Locus Coeruleus Degeneration Induces Forebrain Vascular Pathology in a Transgenic Rat Model of Alzheimer’s Disease

Abstract

Noradrenergic locus coeruleus (LC) neuron loss is a significant feature of mild cognitive impairment and Alzheimer’s disease (AD). The LC is the primary source of norepinephrine in the forebrain, where it modulates attention and memory in vulnerable cognitive regions such as prefrontal cortex (PFC) and hippocampus. Furthermore, LC-mediated norepinephrine signaling is thought to play a role in blood-brain barrier (BBB) maintenance and neurovascular coupling, suggesting that LC degeneration may impact the high comorbidity of cerebrovascular disease and AD. However, the extent to which LC projection system degeneration influences vascular pathology is not fully understood. To address this question in vivo, we stereotactically lesioned LC projection neurons innervating the PFC of six-month-old Tg344–19 AD rats using the noradrenergic immunotoxin, dopamine-β-hydroxylase IgG-saporin (DBH-sap), or an untargeted control IgG-saporin (IgG-sap). DBH-sap-lesioned animals performed significantly worse than IgG-sap animals on the Barnes maze task in measures of both spatial and working memory. DBH-sap-lesioned rats also displayed increased amyloid and inflammation pathology compared to IgG-sap controls. However, we also discovered prominent parenchymal albumin extravasation with DBH-sap lesions indicative of BBB breakdown. Moreover, microvessel wall-to-lumen ratios were increased in the PFC of DBH-sap compared to IgG-sap rats, suggesting that LC deafferentation results in vascular remodeling. Finally, we noted an early emergence of amyloid angiopathy in the DBH-sap-lesioned Tg344–19 AD rats. Taken together, these data indicate that LC projection system degeneration is a nexus lesion that compromises both vascular and neuronal function in cognitive brain areas during the prodromal stages of AD.

Locus Coeruleus and neurovascular unit: From its role in physiology to its potential role in Alzheimer’s disease pathogenesis

“…Astrogliosis itself, which is significantly increased by LC loss (Heneka et al, 2006;Kelly et al, 2019) is often associated with neuroinflammation, and it might also further interfere with BBB permeability, as reactive astrocytes could have lost at least in part their supporting role on BBB as shown by Kalinin et al (2006).…”

Locus Coeruleus Magnetic Resonance Imaging in Neurological Diseases

“…Finally, it is worth noting that Betts and colleagues observed a relation between CSF amyloid and LC-CR, in line with preclinical data. Indeed in animal model of AD, LC damage has been associated to increased amyloid burden [29,33], in parallel with a more severe neuroinflammation [30] and to worse neurovascular pathology [31], and neuropathological post-mortem data in humans support these observations [10,100]. Since neuroinflammatory, amyloid and vascular burdens can be evaluated in vivo by specific neuroimaging approaches (e.g., TSPO-specific PET tracer for neuroinflammation [101], amyloid PET and specific MRI sequences for amyloid and vascular alterations, respectively), LC-MRI represents a very interesting opportunity to assess the abovementioned correlations in vivo also in AD patients.…”

“…Thus, Heneka and colleagues concluded that LC-NA may be key in promoting amyloid clearance system and in modulating microglial activity [29,30,32], and several more recent experimental studies support this hypothesis [3,[33][34][35]. Furthermore, LC impairment has also been linked to AD vascular pathology by Kelly and colleagues who observed a significant exacerbation of microvascular injury and amyloid angiopathy, in AD transgenic mice submitted to selective LC lesion [31].…”

“…In AD, several studies performed in experimental models have linked LC impairment with amyloid/tau pathology, neuroinflammation, and neurovascular disfunction [29][30][31]. In particular, selective LC lesion in AD transgenic mice causes a dramatic increase in amyloid plaques burden compared with LC-intact animals, in parallel with increased neuroinflammation [29].…”

Saporin from Saponaria officinalis as a Tool for Experimental Research, Modeling, and Therapy in Neuroscience

“…However, the mechanisms of amyloidosis may vary under different conditions and may also involve impaired functioning of blood vessels and blood-brain barrier. For example, it was recently shown that amyloidosis is enhanced in the frontal cortex of Tg344 rats (rats overexpressing APPswe/PS1dE9) after elimination of noradrenergic projections by anti-DBH-saporin [123]. The authors also found that cortical noradrenergic deficit was associated with compromised function of blood-brain barrier and remodeling of vessel structure, which resembled pathological stenosis.…”