Differential response of the central noradrenergic nervous system to the loss of locus coeruleus neurons in Parkinson's disease and Alzheimer's disease

Abstract

In Parkinson's disease (PD), there is a significant loss of noradrenergic neurons in the locus coeruleus (LC) in addition to the loss of dopaminergic neurons in the substantia nigra (SN). The goal of this study was to determine if the surviving LC noradrenergic neurons in PD demonstrate compensatory changes in response to the neuronal loss, as observed in Alzheimer's disease (AD). Tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH) mRNA expression in postmortem LC tissue of control and age-matched PD subjects demonstrated a significant reduction in the number of noradrenergic neurons in the LC of PD subjects. TH mRNA expression/neuron did not differ between control and PD subjects, but DBH mRNA expression/neuron was significantly elevated in PD subjects compared to control. This increase in DBH mRNA expression in PD subjects is not a response to neuronal loss because the amount of DBH mRNA expression/neuron in AD subjects was not significantly different from control. Norepinephrine transporter (NET) binding site concentration in the LC of PD subjects was significantly reduced over the cell body region as well as the peri-LC dendritic zone. In PD subjects, the loss of dendrites from surviving noradrenergic neurons was also apparent with TH-immunoreactivity (IR). This loss of LC dendritic innervation in PD subjects as measured by TH-IR was not due to LC neuronal loss because TH-IR in AD subjects was robust, despite a similar loss of LC neurons. These data suggest that there is a differential response of the noradrenergic nervous system in PD compared to AD in response to the loss of LC neurons.

Critical role of somatostatin receptor 2 in the vulnerability of the central noradrenergic system: new aspects on Alzheimer’s disease

“…However and interestingly, no change in MAP2 expression was noted in the Braak V-VI stage, compared to control, which supports a previous report on dendritic spouting of remaining LC neurons in the terminal phase of Alzheimer's disease [99]. mRNA expression of TH, the rate limiting enzyme of NA synthesis, and of DBH did not decrease, in agreement with previous studies [70,99].…”

The Noradrenergic System is a Major Component in Parkinson’s Disease

“…Therefore, NETs are localized only to noradrenergic cell bodies, dendrites (peri-LC dendritic zone), and axon terminals of noradrenergic neurons. NET binding over cell body region and peri-LC dendritic zone in PD subjects is significantly reduced compared to age-matched control subjects and the loss of NET binding over the cell body region corresponds to the number of LC noradrenergic neurons in the LC (McMillan et al, 2011). The loss of NET binding in the peri-LC dendritic zone in PD subjects indicates the surviving LC neurons are not compensating for neuronal loss by increasing dendritic innervation.…”

“…The loss of NET binding in the peri-LC dendritic zone in PD subjects indicates the surviving LC neurons are not compensating for neuronal loss by increasing dendritic innervation. The loss of dendritic innervation in PD subjects, as determined by NET binding, is supported by reduced dendritic TH-IR labeling in the LC region of PD subjects as compared to age-matched controls (McMillan et al, 2011). However, the surviving LC neurons in PD subjects do demonstrate compensation in the expression of DBH mRNA (McMillan et al, 2011).…”

“…The number of TH and DBH mRNA positively labeled neurons in the LC of PD subjects are significantly reduced as compared to age-matched control subjects (Szot, 2000(Szot, , 2006McMillan et al, 2011) and corresponds to the documented loss of noradrenergic neurons by other laboratories (Bertrand et al, 1997;Cash et al, 1987;Chan-Palay & Asan, 1989;Hornykiewicz & Kish, 1987;Marien et al, 2004;McMillan et al, 2011;Patt & Gerhard, 1993;Zarow et al, 2003). The degree of LC noradrenergic neuronal loss determined by TH and DBH mRNA expression in PD subjects is verified by counting the number of LC TH-IR positive labeled neurons (McMillan et al, 2011). TH mRNA expression/neuron of the surviving LC noradrenergic neurons in PD subjects did not differ from TH mRNA expression/neuron in age-matched control subjects, indicating a lack of compensation of the surviving LC neurons (McMillan et al, 2011).…”

“…The degree of LC noradrenergic neuronal loss determined by TH and DBH mRNA expression in PD subjects is verified by counting the number of LC TH-IR positive labeled neurons (McMillan et al, 2011). TH mRNA expression/neuron of the surviving LC noradrenergic neurons in PD subjects did not differ from TH mRNA expression/neuron in age-matched control subjects, indicating a lack of compensation of the surviving LC neurons (McMillan et al, 2011). Another marker of noradrenergic neurons, NE transporter (NET), was measured in the LC of age-matched and PD subjects.…”