Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice

Leslie Doucette; Victoria Turnbill; Katherine Carlin; Andrew Cavanagh; Benjamin Sollinger; Nazli Kuter; Debra L. Flock; Shenandoah Robinson; Raul Chavez-Valdez; Lauren Jantzie; Lee J. Martin; Frances J. Northington

Neurobiology of Disease (Oct 2024)

Neocortical cholinergic pathology after neonatal brain injury is increased by Alzheimer's disease-related genes in mice

Leslie Doucette,
Victoria Turnbill,
Katherine Carlin,
Andrew Cavanagh,
Benjamin Sollinger,
Nazli Kuter,
Debra L. Flock,
Shenandoah Robinson,
Raul Chavez-Valdez,
Lauren Jantzie,
Lee J. Martin,
Frances J. Northington

Affiliations

Leslie Doucette: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Victoria Turnbill: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Katherine Carlin: US Air Force Medical Corps, US Naval Hospital Okinawa, Okinawa, Japan
Andrew Cavanagh: Department of Neuroscience, Undergraduate Education, Johns Hopkins University, Baltimore, MD 21287, USA
Benjamin Sollinger: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Nazli Kuter: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Debra L. Flock: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Shenandoah Robinson: Phelps Center for Cerebral Palsy and Neurodevelopmental Medicine, Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21287, USA; Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Raul Chavez-Valdez: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Lauren Jantzie: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Phelps Center for Cerebral Palsy and Neurodevelopmental Medicine, Department of Neurology and Developmental Medicine, Kennedy Krieger Institute, Baltimore, MD 21287, USA; Department of Neurosurgery, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Lee J. Martin: Department of Neuroscience, Pathology, and Anesthesiology & Critical Care Medicine, and the Pathobiology Graduate Training Program, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA
Frances J. Northington: Department of Pediatrics, Johns Hopkins School of Medicine, Baltimore, MD 21287, USA; Corresponding author at: CMSC 6-104, Johns Hopkins Hospital, 600 North Wolfe Street, Baltimore, MD 21287, USA.

Journal volume & issue: Vol. 200
p. 106629

Abstract

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Hypoxic-ischemic encephalopathy (HIE) in neonates causes mortality and neurologic morbidity, including poor cognition with a complex neuropathology. Injury to the cholinergic basal forebrain and its rich innervation of cerebral cortex may also drive cognitive pathology. It is uncertain whether genes associated with adult cognition-related neurodegeneration worsen outcomes after neonatal HIE. We hypothesized that neocortical damage caused by neonatal HI in mice is ushered by persistent cholinergic innervation and interneuron (IN) pathology that correlates with cognitive outcome and is exacerbated by genes linked to Alzheimer's disease. We subjected non-transgenic (nTg) C57Bl6 mice and mice transgenically (Tg) expressing human mutant amyloid precursor protein (APP-Swedish variant) and mutant presenilin (PS1-ΔE9) to the Rice-Vannucci HI model on postnatal day 10 (P10). nTg and Tg mice with sham procedure were controls. Visual discrimination (VD) was tested for cognition. Cortical and hippocampal cholinergic axonal and IN pathology and Aβ plaques, identified by immunohistochemistry for choline acetyltransferase (ChAT) and 6E10 antibody respectively, were counted at P210. Simple ChAT+ axonal swellings were present in all sham and HI groups; Tg mice had more than their nTg counterparts, but HI did not affect the number of axonal swellings in APP/PS1 Tg mice. In contrast, complex ChAT+ neuritic clusters (NC) occurred only in Tg mice; HI increased that burden. The abundance of ChAT+ clusters in specific regions correlated with decreased VD. The frequency of attritional ChAT+ INs in the entorhinal cortex (EC) was increased in Tg shams relative to their nTg counterparts, but HI obviated this difference. Cholinergic IN pathology in EC correlated with NC number. The Aβ deposition in APP/PS1 Tg mice was not exacerbated by HI, nor did it correlate with other metrics. Adult APP/PS1 Tg mice have significant cortical cholinergic axon and EC ChAT+ IN pathologies; some pathology was exacerbated by neonatal HI and correlated with VD. Mechanisms of neonatal HI induced cognitive deficits and cortical neuropathology may be modulated by genetic risk, perhaps accounting for some of the variability in outcomes.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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