Compensatory Changes in the Noradrenergic Nervous System in the Locus Ceruleus and Hippocampus of Postmortem Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

Abstract

In Alzheimer's disease (AD), there is a significant loss of locus ceruleus (LC) noradrenergic neurons. However, functional and anatomical evidence indicates that the remaining noradrenergic neurons may be compensating for the loss. Because the noradrenergic system plays an important role in learning and memory, it is important to determine whether compensation occurs in noradrenergic neurons in the LC and hippocampus of subjects with AD or a related dementing disorder, dementia with Lewy bodies (DLB). We observed profound neuronal loss in the LC in AD and DLB subjects with three major changes in the noradrenergic system consistent with compensation: (1) an increase in tyrosine hydroxylase (TH) mRNA expression in the remaining neurons; (2) sprouting of dendrites into peri-LC dendritic zone, as determined by ␣ 2 -adrenoreceptors (ARs) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections to the hippocampus as determined by ␣ 2 -ARs. In AD and DLB subjects, the postsynaptic ␣ 1 -ARs were normal to elevated. Expression of ␣ 1A -and ␣ 2A -AR mRNA in the hippocampus of AD and DLB subjects were not altered, but expression of ␣ 1D -and ␣ 2C -AR mRNA was significantly reduced in the hippocampus of AD and DLB subjects. Therefore, in AD and DLB subjects, there is compensation occurring in the remaining noradrenergic neurons, but there does appear to be a loss of specific AR in the hippocampus. Because changes in these noradrenergic markers in AD versus DLB subjects were similar (except neuronal loss and the increase in TH mRNA were somewhat greater in DLB subjects), the presence of Lewy bodies in addition to plaques and tangles in DLB subjects does not appear to further affect the noradrenergic compensatory changes.

Selective Loss of Catecholaminergic Wake–Active Neurons in a Murine Sleep Apnea Model

“…Having demonstrated in the present study that oxygenation patterns, as observed in sleep apnea, can significantly injure the locus ceruleus, it will be of interest to look for disease interactions between obstructive sleep apnea (present in Ͼ10% of elderly humans) and Alzheimer's disease. In Alzheimer's disease, locus ceruleus loss may be accompanied by compensatory changes, including dendritic and axonal sprouting (Szot et al, 2006). In the present model of hypoxia/reoxygenation injury, neuronal compensation is not evident, because dendrites are substantially reduced and many remaining dendrites show vacuolization.…”

Locus ceruleus controls Alzheimer's disease pathology by modulating microglial functions through norepinephrine

“…Importantly, the loss of LC neurons was found to be more extensive and to correlate better with the progression of AD than the cholinergic cell loss observed in the nucleus basalis of Meynert (15,16). In contrast, compensatory mechanisms regarding NE levels in the CSF and the mRNA expression of α2-adrenoreceptors in the hippocampus of AD patients have been suggested (17)(18)(19). However, it is unclear whether increased NE measured form the CSF is congruent with the NE secreted from LC projection areas, but being produced in the brainstem or by terminally degenerated LC neurons.…”

Transgenic mice overexpressing the full-length neurotrophin receptor TrkC exhibit increased catecholaminergic neuron density in specific brain areas and increased anxiety-like behavior and panic reaction

“…)), thus indicating that cell shape/size were not confounding the cell counts. Because different portions of the LC innervate different structures (Szot et al, 2006), sections were systematically taken to include the 30, 50, and 70% levels of the LC (Fig. 6d).…”