Increased activity of surviving locus ceruleus neurons in Alzheimer's disease

Abstract

In Alzheimer's disease (AD) there is neuronal loss in the locus ceruleus (LC), and the noradrenergic system may be even more affected in depressed AD patients. However, this neuronal loss may go together with an increase in activity of the remaining noradrenergic neurons. We prospectively evaluated 16 AD patients (6 depressed, 5 transiently depressed, and 5 nondepressed) and 10 controls. We determined norepinephrine and its metabolite 3‐methoxy‐4‐hydroxyphenylglycol (MHPG) in various brain areas, and compared these data with previously established neuron numbers in the LC in the same patients. We could not confirm earlier studies reporting lower norepinephrine concentrations in depressed than in nondepressed dementia patients. The mean norepinephrine concentrations in AD patients were significantly lower than those in control patients, whereas the mean concentrations of MHPG were not different. Moreover, we found significant inverse relationships between the number of remaining pigmented LC neurons and the MHPG/norepinephrine ratio in the frontal cortex and LC. These data are the first to provide direct evidence for the hypothesis that remaining LC neurons are activated to compensate for decreased cerebral norepinephrine levels in AD, by demonstrating that the MHPG/norepinephrine ratio is significantly higher in AD, indicating increased metabolism. Ann Neurol 1999;45:82–91

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.…”

“…Even if remaining LC neurons show an increased activity in an attempt to compensate for the ongoing degeneration (17,19), thereby generating at their terminals locally high NE levels, it seems likely that progressive LC degeneration may consequently cause neuroinflammation and a paralysis of phagocytotic clearance that first affects single spots but later the entire LC projection area. Such a chronic impairment of microglial Aβ clearance may ultimately contribute to the progression of the disease itself.…”

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

“…Since the rostral portion of the LC innervates forebrain structures such as the hippocampus, whereas the caudal portion of the LC innervates hindbrain structures such as the cerebellum and spinal cord Loughlin et al, 1982), the rostral-tocaudal distance of the LC was separately analyzed. Sections were systematically analyzed to include the 30, 50, and 70% levels of the LC, considering the rostral part (or 0%) as the beginning of the trochlear nucleus, and the caudal pole (100%) ended at the rostral level of the trigeminal motor nucleus (Hoogendijk et al, 1999). Estimation of the volume (Vref) of LC and SN was performed with the Cavalieri method, and the optical dissector method was used to estimate neuronal density (Nv).…”

Changes in adrenoreceptors in the prefrontal cortex of subjects with dementia: Evidence of compensatory changes

“…There is a significant loss of noradrenergic neurons in the LC in AD (Mann et al, 1980;Tomlinson et al, 1981;Bondareff et al, 1982;Marcyniuk et al, 1986;Chan-Palay and Asan, 1989;German et al, 1992). However, the surviving neurons in the LC appear to be compensating for the neuronal loss (Adolfsson et al, 1979;Cross et al, 1981;Mann et al, 1981;Perry et al, 1981;Tomlinson et al, 1981;Gottfries et al, 1983;Raskind et al, 1984;Palmer et al, 1987;Reinikainen et al, 1988;Tohgi et al, 1992;Elrod et al, 1997;Russo-Neustadt et al, 1998;Hoogendijk et al, 1999;Szot et al, 2000). Recently, our laboratory showed that the remaining noradrenergic neurons in the LC of AD and a related dementing disorder, dementia with Lewy bodies (DLB), showed three different compensatory changes: (1) an increase in tyrosine hydroxylase mRNA expression in the remaining neurons; (2) sprouting of dendrites into the peri-LC dendritic zone, as determined by α 2 -adrenoreceptor (AR) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections into the hippocampus as determined by α 2 -ARs (Szot et al, 2006).…”