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Localization of endogenous amyloid-β to the coeruleo-cortical pathway: consequences of noradrenergic depletion
Journal article   Open access   Peer reviewed

Localization of endogenous amyloid-β to the coeruleo-cortical pathway: consequences of noradrenergic depletion

Jennifer A Ross, Beverly A S Reyes, Steven A Thomas and Elisabeth J Van Bockstaele
Brain structure & function, v 223(1)
Jan 2018
DOI: https://doi.org/10.1007/s00429-017-1489-9
PMID: 28779307
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://europepmc.org/articles/pmc5773352View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

ADAM10 Protein - metabolism Adrenergic Neurons - drug effects Amyloid beta-Peptides - metabolism Amyloid beta-Peptides - ultrastructure Amyloid beta-Protein Precursor - deficiency Amyloid beta-Protein Precursor - genetics Amyloid Precursor Protein Secretases - metabolism Animals Aspartic Acid Endopeptidases - metabolism Benzylamines - toxicity Cerebral Cortex - metabolism Cerebral Cortex - ultrastructure Dopamine beta-Hydroxylase - deficiency Dopamine beta-Hydroxylase - genetics Dopamine beta-Hydroxylase - ultrastructure Female Locus Coeruleus - metabolism Locus Coeruleus - ultrastructure Male Mice, Knockout Microscopy, Electron Neural Pathways - metabolism Neurotransmitter Uptake Inhibitors - toxicity Norepinephrine - deficiency Peptide Fragments - metabolism Peptide Fragments - ultrastructure Rats Rats, Sprague-Dawley Subcellular Fractions - metabolism Subcellular Fractions - ultrastructure Tyrosine 3-Monooxygenase - metabolism
The locus coeruleus (LC)-norepinephrine (NE) system is an understudied circuit in the context of Alzheimer's disease (AD), and is thought to play an important role in neurodegenerative and neuropsychiatric diseases involving catecholamine neurotransmitters. Understanding the expression and distribution of the amyloid beta (Aβ) peptide, a primary component of AD, under basal conditions and under conditions of NE perturbation within the coeruleo-cortical pathway may be important for understanding its putative role in pathological states. Thus, the goal of this study is to define expression levels and the subcellular distribution of endogenous Aβ with respect to noradrenergic profiles in the rodent LC and medial prefrontal cortex (mPFC) and, further, to determine the functional relevance of NE in modulating endogenous Aβ levels. We report that endogenous Aβ is localized to tyrosine hydroxylase (TH) immunoreactive somatodendritic profiles of the LC and dopamine-β-hydroxylase (DβH) immunoreactive axon terminals of the infralimbic mPFC (ILmPFC). Male and female naïve rats have similar levels of amyloid precursor protein (APP) cleavage products demonstrated by western blot, as well as similar levels of endogenous Aβ as determined by enzyme-linked immunosorbent assay. Two models of NE depletion, DSP-4 lesion and DβH knockout (KO) mice, were used to assess the functional relevance of NE on endogenous Aβ levels. DSP-4 lesioned rats and DβH-KO mice show significantly lower levels of endogenous Aβ . Noradrenergic depletion did not change APP-cleavage products resulting from β-secretase processing. Thus, resultant decreases in endogenous Aβ may be due to decreased neuronal activity of noradrenergic neurons, or, by decreased stimulation of adrenergic receptors which are known to contribute to Aβ production by enhancing γ-secretase processing under normal physiological conditions.

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9 citations in Scopus

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UN Sustainable Development Goals (SDGs)

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#3 Good Health and Well-Being

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Collaboration types
Domestic collaboration
Web of Science research areas
Anatomy & Morphology
Neurosciences
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