical and functional intercorrelation [26,27,28,29,30]. Due to this reciprocal connectivity, the hippocampal self-regulation of cholinergic input from the MS [23,31,32], the spatial representation of the hippocampus through activation of the MS [33], and memory formation in the hippocampus [25] are all manipulated by the SHS loop. The degeneration of the septo-hippocampal pathway has been reported in AD patients as well as AD animal models [10,34,35,36], there is no topographical study demonstrating the alterations in the SHS loop at the mesoscale level in the AD brain

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Conclusion