Abstract
Axonopathy is a pathological feature observed in both Alzheimer’s disease (AD) patients and animal models. However, identifying the temporal and regional progression of axonopathy during AD development remains elusive. Using the fluorescence micro-optical sectioning tomography system, we acquired whole-brain datasets in the early stage of 5xFAD/Thy1-GFP-M mice. We reported that among GFP labeled axons, GFP-positive axonopathy first formed in the lateral septal nucleus, subiculum, and medial mammillary nucleus. The axonopathy further increased in most brain regions during aging. However, most of the axonopathic varicosities disappeared significantly in the medial mammillary nucleus after 8 weeks old. Continuous three-dimensional datasets showed that axonopathy in the medial mammillary nucleus was mainly located on axons from hippocampal GFP-positive neurons. Using the rabies viral tracer in combination with immunohistochemistry, we found that axons in the medial mammillary nucleus from the subiculum were susceptible to lesions that prior to the occurrence of behavioral disorders. In conclusion, we created an early-stage spatiotemporal map of axonopathy in 5xFAD/Thy1-GFP-M mice and identified specific neural circuits which are vulnerable to axon lesions in an AD mouse model. These findings underline the importance of early interventions for AD, and may contribute to the understanding of its progression and its early symptom treatment.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment (Canter et al, 2016), which are both associated with synaptic loss and neuronal degeneration (Long and Holtzman, 2019)
To locate the neuronal soma and identify the individual axon throughout the entire brain without losing crucial information, we generated whole-brain three-dimensional datasets of GFPpositive neurons in 16-week-old Thy1-GFP-M mice by fluorescence micro-optical sectioning tomography (fMOST) at a voxel resolution of 0.32 × 0.32 × 2 μm3 (Figures 1A,B). Through these continuous three-dimensional datasets, we found that the vast majority of GFP-positive neurons were located in the deep layer of the cortex, hippocampus, and amygdala (Figure 1C), which is consistent with previous studies (Feng et al, 2000; Porrero et al, 2010)
Based on the whole-brain three-dimensional datasets acquired via the fMOST system, we compared the axonal morphological differences between 5xFAD/GFP mice and Thy1GFP-M mice
Summary
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment (Canter et al, 2016), which are both associated with synaptic loss and neuronal degeneration (Long and Holtzman, 2019). Immunohistochemical staining and ultrastructural analysis revealed aberrant accumulation of axonal cargo within the locally swollen axons, including microtubulebinding proteins, neurotransmitters, mitochondria, and other organelles (Gowrishankar et al, 2015; Sadleir et al, 2016) These pathological changes were reported to occur at different time points in AD animal models. In TgCRND8/Thy1-YFP mice, for instance, cortical projection neurons showed axonopathy at 2 months old (Adalbert et al, 2009), while, it happened in 4-months-old PSAPP/Thy1-YFP mice (Tsai et al, 2004) These differences may be related to the different strains of experimental animals used in these studies. Confirming the temporal and spatial progression of axonopathy at the whole-brain level is important for understanding the pathological development of impaired brain functions and for determining early treatment strategies in AD mouse models, which may in turn shed light on the possible treatments to alleviate the symptoms of AD patients at an early stage
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