Reduced density of noradrenergic fibers without prominent neuron loss or tau pathology in the locus coeruleus in APP knock‐in mouse models of Aβ amyloidosis

• Published in: Alzheimer's & Dementia
• Main Authors: Iijima, Koichi M., Sakakibara, Yasufumi, Ibaraki, Kyoko, Takei, Kimi, Saito, Takashi, Saido, Takaomi C., Sekiya, Michiko
• Format: Article in Journal/Newspaper
• Language: English
• Published: Wiley 2020
• Subjects: Arctic
• Online Access: http://dx.doi.org/10.1002/alz.044318; https://onlinelibrary.wiley.com/doi/pdf/10.1002/alz.044318

Abstract Background Locus coeruleus (LC) is a nucleus containing the cell bodies of noradrenergic neurons in the brain, and is one of the earliest regions affected by Alzheimer’s disease (AD). Norepinephrine (NE) is critical for cognitive functions as well as anti‐inflammatory and neuroprotective properties, both of which are implicated in AD. LC neurons are among the first to display tau pathology and that significant loss of forebrain noradrenergic projections is evident at prodromal stage of AD, suggesting that abnormality in LC‐NE system initiates the disease pathogenesis. However, mechanisms underlying neurodegeneration in LC‐NE system remain elusive. We have previously reported that App NL‐G‐F/NL‐G‐F mice, which harbor three familial AD mutations (Swedish, Beyreuther/Iberian, and Arctic) exhibited cognitive deficits and severe neuroinflammation accompanied by massive amyloid‐β (Aβ) pathology. In this study, we asked whether and how LC‐NE system is altered in App NL‐G‐F/NL‐G‐F mice. Method To ask whether App NL‐G‐F/NL‐G‐F mice exhibit noradrenergic degeneration, we compared the density of norepinephrine transporter (NET)‐positive fibers in the cortex and hippocampus as well as the number of dopamine β‐hydroxylase (DBH)‐positive neurons in the LC between App NL‐G‐F/NL‐G‐F and wild‐type (WT) C57BL/6J mice at 24 months of age. We also examined whether tau pathology occurs in the LC‐NE system in these mice. Result Histochemical analyses revealed that 24‐month‐old App NL‐G‐F/NL‐G‐F mice exhibited significant decreases in the density of NET‐positive fibers in the prefrontal and entorhinal cortices and the hippocampal CA1, the regions associated with learning and memory, compared to WT mice. In contrast, App NL‐G‐F/NL‐G‐F mice did not display loss of DBH‐positive neurons in the LC even at 24 months of age. Furthermore, App NL‐G‐F/NL‐G‐F mice did not develop prominent tau pathology either in the nerve terminals or in the cell bodies of LC neurons. Conclusion This study demonstrates that Aβ pathology is sufficient ...