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Localization of amyloid beta peptides to locus coeruleus and medial prefrontal cortex in corticotropin releasing factor overexpressing male and female mice
Journal article   Open access   Peer reviewed

Localization of amyloid beta peptides to locus coeruleus and medial prefrontal cortex in corticotropin releasing factor overexpressing male and female mice

Jennifer A. Ross, Rody Alexis, Beverly A. S. Reyes, Victoria Risbrough and Elisabeth J. Van Bockstaele
Brain structure & function, v 224(7), pp 2385-2405
01 Sep 2019
DOI: https://doi.org/10.1007/s00429-019-01915-8
PMID: 31250157
Featured in Collection :   UN Sustainable Development Goals @ Drexel
url
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7371412View
Accepted (AM)Open Access (License Unspecified),  Open

Abstract

Anatomy & Morphology Life Sciences & Biomedicine Neurosciences Neurosciences & Neurology Science & Technology
A culmination of evidence from the literature points to the Locus Coeruleus (LC)-Norepinephrine system as an underappreciated and understudied area of research in the context of Alzheimer's Disease (AD). Stress is a risk factor for developing AD, and is supported by multiple clinical and preclinical studies demonstrating that amplification of the stress system disrupts cellular and molecular processes at the synapse, promoting the production and accumulation of the amyloid beta (A beta(42)) peptide. Stress-induced activation of the LC is mediated by corticotropin releasing factor (CRF) and CRF receptors exhibit sex-biased stress signaling. Sex differences are evident in the neurochemical, morphological and molecular regulation of LC neurons by CRF, providing a compelling basis for the higher prevalence of stress-related disorders such as AD in females. In the present study, we examined the cellular substrates for interactions between A beta and tyrosine hydroxylase a marker of noradrenergic somatodendritic processes in the LC, and Dopamine-beta-Hydroxylase (D beta H) in the infralimbic medial prefrontal cortex (ILmPFC) in mice conditionally overexpressing CRF in the forebrain (CRFOE) under a Doxycycline (DOX) regulated tetO promoter. CRFOE was sufficient to elicit a redistribution of A beta peptides in the somatodendritic processes of the LC of male and female transgenic mice, without altering total A beta(42) protein expression levels. DOX treated groups exhibited lysosomal compartments with apparent lipofuscin and abnormal morphology, indicating potential dysfunction of these A beta(42)-clearing compartments. In female DOX treated groups, swollen microvessels with lipid-laden vacuoles were also observed, a sign of blood-brain-barrier dysfunction. Finally, sex differences were observed in the prefrontal cortex, as females responded to DOX treatment with increased frequency of co-localization of A beta(42) and D beta H in noradrenergic axon terminals compared to vehicle treated controls, while male groups showed no significant changes. We hypothesize that the observed sex differences in A beta(42) distribution in this model of CRF hypersignaling is based on increased responsivity of female rodent CRFR1 in the LC. A beta(42) production is enhanced during increased neuronal activation, therefore, the excitation of DOX treated female CRFOE LC neurons projecting to the mPFC may exhibit more frequent co-localization with A beta due to increased neuronal activity of noradrenergic neurons.

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