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

Abstract

AbstractBackgroundLocus 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 AppNL‐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 AppNL‐G‐F/NL‐G‐F mice.MethodTo ask whether AppNL‐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 AppNL‐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.ResultHistochemical analyses revealed that 24‐month‐old AppNL‐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, AppNL‐G‐F/NL‐G‐F mice did not display loss of DBH‐positive neurons in the LC even at 24 months of age. Furthermore, AppNL‐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.ConclusionThis study demonstrates that Aβ pathology is sufficient to reduce the density of noradrenergic fibers independent of neuron loss and tau pathology in the LC. These results also suggest that age‐dependent accumulation of Aβ in the cortex or tau in the LC may additively and independently damage LC neurons from the nerve terminals or from the cell bodies, respectively.