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

• Published in: The Journal of neuroscience Vol. 26; no. 2; pp. 467 - 478
• Main Authors: Szot, Patricia, White, Sylvia S, Greenup, J. Lynne, Leverenz, James B, Peskind, Elaine R, Raskind, Murray A
• Format: Journal Article
• Language: English
• Published: United States Soc Neuroscience 11.01.2006; Society for Neuroscience
• Subjects: Adrenergic alpha-Antagonists - metabolism; Adult; Aged; Aged, 80 and over; Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Dendrites - ultrastructure; Female; Fluoxetine - analogs & derivatives; Fluoxetine - metabolism; Hippocampus - chemistry; Hippocampus - pathology; Humans; Idazoxan - analogs & derivatives; Idazoxan - metabolism; In Situ Hybridization; Lewy Body Disease - metabolism; Lewy Body Disease - pathology; Locus Coeruleus - chemistry; Locus Coeruleus - pathology; Male; Middle Aged; Nerve Tissue Proteins - analysis; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurobiology of Disease; Norepinephrine - chemistry; Norepinephrine - physiology; Norepinephrine Plasma Membrane Transport Proteins - analysis; Norepinephrine Plasma Membrane Transport Proteins - metabolism; Prazosin - metabolism; Receptors, Adrenergic, alpha-1 - analysis; Receptors, Adrenergic, alpha-1 - genetics; Receptors, Adrenergic, alpha-1 - metabolism; Receptors, Adrenergic, alpha-2 - analysis; Receptors, Adrenergic, alpha-2 - genetics; Receptors, Adrenergic, alpha-2 - metabolism; RNA, Messenger - analysis; RNA, Messenger - biosynthesis; Tetralones - metabolism; Tyrosine 3-Monooxygenase - analysis; Tyrosine 3-Monooxygenase - biosynthesis; Tyrosine 3-Monooxygenase - genetics
• ISSN: 0270-6474; 1529-2401; 1529-2401
• DOI: 10.1523/JNEUROSCI.4265-05.2006

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 α 2 -adrenoreceptors (ARs) and norepinephrine transporter binding sites; and (3) sprouting of axonal projections to the hippocampus as determined by α 2 -ARs. In AD and DLB subjects, the postsynaptic α 1 -ARs were normal to elevated. Expression of α 1A - and α 2A -AR mRNA in the hippocampus of AD and DLB subjects were not altered, but expression of α 1D - and α 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.