Central noradrenergic mechanisms of cerebrovascular pathology in Alzheimer's disease

This research investigates how degeneration of the locus coeruleus (LC) noradrenergic projection system contributes to forebrain cerebrovascular (CV) pathology in models of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). Prior observations indicated a 30–40% loss of LC neurons in MCI subjects correlated with worse antemortem cognition. The primary goal of the study was to determine whether LC degeneration in an AD rat model dysregulates cerebrovascular function and thereby contributes to cognitive deterioration. To address this, investigators induced LC degeneration via immunotoxin-mediated lesions targeted to the prefrontal cortex of Tg344-19 AD rats, exploiting a reciprocal coeruleocortical circuit. They combined in vivo perfusion imaging, parenchymal arteriole (PA) pressure myography, and pathological analyses to assess vascular and cognitive outcomes. Complementary molecular interrogation included RNA sequencing of fluorescently labeled, laser-captured prefrontal cortical PAs from non-transgenic F344 rats treated with control or LC lesions, sacrificed at 21 days, enabling identification of lesion-associated transcriptional changes in PA tissue.

The study found that LC degeneration promoted cognitive impairment associated with multiple indices of cerebrovascular dysfunction. LC-lesioned Tg344-19 AD rats exhibited decreased blood–brain barrier integrity, increased PA stenosis, and exacerbated cerebral amyloid angiopathy (CAA), all of which corresponded with decreased in vivo cerebral perfusion. Functional studies using pressure myography of prefrontal cortical PAs demonstrated that LC lesions blunted dilatory responses mediated by carbachol/muscarinic receptor activation and by GSK101/TRPV4 Ca2+ channel stimulation. Importantly, pharmacological augmentation of norepinephrine (NE) signaling reversed several deficits: administration of the NE prodrug L-DOPS together with the NE uptake inhibitor atomoxetine restored cognitive function and rescued GSK101-mediated PA dilatation in LC-lesioned animals. With respect to CAA pathology, preliminary evidence indicated that LC degeneration impairs intramural periarterial drainage, leading to increased Abeta40 retention within vascular smooth muscle cell basement membranes.

At the molecular level, LC-lesioned non-transgenic rats exhibited significant dysregulation of 203 genes in prefrontal cortical PAs, with 170 downregulated and 33 upregulated. Downregulated genes spanned multiple functional classes, including solute transporter function exemplified by SLC6A8 (the creatine transporter, primarily located in endothelial cells), cytoskeletal regulation of cell morphogenesis such as CLMN (calmin), and several unidentified mitochondrial “LOC” transcripts. Ongoing work highlighted by the authors focuses on characterizing LC regulation of the SLC6A8 creatine transporter in forebrain PAs as a potential mechanistic link between LC degeneration and vascular dysfunction.

Collectively, the findings implicate LC degeneration as a driver of diverse forebrain CV pathologies that may contribute to cognitive decline in MCI and AD. The study identifies noradrenergic modulation and specific molecular targets in PAs, such as SLC6A8, as promising avenues for therapeutic exploration to preserve cerebrovascular function and cognition in neurodegenerative disease.